Cellular Signalling

LINC02593 impedes cell senescence via COP1-mediated p53 degradation in cervical cancer

Evasion of cellular senescence is one of the hallmarks of cervical carcinoma (CC) to maintain malignant development. Even though the regulators driving CC cell senescence are widely recognized, the underlying upstream mechanisms are still not fully understood. Long non-coding RNAs (lncRNAs) are emerging as important regulators in cell senescence. Here, we conducted a lncRNA profiling and identified LINC02593 as a significantly downregulated lncRNA in induced senescent cervical squamous cell carcinoma (CSCC) cells. LINC02593 is upregulated in CSCC tissues. Depletion of LINC02593 resulted in a marked cellular senescence phenotype and tumor growth inhibition in vitro and in vivo, whereas LINC02593 overexpression suppressed doxorubicin-induced cell senescence. LINC02593 was shown to impede cell senescence by inhibiting p21 expression, and this regulation was mainly dependent on p53 protein degradation. Mechanistically, LINC02593 served as a scaffold, bridging the coiled-coil domain of COP1 and the C-terminal domain of p53, enhancing the affinity between p53 and its E3 ubiquitin ligase COP1. The "scaffold" function facilitated p53 degradation by COP1 as well as the downstream p21 repression, eventually evading cell senescence. Overall, we characterized a previously unknown mechanism by which LINC02593 manipulated senescence to promote CC progression.

Oncogenic role of PLOD3 mediated by SOX9 through IL-6/JAK/STAT3 pathway in cervical cancer

As a major global health challenge, cervical cancer remains poorly understood in terms of its underlying molecular mechanisms, a limitation that hinders the development of targeted therapies. This study investigated the role of PLOD3 in cervical cancer progression and its regulatory pathways. Bioinformatic analysis and clinical sample validation revealed that cervical cancer tissues exhibited increased accumulation of PLOD3, related to poor survival prognosis. Functional experiments demonstrated that PLOD3 silencing restrained cell proliferation, clone formation, migration, invasion, and angiogenesis, while inducing apoptosis in cervical cancer. Mechanistically, the transcription factor SOX9 directly bound to the PLOD3 promoter to activate its transcription, as confirmed by dual-luciferase reporter assays, EMSA, and ChIP-qPCR. Rescue experiments showed that PLOD3 overexpression reversed the anti-tumor effects of SOX9 knockdown, indicating a SOX9/PLOD3 regulatory axis. Further studies revealed that PLOD3 promoted cervical cancer progression via inducing the activation of IL-6/JAK/STAT3 signaling pathway, and inhibiting this pathway mitigated PLOD3-mediated oncogenic effects. In vivo experiments using nude mouse models validated that SOX9 knockdown suppressed tumor growth and metastasis through downregulating PLOD3. Collectively, these findings identified PLOD3 as a SOX9-regulated oncogene that drives cervical cancer via the IL-6/JAK/STAT3 pathway, highlighting its possibility as a therapeutic target for cervical cancer.

Targeting ferroptosis in cervical cancer: Mechanistic insights and therapeutic opportunities

Cervical cancer is the fourth most common malignancy among women worldwide. Despite standard chemoradiotherapy, a significant number of patients experience recurrence or distant metastasis. Accumulating evidence highlights ferroptosis-an iron-dependent form of regulated cell death driven by lipid peroxidation (LPO)-as a key mechanism influencing cervical carcinogenesis and treatment outcomes. Ferroptosis is marked by intracellular iron overload, excessive reactive oxygen species (ROS) production, and loss of redox balance. This review provides a comprehensive overview of the emerging roles of ferroptosis in the initiation, progression, and therapeutic resistance of cervical cancer. We outline the regulatory networks and signaling pathways that control ferroptosis in cervical cancer cells and assess the therapeutic potential of inducing ferroptosis using small-molecule compounds and nanomedicine approaches. Additionally, we discuss the prognostic value of ferroptosis-related genes (FRGs), their association with immune infiltration, and their implications for personalized immunotherapy. Collectively, these insights emphasize the translational promise of targeting ferroptosis as a novel strategy for precision oncology and targeted therapy in cervical cancer.

Notch signaling pathway in cervical cancer: From molecular mechanism to therapeutic potential

The Notch signaling pathway, an evolutionarily conserved cell-cell communication system, regulates fundamental processes such as cell proliferation, differentiation, development, and tissue homeostasis. In cervical cancer (CC), the Notch signaling pathway exhibits dual oncogenic and tumor-suppressive functions. These opposing effects arise from microenvironmental interactions and crosstalk with other oncogenic pathways, such as the Wnt and Hippo pathways. Emerging evidence indicates that dysregulated Notch signaling is prevalent in solid tumors like cervical cancer, where it drives tumor progression via epithelial-mesenchymal transition (EMT), therapy resistance, angiogenesis, and other mechanisms. In this comprehensive review, we elucidate the molecular mechanisms of Notch signaling in cervical carcinogenesis, highlighting its roles in maintaining cancer stem cells (CSCs) and promoting metastasis. We further evaluate emerging Notch-targeted therapeutic strategies and their clinical potential.

GRHL3 specifically initiated by the TP63 transcription factor promotes the metastasis of squamous cell carcinogenesis

Metastasis is the primary cause of death in squamous cell carcinoma (SCC) patients; thus, identification of highly sensitive tumor biomarkers and therapeutic targets that can be exploited to prevent SCC metastasis and clarification of the underlying molecular mechanism is critically important. Reports have shown that Grainyhead-like 3 (GRHL3) plays a crucial role in tumorigenesis and cancer progression; nevertheless, its functions and molecular mechanism in the development of cancer remain controversial. In the present study, GRHL3 was found to be specifically overexpressed in SCCs, including lung squamous cell carcinoma (LUSC), esophageal squamous cell carcinoma (ESCC), and cervical squamous cell carcinoma (CSCC). In particular, the study revealed that high GRHL3 expression is correlated with poor overall survival (OS) and progression-free survival (PFS) in LUSC patients. Functionally, GRHL3 knockdown suppressed the invasion and migration of SCC cells in vitro and decreased their lung metastasis potential in vivo but had little effect on cell proliferation. Mechanistically, the specific overexpression of GRHL3 in SCCs is orchestrated by a well-known oncogenic transcription factor: tumor protein p63 (TP63). GRHL3 stimulates the expression of heparanase (HPSE), thereby activating the AKT-SRC signaling axis. Taken together, our work reveals a novel molecular pathway through which GRHL3 mediates the metastasis of SCCs, which has important implications for the diagnosis and targeted treatment of SCC.

Decoding intricate interactions between m6A modification with mRNAs and non-coding RNAs in cervical cancer: Molecular mechanisms and clinical implications

N6-methyladenosine (m6A) methylation is the most prevalent RNA modification that is regulated by three regulatory factors: "writers", "erasers" and "readers". m6A modification regulates RNA stability and other mechanisms, including translation, cleavage, and degradation. Current research has demonstrated that m6A methylation is involved in the regulation of occurrence and development of cancers by controlling the expression of cancer-related genes. This review summarizes the role of m6A modification on messenger RNAs (mRNAs) and non-coding RNAs (ncRNAs) in cervical cancer (CC). We highlight the dual role of m6A regulatory factors, which act as oncogenes or tumor suppressors depending on the cellular context and downstream targets. Additionally, we examine how ncRNAs reciprocally regulate m6A modification in two ways: by guiding the deposition or removal of m6A modifications on RNA targets, and by modulating the expression of m6A regulatory factors. These interactions further contribute to tumor progression. Furthermore, the therapeutic potential of targeting m6A modification has been emphasized in CC. Moreover, recent advances in small-molecule inhibitors targeting m6A regulators and RNA-based therapies which may offer new treatment strategies have been summarized. Finally, we discuss the current challenges in m6A modification research and provide suggestions for future research directions. This review aims to deepen the understanding of m6A modification in CC and contribute to the development of targeted and personalized treatment strategies.

Mechanistic study of METTL3 inducing ferroptosis to promote cervical cancer progression through mediating m6A modification of COTE-1

Cervical Cancer (CC) is one of the leading causes of tumor-related deaths among women worldwide, and the mechanisms underlying the anti-ferroptosis of CC cells are still unclear. Methyltransferase like 3 (METTL3) is widely expressed various types of tissues and plays a crucial role in tumorigenesis in part by mediating cell death. However, its regulatory function in CC progression and especially the underlying mechanisms have not been fully elucidated. This study aims to explore the role of METTL3 in the ferroptosis of CC cells. Mechanistically, by MeRIP-seq, we identified COTE-1 as a target of METTL3 mediated m6A modification, and revealed that METTL3-mediated COTE-1 expression was dependent on the m6A reader-dependent manner. Functionally, in vitro and in vivo experiments that METTL3 promotes proliferation and metastasis of CC cells by regulating COTE-1 expression. In addition, the study verified the effect of the METTL3/COTE-1 axis on autophagy-dependent ferroptosis. In summary, METTL3 influences CC progression by mediating COTE-1 to influence autophagy-dependent ferroptosis, representing a potential therapeutic approach for treating CC.

Pharmacological inhibition of protein kinase D suppresses epithelial ovarian cancer via MAPK/ERK1/2/Runx2 signalling axis

Epithelial ovarian cancer (EOC) is the most lethal gynaecological malignancy with poor prognosis and dismal patient survival. Although protein kinase D (PKD) isoforms, especially PKD2 and PKD3 are critical for many cellular and physiological functions involved in carcinogenesis including cell proliferation and angiogenesis, their role in human EOC remains unknown. Towards the goal to identify novel prognostic biomarker and therapeutic interventions against EOC, this study aimed to elucidate the molecular roles of PKD2, PKD3 and highly selective, pan-PKD inhibitor CRT0066101 in this lethal pathology. Our results indicated that inactivation of PKD2 and PKD3 by 1 μM CRT0066101 suppressed EOC cell proliferation, colony formation, cell migration and invasion. Moreover, CRT0066101 induced apoptosis and inhibited cell cycle at G2-M phase in EOC cells. Genetic knockdown of PKD2 and PKD3 confirmed the anti-carcinogenic effects of CRT0066101 against EOC. The anti-cancer phenotype of EOC cells resulted from CRT0066101-mediated PKD2 and PKD3 inactivation or genetic depletion was, in part, mediated by transcription factor Runx2 as abrogation of PKD2 and PKD3 caused downregulation of Runx2 and its downstream target genes including osteopontin, focal adhesion kinase and ERK1/2. Moreover, overexpression of a constitutively active PKD2 augmented the expression levels of phosphor-ERK1/2

A tumor-infiltrating immune cells-related pseudogenes signature based on machine-learning predicts outcomes and immunotherapy responses in ovarian cancer

Previous researches have provided evidence for the significant involvement of pseudogenes in immune-related functions across different types of cancer. However, the mechanisms by which pseudogenes regulate immunity in ovarian cancer (OV) and their potential impact on clinical outcomes remain unclear. To address this gap in knowledge, our study utilized a novel computational framework to analyze a total of 491 samples from three public datasets. We employed a combination of 10 machine-learning algorithms to construct a signature known as the tumor-infiltrating immune cells-related pseudogenes signature (TIICPS). The TIICPS, consisting of 12 pseudogenes, demonstrated independent prognostic value for overall survival, surpassing conventional clinical traits, 62 published signatures, and TP53 and BRCA mutation status in three cohorts. Patients with low TIICPS exhibited heightened immune-related pathways, intricate genomic alterations, substantial immune infiltration, and greater potential for immunotherapy efficacy. Consequently, TIICPS holds promise as a predictive tool for prognosis and immunotherapy response in ovarian cancer.

SAR131675 exhibits anticancer activity on human ovarian cancer cells through inhibition of VEGFR-3/ERK1/2/AKT signaling pathway

Vascular endothelial growth factor receptor-3 (VEGFR-3) is known to participate in tumorigenesis and lymphangiogenesis, and as such, has the potential to serve as a molecular target for cancer therapy. SAR131675 is a highly selective VEGFR-3 antagonist that has an inhibitive effect on lymphatic cell growth. However, the anticancer effects and underlying mechanisms of SAR131675 in ovarian cancer remain poorly understood. In this study, we investigated the pathological role of VEGFR-3, and the effects of SAR131675 on proliferation, cell cycle, migration, and apoptosis in ovarian cancer cells. Our results showed that the mRNA and protein of VEGFR-3 were expressed in OVCAR3 and SKOV3 ovarian cancer cells, and this receptor was activated following stimulation with 50 ng/ml VEGF-C Cys156Ser (VEGF-CS), a selective ligand for VEGFR-3. Enhancing VEGFR-3 phosphorylation by treatment of ovarian cancer cells with VEGF-CS resulted in increased levels of phosphorylated extracellular signal-regulated kinases 1/2 (ERK1/2) and AKT. Moreover, our data demonstrated that SAR131675 inhibited VEGF-CS-mediated proliferation, colony formation, and migration of cancer cells in a dose-dependent manner. In addition, inhibition of VEGFR-3 activation with SAR131675 significantly increased cell cycle arrest and promoted apoptosis in both OVCAR3 and SKOV3 cells. Mechanistically, SAR131675 effectively suppressed the VEGF-CS-induced phosphorylation of VEGFR-3 and its downstream effectors including activated ERK1/2 and AKT in ovarian cancer cells. Our results reveal an anticancer activity of SAR131675 on the growth and migration of ovarian cancer cells, which may be through inhibiting VEGFR-3/ERK1/2/AKT pathway. SAR131675 may serve as an effective targeted drug for ovarian cancer.

IRAK1 deficiency potentiates the efficacy of radiotherapy in repressing cervical cancer development

IRAK1 has been implicated in promoting development of various types of cancers and mediating radioresistance. However, its role in cervical cancer tumorigenesis and radioresistance, as well as the potential underlying mechanisms, remain poorly defined. In this study, we evaluated IRAK1 expression in radiotherapy-treated cervical cancer tissues and found that IRAK1 expression is negatively associated with the efficacy of radiotherapy. Consistently, ionizing radiation (IR)-treated HeLa and SiHa cervical cancer cells express a lower level of IRAK1 than control cells. Depletion of IRAK1 resulted in reduced activation of the NF-κB pathway, decreased cell viability, downregulated colony formation efficiency, cell cycle arrest, increased apoptosis, and impaired migration and invasion in IR-treated cervical cancer cells. Conversely, overexpressing IRAK1 mitigated the anti-cancer effects of IR in cervical cancer cells. Notably, treatment of IRAK1-overexpressing IR-treated HeLa and SiHa cells with the NF-κB pathway inhibitor pyrrolidine dithiocarbamate (PDTC) partially counteracted the effects of excessive IRAK1. Furthermore, our study demonstrated that IRAK1 deficiency enhanced the anti-proliferative role of IR treatment in a xenograft mouse model. These collective observations highlight IRAK1's role in mitigating the anti-cancer effects of radiotherapy, partly through the activation of the NF-κB pathway. SUMMARY: IRAK1 enhances cervical cancer resistance to radiotherapy, with IR treatment reducing IRAK1 expression and increasing cancer cell vulnerability and apoptosis.

Curcumin derivative NL01 induces ferroptosis in ovarian cancer cells via HCAR1/MCT1 signaling

Curcumin has been shown to have anti-tumor proliferative properties, but its clinical application is limited by its low bioavailability, etc. Derivatives of curcumin have been developed and tested to improve its therapeutic efficacy. Derivative NL01 could induce ferroptosis through the HCAR1/MCT1 pathway. CCK-8 was used to detect curcumin and derivative IC NL01 inhibited cell growth of Anglne and HO8910PM ovarian cancer cells by 13 times more potent than curcumin and induced ferroptosis of these two cells. we found that NL01 was able to reduce the expression of HCAR1/MCT1 and activate the AMPK signaling pathway, which in turn induced cellular ferroptosis via SREBP1 pathway. Knock-down HCAR1 expression revealed similar phenotype and pathway alterations to NL01 treatment. HCAR1 overexpression promoted a malignant phenotype and resistance to cisplatin in both cancer cells, whereas knockdown of HCAR1 showed the opposite phenotype. Subcutaneous transplantation tumor experiments in nude mice also showed that NL01 induced iron death and inhibited ovarian cancer proliferation. Further study showed that NL01 promoted the downregulation of GPX4 expression, which is related to ferroptosis, and that addition of ferrostatin-1 partially reversed NL01-mediated inhibition of the growth of two cell lines. NL01 exhibits better anti-tumor growth properties than curcumin, and NL01 induces ferroptosis in ovarian cancer cells.

LOC644656 promotes cisplatin resistance in cervical cancer by recruiting ZNF143 and activating the transcription of E6-AP

Cisplatin resistance remains a persistent challenge in cervical cancer (CC) treatment. Molecular biomarkers have garnered attention for their association with cisplatin resistance in various diseases. Long non-coding RNAs (lncRNAs) exert significant influence on CC development. This study explores the role of LOC644656 in regulating cisplatin resistance in CC. Parental and cisplatin-resistant CC cells underwent cisplatin treatment. Functional assays assessed cell proliferation and apoptosis under different conditions. RNA pull-down with mass spectrometry, along with literature review, elucidated the interaction between LOC644656, ZNF143, and E6-AP. Mechanistic assays analyzed the relationship between different factors. RT-qPCR and western blot quantified RNA and protein levels, respectively. In vivo models validated E6-AP's function. Results revealed LOC644656 overexpression in cisplatin-resistant CC cells, exacerbating cell growth. LOC644656 recruited ZNF143 to activate E6-AP transcription, promoting cisplatin resistance in CC. In conclusion, LOC644656 positively modulates E6-AP expression via ZNF143-mediated transcriptional activation, contributing to cisplatin resistance in CC.

Tumor-suppressive role of miR-139-5p in angiogenesis and tumorigenesis of ovarian cancer: Based on GEO microarray analysis and experimental validation

This study clarified the possible molecular mechanisms by which the miR-139-5p/SOX4/TMEM2 axis affected angiogenesis and tumorigenesis of ovarian cancer (OC) based on GEO microarray datasets and experimental support. The expression of miR-139-5p and SOX4 was examined in clinical OC samples. Human umbilical vein endothelial cells (HUVECs) and human OC cell lines were included in vitro experiments. Tube formation assay was conducted in HUVECs. The expression of SOX4, SOX4, and VEGF in OC cells was identified using Western blot and immunohistochemistry. Luciferase assays were conducted to validate the targeting relationship between miR-139-5p and SOX4 and between SOX4 and TMEM2. A RIP assay assessed the binding of SOX4 and miR-139-5p. The impact of miR-139-5p and SOX4 on OC tumorigenesis in vivo was evaluated in nude mice. SOX4 was up-regulated, while miR-139-5p was down-regulated in OC tissues and cells. Ectopic miR-139-5p expression or SOX4 knockdown inhibited angiogenesis and tumorigenicity of OC. By targeting SOX4 in OC, miR-139-5p lowered VEGF expression, angiogenesis, and TMEM2 expression. The miR-139-5p/SOX4/TMEM2 axis also reduced VEGF expression and angiogenesis, which might curtail OC growth in vivo. Collectively, miR-139-5p represses VEGF expression and angiogenesis by targeting the transcription factor SOX4 and down-regulating TMEM2 expression, thereby impeding OC tumorigenesis.

Transcriptome sequencing analysis reveals miR-30c-5p promotes ferroptosis in cervical cancer and inhibits growth and metastasis of cervical cancer xenografts by targeting the METTL3/KRAS axis

Cervical cancer is the most common malignant tumor in the female reproductive system worldwide, and its molecular mechanisms remain complex and poorly understood. Various techniques, including transcriptome sequencing, RT-qPCR, ELISA, immunofluorescence, Western blot, CCK-8 assay, Transwell assay, and xenograft models, were employed to investigate gene/miRNA expression, cellular proliferation, migration, and the interactions between miR-30c-5p, METTL3, and KRAS. Our transcriptome sequencing results demonstrated a significant downregulation of miR-30c-5p in cervical cancer cells. Further investigations using RNA pull-down, dual-luciferase reporter assay, Me-RIP, and PAR-CLIP confirmed METTL3 as one of the downstream targets of miR-30c-5p, while KRAS was identified as an iron-death suppressor gene susceptible to m6A modification. Notably, our Me-RIP analysis demonstrated the involvement of METTL3 in m6A modification of KRAS. In vitro experiments revealed that miR-30c-5p facilitated ferroptosis in cervical cancer cells by inhibiting the METTL3/KRAS axis, thus suppressing proliferation and migration. Additionally, in vivo studies demonstrated that miR-30c-5p repressed the growth and metastasis of cervical cancer xenografts through the inhibition of the METTL3/KRAS axis. Overall, this study highlights the critical role of miR-30c-5p in modulating cervical cancer progression by targeting the METTL3/KRAS axis, providing new insights into the molecular mechanisms underlying cervical cancer growth and metastasis.

LINC00426, a novel m6A-regulated long non-coding RNA, induces EMT in cervical cancer by binding to ZEB1

To explore the function and molecular mechanism of LINC00426 in Cervical Cancer (CC), and to explore the clinical treatment strategy of LINC00426 for CC. Bioinformatics analysis was used to explore the expression of LINC00426 and patient prognosis of CC. Cell function experiments were conducted to explore the potential effect of LINC00426 on CC malignant phenotypes. The difference in m LINC00426 is up-regulated in CC, which can enhance the proliferation, migration and invasion of CC cells. METTL3 promotes the expression of LINC00426 by m LINC00426 is a cancer-promoting lncRNA related to m

Disulfiram suppresses epithelial-mesenchymal transition (EMT), migration and invasion in cervical cancer through the HSP90A/NDRG1 pathway

Disulfiram (DSF) has proven to be a promising anti-tumor drug in preclinical studies. However, its anti-cancer mechanism has not yet been elucidated. As an activator in tumor metastasis, N-myc downstream regulated gene-1 (NDRG1) is involved in multiple oncogenic signaling pathways and is upregulated by cell differentiation signals in various cancer cell lines. DSF treatment results in a significant reduction in NDRG1, while down-regulated NDRG1 has a pronounced effect on invading cancer cells, as shown in our previous work. Here, in vitro and in vivo experiments confirm that DSF contributes to regulating tumor growth, EMT, and the migration and invasion of cervical cancer. Furthermore, our results show DSF binds to the ATP-binding pocket in the N-terminal domain of HSP90A, thereby affecting the expression of its client protein NDRG1. To our knowledge, this is the first report of DSF binding to HSP90A. In conclusion, this study sheds light on the molecular mechanism by which DSF inhibits tumor growth and metastasis through the HSP90A/NDRG1/β-catenin pathway in cervical cancer cells. These findings provide novel insights into the mechanism underlying DSF function in cancer cells.

Regulator of G protein signaling 10: Structure, expression and functions in cellular physiology and diseases

Regulator of G protein signaling 10 (RGS10) belongs to the superfamily of RGS proteins, defined by the presence of a conserved RGS domain that canonically binds and deactivates heterotrimeric G-proteins. RGS proteins act as GTPase activating proteins (GAPs), which accelerate GTP hydrolysis on the G-protein α subunits and result in termination of signaling pathways downstream of G protein-coupled receptors. RGS10 is the smallest protein of the D/R12 subfamily and selectively interacts with Gαi proteins. It is widely expressed in many cells and tissues, with the highest expression found in the brain and immune cells. RGS10 expression is transcriptionally regulated via epigenetic mechanisms. Although RGS10 lacks multiple of the defined regulatory domains found in other RGS proteins, RGS10 contains post-translational modification sites regulating its expression, localization, and function. Additionally, RGS10 is a critical protein in the regulation of physiological processes in multiple cells, where dysregulation of its expression has been implicated in various diseases including Parkinson's disease, multiple sclerosis, osteopetrosis, chemoresistant ovarian cancer and cardiac hypertrophy. This review summarizes RGS10 features and its regulatory mechanisms, and discusses the known functions of RGS10 in cellular physiology and pathogenesis of several diseases.

STIM1 promotes cervical cancer progression through autophagy activation via TFEB nuclear translocation

Autophagy plays an important role in maintaining the stability of intracellular environment, abnormal autophagy is associated with the occurrence and progression of cancer, the role of STIM1 in regulating cancer autophagy remains controversial, and its clinical relevance is unclear. Our study aimed to investigate the effect and mechanism of STIM1 on cervical cancer, thus to provide new molecular therapeutic targets for cervical cancer in clinic. We collected CIN III, FIGO IB and IIA fresh Specimens without chemotherapy from patients in Renmin Hospital of Hubei University of Medicine (n = 10). STIM1, TFEB and autophagy related proteins of different stage tissues were detected. In vitro, SKF96365 and AncoA4 were used to inhibit STIM1-administrated Ca The expression levels of STIM1, TFEB and autophagy related proteins were positively correlated with the progression of cervical cancer. Inhibition of STIM1-mediated SOCE can decrease proliferation and migration, and promoted the apoptosis of cervical cancer cells. Knockdown STIM1 can inhibit autophagy and TFEB nuclear translocation. STIM1 can promote autophagy and accelerate cervical cancer progression by increasing TFEB nuclear translocation of cervical cancer cells.

Sphingolipids as multifaceted mediators in ovarian cancer

Ovarian cancer is the most lethal gynaecological malignancy. It is commonly diagnosed at advanced stage when it has metastasised to the abdominal cavity and treatment becomes very challenging. While current standard therapy involving debulking surgery and platinum + taxane-based chemotherapy is associated with high response rates initially, the large majority of patients relapse and ultimately succumb to chemotherapy-resistant disease. In order to improve survival novel strategies for early detection and therapeutics against treatment-refractory disease are urgently needed. A promising new target against ovarian cancer is the sphingolipid pathway which is commonly hijacked in cancer to support cell proliferation and survival and has been shown to promote chemoresistance and metastasis in a wide range of malignant neoplasms. In particular, the sphingosine kinase 1-sphingosine 1-phosphate receptor 1 axis has been shown to be altered in ovarian cancer in multiple ways and therefore represents an attractive therapeutic target. Here we review the roles of sphingolipids in ovarian cancer progression, metastasis and chemoresistance, highlighting novel strategies to target this pathway that represent potential avenues to improve patient survival.

Targeting eukaryotic elongation factor-2 kinase suppresses the growth and peritoneal metastasis of ovarian cancer

Ovarian cancer (OC) is the deadliest gynecological cancer and is currently incurable with standard treatment regimens. Early invasion, intraperitoneal metastasis, and an aggressive course are the hallmarks of OC. The major reason for poor prognosis is a lack of molecular targets and highly effective targeted therapies. Therefore, identification of novel molecular targets and therapeutic strategies is urgently needed to improve OC survival. Herein we report that eukaryotic elongation factor-2 kinase (EF2K) is highly upregulated in primary and drug-resistant OC cells and its expresssion associated with progression free survival TCGA database) and promotes cell proliferation, survival, and invasion. Downregulation of EF2K reduced expression of integrin β1 and cyclin D1 and the activity of the Src, phosphoinositide 3-kinase/AKT, and nuclear factor-κB signaling pathways. Also, in vivo, therapeutic targeting of EF2K by using single-lipid nanoparticles containing siRNA led to substantial inhibition of ovarian tumor growth and peritoneal metastasis in nude mouse models. Furthermore, EF2K inhibition led to robust apoptosis and markedly reduced intratumoral proliferation in vivo in ovarian tumor xenografts and intraperitoneal metastatic models. Collectively, our data suggest for the first time that EF2K plays an important role in OC growth, metastasis, and progression and may serve as a novel therapeutic target in OCs.

Compartmentalized activities of HMGCS1 control cervical cancer radiosensitivity

The underlying mechanisms by which cellular metabolism affects cervical cancer cell radiosensitivity remain poorly understood. Here, we found that loss of 3-hydroxy-3-methylglutaryl coenzyme A synthase 1 (HMGCS1), a key enzyme catalyzing the conversion of acetoacetyl-CoA to HMG-CoA in the cholesterol biosynthesis pathway, sensitizes the cervical cancer cells to radiation. We observed a compartmentalized cellular distribution of HMGCS1 in nuclei, cytosol, and mitochondria of cervical cancer cells and found that cytosolic HMGCS1 and mitochondrial HMGCS1 contribute together to the regulation of radiosensitivity. Mechanistically, we show that cytosolic HMGCS1 regulates radiosensitivity via manipulating the cholesterol metabolism, while mitochondrial HMGCS1 controls mitochondrial gene expression, thereby sustaining the mitochondrial function of cervical cancer cells. Together, our study identifies HMGCS1 as a novel regulator of radiosensitivty in cervical cancer cells, providing a molecular link between altered cholesterol metabolism, mitochondrial respiration, and radiosensitivity. Thus, targeting HMGCS1 may improve the therapeutic outcome of cervical cancer radiotherapy.

LncRNA HIF1A-AS2 modulated by HPV16 E6 regulates apoptosis of cervical cancer cells via P53/caspase9/caspase3 axis

Plentiful evidence proves that lncRNAs play a crucial role in tumor development. However, the function and mechanism that were mediated by lncRNA HIF1A-AS2 in cervical cancer remain unclear. The lncRNA HIF1A-AS2 was identified via high-throughput microarray analysis of three HPV 16-positive cervical squamous cell carcinoma (CSCC) samples and three HPV-negative normal controls. The expression of HIF1A-AS2 was detected by qRT-PCR in clinical tissues and cancer cells. In vitro and in vivo assays were performed through downregulation or upregulation of HIF1A-AS2. The possible mechanisms of HIF1A-AS2 in cervical cancer cells were explored by western blot, flow cytometric analysis and rescue assays. HIF1A-AS2 was significantly increased in cervical cancer tissue, and in the HPV- positive cervical cancer cells. Further investigation showed that the inhibition of HIF1A-AS2 suppressed cell proliferation, migration, invasion, and induced apoptosis, while up-regulation of HIF1A-AS2 revealed opposite results. In terms of mechanism, we found that HIF1A-AS2 was mediated by HPV16 E6 and regulated cell apoptosis via P53/caspase 9/caspase 3 axis. Our findings demonstrate that HIF1A-AS2 functions as a carcinogenic lncRNA that promotes tumor development, and serves as a candidate prognostic factor, which may contribute to the treatment of cervical cancer.

USP7 inhibits TIMP2 by up-regulating the expression of EZH2 to activate the NF-κB/PD-L1 axis to promote the development of cervical cancer

Cervical cancer belongs to the most common gynecological malignant cancers. EZH2 has been found to be dysregulated in different kinds of tumors and acts as an oncogene to promote cancer development. However, its upstream regulators and downstream targets in cervical cancer remain unclear. PD-L1 is a surface marker of cancer cells, facilitating the immunosuppressive microenvironment for escape from immunity attack. The molecular mechanism of increased PD-L1 expression in cervical cancer is needed to be explored. The expression levels of USP7, EZH2 and TIMP2 in cervical cancer patients' samples and cell lines were detected by qRT-PCR and histopathology staining. The functions of USP7, EZH2 and TIMP2 were evaluated by MTT, cell migration and invasion assays after knocking down or overexpression of indicated genes. The tumor microenvironment was determined by testing of PD-L1 expression and cytotoxicity when co-cultured with NK-92 cells. Xenograft model was used to test the function of USP7 in vivo. Our data demonstrated that USP7 and EZH2 were upregulated in cervical cancer, while TIMP2 was downregulated. Inhibition of USP7 and EZH2, or overexpression of TIMP2 suppressed proliferation, migration, invasion and immune escape ability of cervical cancer cells. USP7 could increase EZH2 level, which in turn inhibited TIMP2 expression via methylation in its promoter. TIMP2 was able to mediate PD-L1 expression via NF-κB signaling pathway. Knocking down of USP7 could inhibit tumor development in vivo of cervical cancer. The study discovered the function and mechanism of USP7 and highlighted its oncogenic role in cervical cancer development. Our results indicated that targeting USP7 could be a therapeutic strategy the treatment of cervical cancer.

Tumor suppressor FBXO11 drives ubiquitin proteasomal degradation of KIF2C to limit ovarian cancer progression and is transcriptionally repressed by ZNF217

Recent findings have indicated that the F-box E3 ubiquitin ligase, F-box only protein 11 (FBXO11), may serve a tumor-suppressing role in certain types of cancers. However, its specific function in ovarian cancer (OC) remains to be elucidated. This study revealed that FBXO11 expression is reduced in OC tissues compared to normal tissues. To assess the role of FBXO11 in OC cells, we established stable human OC cell lines with tetracycline-inducible (Tet-on) expression of FBXO11 CDS or shRNA. FBXO11 inhibited OC cell proliferation, colony formation, migration, invasion, and cell cycle transition from G0/G1 to S phase in vitro. Moreover, FBXO11 suppressed xenograft tumor growth in mice in vivo. Concurrently, FBXO11 reduced the volume of ascites and the number of metastatic tumor nodules in the peritoneal metastasis model. Mechanistically, FBXO11 promoted kinesin family member 2C (KIF2C) to undergo K48-linked ubiquitination and proteasomal degradation, and KIF2C knockdown reversed the tumor-promoting function of FBXO11 downregulation. Additionally, we demonstrated that FBXO11 is a transcriptional target of zinc-finger protein 217 (ZNF217), a known transcriptional repressor that has been implicated in the promotion of OC progression and the prediction of poor prognosis. In summary, FBXO11 functions as a tumor suppressor in OC through ubiquitin-proteasomal degradation of KIF2C; and the low expression level of FBXO11 in OC may be attributed to its transcriptional inhibition by transcription factor ZNF217. These findings provided new insights into understanding the molecular mechanism of OC progression.

CX-5461 inhibits cell proliferation and induces ferroptosis of colorectal cancer cells by inactivating Nrf2 pathway

Epithelial splicing regulatory protein 1 promotes peritoneal dissemination of ovarian cancer by inducing the formation of circular RNAs modulating epithelial plasticity

Peritoneal metastases prevalently occur in ovarian cancer, deteriorating patient prognosis. During the metastatic cascade, tumor plasticity enables cells to adapt to environmental changes, thereby facilitating dissemination. We previously found that epithelial splicing regulatory protein 1 (ESRP1) is linked to peritoneal metastasis and epithelial-mesenchymal plasticity in ovarian cancer. This study delves into the underlying mechanism. We found that ESRP1 preserves epithelial plasticity in ovarian cancer cells in vitro and in vivo. Functionally, ESRP1 enhances ovarian cancer cell growth and peritoneal dissemination. High-throughput sequencing revealed several ESRP1-related epithelial RNAs, encompassing both linear and circular forms. Specifically, ESRP1 triggers the cyclization of circPAFAH1B2 and circUBAP2 through binding to the GGU sequences in adjacent introns. The two ESRP1-induced circular RNAs stabilize DKK3 and AHR mRNAs, which are critical for epithelial plasticity, through interaction with IGF2BP2. Collectively, ESRP1 triggers the formation of circPAFAH1B2 and circUBAP2, which in turn stabilizes DKK3 and AHR through IGF2BP2 binding, thereby modulating the epithelial plasticity and aiding the peritoneal spread of ovarian cancer cells. The findings unveiled a biological network, orchestrated by ESRP1, that governs the epithelial-mesenchymal plasticity of ovarian cancer cells, emphasizing the therapeutic potential of ESRP1 and its induced circular RNAs for ovarian cancer treatment.

N-glycosylation stabilized TNFAIP6 promotes ovarian cancer metastasis by activating the PI3K-AKT signaling pathway

Ovarian cancer (OC) represents the most lethal gynecological malignancy, with a dismal 5-year survival rate of ∼30 % in advanced-stage patients, largely due to metastatic dissemination and limited therapeutic options. Elucidating the molecular drivers of OC metastasis remains imperative for developing targeted interventions. Integrative multi-omics analyses were performed using bulk RNA-seq and scRNA-seq data from TCGA and GEO repositories. Protein dynamics were validated via Western blot and immunofluorescence. Prognostic significance was assessed through Kaplan-Meier survival analysis with log-rank tests. Functional characterization of TNFAIP6 was achieved through lentivirus-mediated shRNA knockdown/overexpression, complemented by in vitro assays and in vivo metastasis models. The ubiquitination levels of TNFAIP6 were detected through Co-IP experiments. Immune cell infiltration was quantified via computational deconvolution algorithms. TNFAIP6 emerged as a metastasis-associated oncogene, with elevated expression correlating significantly with poor prognoses. Mechanistically, N-glycosylation stabilized TNFAIP6 by impeding ubiquitin-proteasomal degradation. TNFAIP6 knockdown genetically attenuated OC cell invasion, migration, and peritoneal dissemination. Pathway analyses revealed TNFAIP6-driven activation of the PI3K/AKT signaling pathway, which orchestrated epithelial-mesenchymal transition. Notably, TNFAIP6 upregulation was significantly correlated with tumor immune-suppressing microenvironment and predicted resistance to immune checkpoint inhibitors and chemotherapy. Our study establishes TNFAIP6 as a critical regulator of OC metastasis via PI3K/AKT pathway activation and a biomarker of therapeutic resistance. Targeting TNFAIP6 may offer dual strategies to counteract metastatic progression and therapeutic resistance in OC.

Unveiling the role of extracellular matrix elements and regulators in shaping ovarian cancer growth and metastasis

Epithelial ovarian cancer (EOC) progression is determined by numerous intracellular interactions and the interplay between malignant cells, normal cells, and the tumor acellular microenvironment, formed largely by the extracellular matrix (ECM). The structure and biochemical functioning of various ECM components, along with the activity of agents that regulate ECM remodeling, impact the disease's expansion (adhesion, proliferation, invasion), spread, and response to therapy. It is important to note that the involvement of ECM components and their regulators in the progression of EOC is bidirectional and distinctly depends on a particular tissue context. In certain situations, certain components of the ECM enhance the activity of cancer cells, but in other scenarios, they suppress it. In this review, we summarize the newest knowledge regarding diverse aspects of ECM engagement in EOC pathophysiology and chemotherapy. Moreover, we delineate conditions that exacerbate the pro-cancerous properties of ECM, including diabetes-associated glycation, aging, and cellular senescence. We also explore methods to therapeutically alter the properties of the ECM, which could be beneficial in ovarian cancer prevention and treatment.

Extracellular vesicles derived from EZH2-high ovarian cancer cells facilitate omental metastasis by inducing Periostin+ fibroblasts

The frequent omental metastasis of ovarian cancer (OvCa) at initial diagnosis is due to the omental premetastatic microenvironment, which is rich in activated fibroblasts. However, the molecular events driving the phenotypic transformation of omental fibroblasts that favor metastasis remain largely unexplored. Previously, we found that tumoral enhancer of zest homolog 2 (EZH2), a key epigenetic regulator catalyzing trimethylation at H3K27, played a crucial role in OvCa metastasis. In this study, we revealed that extracellular vesicles (EVs) derived from EZH2-high OvCa cells induce the expression of Periostin (POSTN), but not α-SMA, in omental fibroblasts, facilitating tumor metastasis. Nude mice with intraperitoneal injection of EVs before tumor cell inoculation showed that EVs derived from EZH2-high ovarian cancer cells promote omental metastasis. Human primary omental fibroblasts cocultured with EVs, especially those derived from EZH2-high OvCa cells, exhibited boosted migration, invasion capacities and conditioned medium from EV-activated fibroblasts promotes cancer cell migration, invasion and proliferation. These results may provide novel insight into EZH2-targeted therapy for ovarian carcinoma with intraperitoneal dissemination.

FTO triggers NLRP3/GSDMD-dependent pyroptosis to enhance cisplatin-sensitivity in ovarian cancer

Chemotherapy resistance is still the major impediment to poor prognosis of ovarian cancer (OC). The fat mass and obesity associated protein (FTO), as the first recognized RNA N6-methyladenosine (m

Study on the effects and mechanism of RRM2 on three gynecological malignancies

Cervical cancer, endometrial cancer, and ovarian cancer are the three most common gynecological malignancies. Their occurrence seriously affects women's health and life. Despite aggressive treatments, some patients still find it difficult to benefit from available therapies. Ribonucleic acid reductase subunit M2 (RRM2) is a limiting RNR enzyme involved in DNA synthesis and damage repair and plays a crucial role in many key cellular processes such as cell proliferation, migration, invasion, and senescence. Many studies have also shown that RRM2 also has a significant impact on tumor progression. However, the role of RRM2 in gynecological tumors has not been systematically studied. Our bioinformatics analysis of datasets related to cervical, endometrial, and ovarian cancers revealed that RRM2 is a significantly differentially expressed gene common to these cancers. We found that RRM2 was significantly overexpressed in cervical, endometrial, and ovarian cancer tissues and cells, exhibiting overall pro-oncogenic effects. RRM2 promoted cell proliferation, migration invasion, angiogenesis, and cell cycle in gynecological tumors while inhibiting apoptosis. The potential oncogenic effects of RRM2 in gynecologic tumor cell lines were further demonstrated using the RRM2 inhibitor Triapine (3-AP). These pro-tumorigenic effects may then be mediated through the involvement of RRM2 in the p53 and Akt/mTOR signaling pathways, altering the expression of p53 and Akt/mTOR. Thus, RRM2 is potentially a candidate gene for the unified diagnosis of cervical, endometrial, and ovarian cancers.

Mechanism underlying CDC20 affecting epithelial ovarian cancer biological behavior by regulating BAG6 ubiquitination

Epithelial ovarian cancer (EOC) endangers women's life and health. It is reported that cell division cycle 20 (CDC20) plays a role in EOC, but its underlying mechanisms remain unclear. Additionally, the involvement of bcl-2-associated athanogen-6 (BAG6) in EOC has not been previously reported. This study demonstrated that CDC20 was highly expressed in EOC and exhibited oncogenic properties through both in vitro and in vivo molecular biology experiments. In contrast, BAG6 was low expressed and functioned as a tumor suppressor. Both CDC20 and BAG6 were found to correlate with patient stage. Notably, the degradation of BAG6, mediated by CDC20 via ubiquitin-proteasome pathway, was shown to enhance the malignant biological behavior of EOC. Furthermore, the interaction between CDC20 and BAG6 was dependent on the WD40 domain of CDC20 and the D-box of BAG6. These findings provided valuable insights into the molecular mechanisms of EOC and established a theoretical basis for novel therapeutic targets in clinical treatment.

ZFHX2-AS1 interacts with DKC1 to regulate ARHGAP5 pseudouridylation and suppress ovarian cancer progression

Ovarian cancer (OCa) remains a highly lethal disease, largely due to late-stage diagnosis and limited treatment options for recurrent metastatic tumors. Long non-coding RNAs (lncRNAs) have been recognized as key regulators of cancer hallmarks, yet their specific roles in driving OCa progression are not fully understood. In this study, we employed an integrated approach combining clinical correlation, functional assays, and mechanistic investigations to reveal that lncRNA ZFHX2-AS1 is significantly downregulated in OCa tissues and cells, with its reduced expression associated with poor clinical outcomes. Using in vitro and in vivo models, we demonstrated that overexpression of ZFHX2-AS1 suppresses OCa cell proliferation, migration and invasion, whereas ZFHX2-AS1 knockdown enhances these malignant phenotypes. Mechanistically, we defined that ZFHX2-AS1 interacts with and attenuates the enzymatic activity of the pseudouridine synthase DKC1, thereby reducing pseudouridylation and stabilizing the oncogenic ARHGAP5 mRNA. Re-expression of ARHGAP5 could partially reverse the tumor-suppressive effects of ZFHX2-AS1. Further, we found that ARHGAP5 promotes epithelial-mesenchymal transition (EMT) by regulating Rho GTPases activities, and that ZFHX2-AS1 inhibits EMT in OCa by downregulating ARHGAP5 expression and suppressing the Rho GTPase signaling pathway. Taken together, our findings identify ZFHX2-AS1 as a potent tumor suppressor in OCa, acting through the modulation of DKC1-mediated pseudouridylation of ARHGAP5 and the inhibition of the Rho GTPase pathway, thus offering a potential therapeutic target for combating OCa progression.

ALOX5 induces EMT and promotes cell metastasis via the LTB4/BLT2/PI3K/AKT pathway in ovarian cancer

Ovarian cancer represents the most lethal gynecological malignancy with high invasiveness. Epithelial-to-mesenchymal transition (EMT) plays a critical role in cancer metastasis. However, the role of ALOX5 in EMT and cancer metastasis in ovarian cancer (OC) remain unclear. In this study, ALOX5 was significantly upregulated in tumorous and metastatic tissue compared with normal tissue. Furthermore, we found that overexpression of ALOX5 promoted cell migration and invasion, while silencing of ALOX5 suppressed migration and invasion in OC cell lines. Mechanistically, we found that enhanced expression of ALOX5 promoted EMT and cancer metastasis through activation of the PI3K/AKT pathway, whereas SNAIl inhibited the transcription of CDH1 in OC cells. Taken together, our results highlight a role for the ALOX5/PI3K/AKT/ SNAI1 axis in OC, which provides novel strategies for the prevention of metastasis in OC.

ALDH1A3 contributes to tumorigenesis in high-grade serous ovarian cancer by epigenetic modification

High-grade serous ovarian cancer (HGSOC) is the most lethal histotype of ovarian cancer due to its unspecific symptoms in part. ALDH1A3 (aldehyde dehydrogenase 1 family member A3) is a key enzyme for acetyl-CoA production involving aggressive behaviors of cancers. However, ALDH1A3's effects and molecular mechanisms in HGSOC remain to be clarified. Using RNA-seq and publicly available datasets, ALDH1A3 was found to be highly expressed in HGSOC, and associated with poor survival. Knockdown of ALDH1A3 prevented HGSOC tumorigenesis and enhanced cell sensitivity to paclitaxel or cisplatin. ALDH1A3 expression in HGSOC cells was found to be increased by hypoxia, but decreased by HIF-1α inhibitor KC7F2. The dual-luciferase reporter assay showed that the increased transcriptional activity of ALDH1A3 induced by HIF-1α overexpression was reduced by KC7F2. In addition, PITX1 (paired like homeodomain 1) was identified to be inhibited by ALDH1A3 knockdown, and PITX1 depletion inhibited cell proliferation. The mechanistic studies showed that ALDH1A3 knockdown reduced the acetylation of histone 3 lysine 27 (H3K27ac). Treatment of exogenous acetate with NaOAc or inhibition of histone deacetylase with Pracinostat increased H3K27ac and PITX1 levels. CHIP assay demonstrated a significant enrichment of H3K27ac at the PITX1 promoter, and ALDH1A3 knockdown reduced the binding between H3K27ac and PITX1. Taken together, our data suggest that ALDH1A3, transcriptional activated by HIF-1α, promotes tumorigenesis and decreases chemosensitivity by increasing H3K27ac of PITX1 promoter in HGSOC.

miR-29c-3p acts as a tumor promoter by regulating β-catenin signaling through suppressing DNMT3A, TET1 and HBP1 in ovarian carcinoma

Ovarian Carcinoma (OvCa) is characterized by rapid and sustained growth, activated invasion and metastasis. Studies have shown that microRNAs recruit and alter the expression of key regulators to modulate carcinogenesis. Here, we find that miR-29c-3p is increased in benign OvCa and malignant OvCa compared to normal ovary. Univariate and multivariate analyses report that miR-29c-3p overexpression is associated with poor prognosis in OvCa. Furthermore, we investigate that expression of miR-29c-3p is inversely correlated to DNA methyltransferase (DNMT) 3 A and Ten-Eleven-Translocation enzyme TET1. The high-throughput mRNA sequencing, bioinformatics analysis and pharmacological studies confirm that aberrant miR-29c-3p modulates tumorigenesis in OvCa cells, including epithelial-mesenchymal transition (EMT), proliferation, migration, and invasion. This modulation occurs through the regulation of β-catenin signaling by directly targeting 3'UTR of DNMT3A, TET1 and the HMG box transcription factor HBP1 and suppressing their expression. The further 3D spheres assay clearly shows the regulatory effects of miR-29c-3p on OvCa tumorigenesis. Additionally, the receiver operating characteristic (ROC) curve analysis of miR-29c-3p and the clinical detection/diagnostic biomarker CA125 suggests that miR-29c-3p may be conducive for clinical diagnosis or co-diagnosis of OvCa. These findings support miR-29c-3p functions as a tumor promoter by targeting its functional targets, providing new potential biomarker (s) for precision medicine strategies in OvCa.

The NF-κB signalling pathway regulates GLUT6 expression in endometrial cancer

Gene and protein expression of the glucose transporter GLUT6 are elevated in multiple cancers, including endometrial cancer. However, the extrinsic and intrinsic mechanisms that regulate GLUT6 expression in this malignancy are unknown. Herein we investigate the potential mechanisms regulating GLUT6 expression in endometrial cancer. Data mining of the GLUT6 gene (SLC2A6) in The Cancer Genome Atlas (TCGA) PanCan datasets was performed in cBioPortal. A transcriptome PCR array was used to identify regulators of GLUT6 expression. The role of RELA in regulating GLUT6 gene and protein expression was investigated by overexpressing constitutively active and dominant-negative RELA in endometrial cells. Endometrial cells were treated with the pro-inflammatory cytokine TNFα and the expression of RELA, IκBα, TNFα, and GLUT6 were examined by Western blotting and RT-qPCR. GLUT6 is altered in 1% of all cancer samples (157 of 10, 967 samples) within TCGA datasets including 4.7% of uterine (endometrial) cancers. GLUT6 expression was positively co-expressed with multiple members of the NF-κB signalling pathway including NFKB2, RELB, NFKBIE, and TNF in endometrial cancer samples. A transcriptome PCR array identified RELA as the top potential transcriptional regulator of GLUT6 expression. Overexpression of constitutively active RELA increased GLUT6 gene expression in normal endometrial epithelial cells (hUE-Ts), while overexpression of dominant-negative RELA decreased GLUT6 expression in cancerous RL95-2 endometrial cells. TNFα treatment activated canonical NF-κB signalling and increased the expression of GLUT6, but not that of other glucose transporters (GLUTs 1, 3, 4, 8, 10, or 12) in endometrial cells. TNFα is a cytokine that is commonly increased in obesity-related endometrial cancer and the findings herein support a potential mechanism whereby TNFα may contribute to endometrial cancer initiation or progression by increasing GLUT6 expression. Furthermore, we identified RELA, an important downstream mediator of the TNFα signalling cascade, as a regulator of GLUT6 expression in endometrial cells. Future studies are warranted to determine how GLUT6 expression affects endometrial tumourigenesis or cancer progression.

Identification and characterization of tumorigenic circular RNAs in cervical cancer

Circular RNAs (circRNAs) are a distinctive family of ncRNAs, and they function as key regulators in the initiation, development and progression of various diseases. However, the regulatory roles of circRNAs in the tumorigenesis of cervical cancer (CC) have not been fully understood. In this study, we identified a set of circRNAs in CC and paired normal tissues, using RNA sequencing data, and found that the cancer and normal tissues could be told apart by those differentially expressed (DE) circRNAs, indicating that circRNA expression profiles in CC were significantly different from those in the normal tissues. Meanwhile, the upregulated genes in CC were enriched in inflammation-related pathways, and the correlation analysis between the DE circRNAs and genes revealed that the abundance of DE circRNAs was positively related to the expression of their host genes. However, the expression of TGFBR2 and KDM4C were found to exhibit a negative correlation with their corresponding circRNAs. Furthermore, we also predicted the interactions between circRNAs and proteins, and constructed a competing endogenous RNA (ceRNA) network. Specifically, hsa_circ_0001495 was predicted to interact with ESRP2, and acted as a sponge by competing for miRNAs with TBL1XR1. Functionally, hsa_circ_0001495 was predicted to regulate epithelial cell proliferation and NOTCH signaling via ESRP2 and TBL1XR1, respectively. We also evaluated the prognostic values of downstream target genes of selected circRNAs, using clinical records of CC patients. In summary, the present study provided some regulatory circRNAs involved in CC tumorigenesis based on bioinformatics approaches, which brought strong evidences for researchers to further explore their biological and clinical values.

HMGB1-mediated transcriptional activation of circadian gene TIMELESS contributes to endometrial cancer progression through Wnt-β-catenin pathway

TIMELESS (TIM) is a circadian gene which is implicated in the regulation of daily rhythm, DNA replication and repair, and cancer initiation and progression. Nevertheless, the role of TIM in endometrial cancer (EC) development is largely unknown. Bioinformatics analysis showed that TIM was aberrantly up-regulated in EC tissues and positively correlated with clinical or histological grade of EC. Functional studies showed that TIM knockdown reduced EC cell viability and restrained EC cell migration in vitro, as well as blocked xenograft tumor growth in vivo. Mechanistically, HMGB1 transcriptionally up-regulated TIM expression in EC cells. In addition, TIM could activate the transcription of the canonical Wnt ligand WNT8B, and TIM depletion could reduce the malignant potential of EC cells largely by targeting and down-regulating WNT8B. As a conclusion, HMGB1/TIM/WNT8B signal cascade was identified in this study for the first time. HMGB1 exerted its oncogenic role by activating the transcription of TIM, leading to the activation of Wnt signaling and EC progression.

Casein kinase 1 controls the shuttling of epidermal growth factor receptor and estrogen receptor in endometrial carcinoma induced by breast cancer hormonal therapy: Relevance of GPER1/Src

Casein kinase 1 plays a crucial role in carcinogenesis. 4-Hydroxytamoxifen (4-OHT), which is widely used to treat breast cancer, often leads to the development of endometrial carcinoma with poor prognosis, particularly among women who receiving long-term treatment. This study was performed to elucidate whether specific inhibition of casein kinase 1 (CK1) controls 4-OHT-mediated Ishikawa cell carcinogenesis. 4-OHT significantly stimulated the activity of estrogen receptor alpha (ERα) and nuclear translocation and expression of epidermal growth factor receptor (EGFR) from the plasma membrane to perinuclear or nuclear regions, as well as the activities of G-protein-coupled estrogen receptor 1 (GPER1) and Src in Ishikawa cells. However, inhibition of EGFR by Gefitinib blocked all these events, and inhibition of GPER1 or Src produced a partial block. GPER1 and Src controlled Ishikawa cell carcinogenesis in different manners: GPER1 accelerated EGFR mobility without affecting ERα activity, while Src activated ERα and EGFR without any change in GPER1 expression. EGFR and GPER1 performed reciprocal regulation in endometrial cell carcinogenesis via direct interaction in 4-OHT-treated Ishikawa cells, implying a possible key role of GPER1 in these events. Inhibition of CK1 by CKI-7 and IC261, however, impeded all changes beginning with EGFR translocation and activity in 4-OHT-treated Ishikawa cells. These findings indicate that inhibition of CK1 could control 4-OHT-mediated activation and translocation of ER/EGFR and GPER1/Src expression, inhibiting 4-OHT-triggered endometrial carcinogenesis. Therefore, targeting of CK1 by CKI-7 and IC261 could be a prospective adjuvant therapy for breast cancer patients taking tamoxifen.

BMP2-induction of FN14 promotes protumorigenic signaling in gynecologic cancer cells

We previously reported that bone morphogenetic protein (BMP) signaling promotes tumorigenesis in gynecologic cancer cells. BMP2 enhances proliferation of ovarian and endometrial cancer cells via c-KIT induction, and triggers epithelial-mesenchymal transition (EMT) by SNAIL and/or SLUG induction, leading to increased cell migration. However, the downstream effectors of BMP signaling in gynecological cancer cells have not been clearly elucidated. In this study, we performed RNA-sequencing of Ishikawa endometrial and SKOV3 ovarian cancer cells after BMP2 stimulation, and identified TNFRSF12A, encoding fibroblast growth factor-inducible 14 (FN14) as a common BMP2-induced gene. FN14 knockdown suppressed BMP2-induced cell proliferation and migration, confirmed by MTS and scratch assays, respectively. In addition, FN14 silencing augmented chemosensitivity of SKOV3 cells. As a downstream effector of BMP signaling, FN14 modulated both c-KIT and SNAIL expression, which are important for growth and migration of ovarian and endometrial cancer cells. These results support the notion that the tumor promoting effects of BMP signaling in gynecological cancers are partially attributed to FN14 induction.

BHLHA15 promotes cervical cancer cholesterol synthesis and tumor progression

Research suggested that increased cholesterol synthesis is an effect factor in the malignant progression and unfavorable outcome of cervical cancer (CC). Unfortunately, the molecular mechanisms underlying the increased cholesterol synthesis remain elusive. Here, our comprehensive bioinformatics analysis, along with in vitro and in vivo experimental validations, suggests that basic helix-loop-helix family member a15 (BHLHA15) is a pivotal transcription factor (TF) regulating cholesterol synthesis and malignant progression in CC. Our results indicates that BHLHA15, along with its target genes CYP51A1 and FASN, are significantly upregulated in CC tissues, particularly in III-IV stages and dead patients, indicating a strong association with poor prognosis. Additionally, ectopic expression of BHLHA15 increases the levels of free and total cholesterol, thereby enhancing cancer progression in CC cells. Mechanistically, BHLHA15 directly binds and activates the expression of CYP51A1 and FASN, thereby promoting cholesterol synthesis and progression of CC. Notably, stable knockdown of BHLHA15 effectively suppresses the CC progression by suppressing the expression of CYP51A1 and FASN. Furthermore, risk models based on the expression levels of BHLHA15, CYP51A1, and FASN exhibits excellently diagnostic and prognostic efficacy in CC. Collectively, we identified BHLHA15 as a critical TF that regulates cholesterol synthesis in CC, and provides a potentially effective strategy for targeted therapy in CC.

GATA2 promotes cervical cancer progression under the transcriptional activation of TRIP4

The continued rise in recurrence and mortality rates of cervical cancer suggests the need to find novel therapeutic targets. Previous studies suggest that TRIP4 acts as a transcription factor to regulate cervical carcinogenesis and progression. Our aim was to explore whether the key downstream genes of TRIP4 functions same as TRIP4 in promoting cervical cancer development. We analyzed and confirmed the downstream targets of TRIP4 by RNA sequencing in cervical cancer cells with TRIP4 knockdown. The expression correlation between TRIP4 and GATA2 and the effect of GATA2 on cervical cancer cell growth were determined respectively by Western Blot, Scratch, Spheroid, and MTT analyses. Pulldown and ChIP experiments were performed to analyze the binding of TRIP4 to the promoter of GATA2. The clinical significance of GATA2 and TRIP4 expression in cervical cancer patients was analyzed by tissue microarray staining. GATA2 was highly expressed in cervical cancer tissues. Knockdown of GATA2 inhibited the growth, metastasis and stemness of cervical cancer cells and sensitized cervical cancer cells to radiation therapy. The inhibitory effect of TRIP4 knockdown on cervical cancer cells was rescued by GATA2 overexpression. Furthermore, TRIP4 could bind to the specific GATA2 promoter region, thereby activating its transcription. Clinical tissue microarray analysis indicated that the expression of TRIP4 and GATA2 was positively correlated, and high expression of both predicted a poor prognosis in cervical cancer patients. Our study demonstrated that GATA2 functions as the key downstream target of TRIP4 to promote cervical cancer progression and effective intervention of TRIP4/GATA2 signaling is expected to be developed as potential cervical cancer therapeutic strategy.

The myo-inositol biosynthesis rate-limiting enzyme ISYNA1 suppresses the stemness of ovarian cancer via Notch1 pathway

Cancer stem cells (CSCs) play a central role in ovarian cancer (OC), understanding regulatory mechanisms governing their stemness is critical. Here, we report ISYNA1, the rate-limiting enzyme in myo-inositol biosynthesis, as a suppressor of OC regulating cancer stemness. We identified ISYNA1 as a differentially expressed gene in normal ovary and ovarian cancer tissues, as well as OC cells and OCSCs. Low ISYNA1 expression correlated with poor prognosis in OC patients. In addition, ISYNA1 was negatively correlated with cancer stem cell (CSC) markers, and ISYNA1-related pathways were enriched in Wnt, Notch, and other critical cancer pathways. ISYNA1 deficiency promoted OC cell growth, migration, and invasion ability in vitro and in vivo. Knockdown of ISYNA1 increased stemness of OC cells, including self-renewal, CSC markers expression, ALDH activity, and proportion of CD44

The adaptor protein VEPH1 interacts with the kinase domain of ERBB2 and impacts EGF signaling in ovarian cancer cells

Upregulation of ERBB2 and activating mutations in downstream KRAS/BRAF and PIK3CA are found in several ovarian cancer histotypes. ERBB2 enhances signaling by the ERBB family of EGF receptors, and contains docking positions for proteins that transduce signaling through multiple pathways. We identified the adaptor protein ventricular zone-expressed pleckstrin homology domain-containing protein 1 (VEPH1) as a potential interacting partner of ERBB2 in a screen of proteins co-immunoprecipitated with VEPH1. In this study, we confirm a VEPH1 - ERBB2 interaction by co-immunoprecipitation and biotin proximity labelling and show that VEPH1 interacts with the juxtamembrane-kinase domain of ERBB2. In SKOV3 ovarian cancer cells, which bear a PIK3CA mutation and ERBB2 overexpression, ectopic VEPH1 expression enhanced EGF activation of ERK1/2, and mTORC2 activation of AKT. In contrast, in ES2 ovarian cancer cells, which bear a BRAF

OCIAD2-IQGAP1 interaction promotes pancreatic cancer progression by suppressing oxidative stress and mitochondria-mediated apoptosis

HOXA1 promotes aerobic glycolysis and cancer progression in cervical cancer

As a hallmark for cancer, aerobic glycolysis, also known as the Warburg effect contributes to tumor progression. However, the roles of aerobic glycolysis on cervical cancer remain elusive. In this work, we identified transcription factor HOXA1 as a novel regulator of aerobic glycolysis. High expression of HOXA1 is closely associated with poor outcome of patients. And, altered HOXA1 expression enhance or reduce aerobic glycolysis and progression in cervical cancer. Mechanistically, HOXA1 directly regulates the transcriptional activity of ENO1 and PGK1, thus induce glycolysis and promote cancer progression. Moreover, therapeutic knockdown of HOXA1 results in reduce aerobic glycolysis and inhibits cervical cancer progression in vivo and in vitro. In conclusion, these data indicate a therapeutic role of HOXA1 inhibits aerobic glycolysis and cervical cancer progression.

Circular RNA circE2F2 promotes malignant progression of ovarian cancer cells by upregulating the expression of E2F2 protein via binding to HuR protein

Ovarian cancer (OC) is a gynecological malignancy with a poor prognosis and low survival rate. E2F2 is a transcription activator that plays an indispensable role in cell proliferation and cell cycle progression. The preliminary analysis indicated that the E2F2 gene could produce three circular RNAs (circRNAs). This study aimed to investigate whether these circRNAs would be involved in OC tumorigenesis. The results showed that one of the circRNAs (termed circE2F2) was significantly upregulated in OC tissues and cell lines, and high circE2F2 expression was associated with poor survival in OC patients. The knockdown of circE2F2 in OC cells suppressed cell proliferation, migration, invasion, and cellular glucose metabolism. In circE2F2-deficient cells, the half-life of the E2F2 mRNA was significantly shorter than that in the control group, indicating that sufficient circE2F2 expression could strengthen the stability of the E2F2 mRNA. Further analysis revealed that circE2F2 could bind to RNA-binding protein Hu antigen R (HuR). Moreover, circE2F2 enhanced the stability of the E2F2 mRNA via binding to the HuR protein. Also, E2F2 overexpression significantly enhanced the mobility, invasiveness, and glucose metabolism of OC cells with insufficient circE2F2 expression, suggesting that circE2F2 induced OC cell growth and metastasis by upregulating E2F2. In conclusion, circE2F2 promoted OC cell proliferation, metastasis, and glucose metabolism by stabilizing the E2F2 mRNA via binding to the HuR protein. These findings suggest a novel regulatory mechanism for the oncogenic effects of circE2F2, E2F2, and HuR on ovarian carcinogenesis.

Targeting CDK12 rescues C/EBPβ-mediated platinum and PARP inhibitor resistance in ovarian cancer

Despite multimodality treatment efforts, resistance to platinum and PARP inhibitors represents a primary impediment to improve prognosis of ovarian cancer. Here, we found that ovarian cancer tissues had higher C/EBPβ expression compared with normal tissues and high C/EBPβ expression predicted unfavorable survival outcomes. Elevated C/EBPβ expression enhanced cisplatin resistance and olaparib resistance. C/EBPβ could affect DDR signals of ovarian cancer. CDK12, serving as a C/EBPβ-regulated DDR-related gene, was directly targeted by and bound with C/EBPβ. C/EBPβ could promote CDK12 expression and confer drug tolerance via CDK12. Manipulation of CDK12 could reverse the effects of C/EBPβ. Using CDK12 inhibitor THZ531 could rescue C/EBPβ-mediated cisplatin resistance and olaparib resistance. Our findings indicated that C/EBPβ is a potent DDR regulator of ovarian cancer, which directly targets CDK12 and upregulates its expression. High C/EBPβ expression mediates platinum resistance and PARP inhibitor resistance via CDK12. Targeting C/EBPβ via CDK12 inhibition could rescue drug responsiveness of ovarian cancer, thereby counteracting platinum and PARP inhibitor resistance. C/EBPβ could thus be exploited as a candidate prognostic biomarker in ovarian cancer.

Promoter methylation and enhanced SKP2 are associated with the downregulation of CDKN1C in cervical squamous cell carcinoma

Cervical Squamous Cell Carcinoma (CSCC) is one of the significant causes of cancer deaths among women. Distinct genetic and epigenetic-altered loci, including chromosomal 11p15.5-15.4, have been identified. CDKN1C (Cyclin-Dependent Kinase Inhibitor 1C, p57KIP2), a member of the CIP/KIP family of cyclin-dependent kinase inhibitors (CDKIs), located at 11p15.4, is a putative tumor suppressor. Apart from transcriptional control, S-Phase Kinase Associated Protein 2 (SKP2), an oncogenic E3 ubiquitin ligase, regulates the protein turnover of CDKN1C. But the molecular status of CDKN1C in CSCC and the underlying mechanistic underpinnings have yet to be explored. TCGA and other publicly available datasets were analyzed to evaluate the expression of CDKN1C and SKP2. The expression (transcript/protein) was validated in independent CSCC tumors (n = 155). Copy number alteration and promoter methylation were correlated with the expression. Finally, in vitro functional validation was performed. CDKN1C was down-regulated, and SKP2 was up-regulated at the transcript and protein levels in CSCC tumors and the SiHa cell line. Notably, promoter methylation (50%) was associated with the downregulation of the CDKN1C transcript. However, high expression of SKP2 was found to be associated with the decreased expression of CDKN1C protein. Independent treatments with 5-aza-dC, MG132, and SKP2i (SKPin C1) in SiHa cells led to an enhanced expression of CDKN1C protein, validating the mechanism of down-regulation in CSCC. Collectively, CDKN1C was down-regulated due to the synergistic effect of promoter hyper-methylation and SKP2 over-expression in CSCC tumors, paving the way for further studies of its role in the pathogenesis of the disease.

Human omental adipose-derived mesenchymal stem cells enhance autophagy in ovarian carcinoma cells through the STAT3 signalling pathway

Our previous study showed that human omental adipose-derived stem cells (ADSCs) promote ovarian cancer growth and metastasis. In this study, the role of autophagy in the ovarian cancer-promoting effects of omental ADSCs was further determined. The growth and invasion of ovarian cancer cells were detected by CCK-8 and Transwell assays, respectively. The autophagy of ovarian cancer cells transfected with MRFP-GFP-LC3 adenoviral vectors was evaluated by confocal microscopy and western blot assay. Transfection of STAT3 siRNA was used to inhibit the expression of STAT3. Our results show that autophagy plays a vital role in ovarian cancer and is promoted by ADSCs. Specifically, we show that proliferation and invasion are correlated with autophagy induction by ADSCs in two ovarian cancer cell lines under hypoxic conditions. Mechanistically, ADSCs activate the STAT3 signalling pathway, thereby promoting autophagy. Knockdown of STAT3 expression using siRNA decreased hypoxia-induced autophagy and decreased the proliferation and metastasis of ovarian cancer cells. Taken together, our data indicate that STAT3-mediated autophagy induced by ADSCs promotes ovarian cancer growth and metastasis.

IFNγ-induced PD-L1 expression in ovarian cancer cells is regulated by JAK1, STAT1 and IRF1 signaling

Expression of the immune checkpoint programmed death ligand-1 (PD-L1) is increased in ovarian cancer (OC) and correlates with poor prognosis. Interferon-γ (IFNγ) induces PD-L1 expression in OC cells, resulting in their increased proliferation and tumor growth, but the mechanisms that regulate the PD-L1 expression in OC remain unclear. Here, we show that the IFNγ-induced PD-L1 expression in OC cells is associated with increased levels of STAT1, Tyr-701 pSTAT1 and Ser-727 pSTAT1. Suppression of JAK1 and STAT1 significantly decreases the IFNγ-induced PD-L1 expression in OC cells, and STAT1 overexpression increases the IFNγ-induced PD-L1 expression. In addition, IFNγ induces expression of the transcription factor interferon regulatory factor 1 (IRF1) and IRF1 suppression attenuates the IFNγ-induced gene and protein levels of PD-L1. Chromatin immunoprecipitation results show that IFNγ induces PD-L1 promoter acetylation and recruitment of STAT1, Ser-727 pSTAT1 and IRF1 in OC cells. Together, these findings demonstrate that the IFNγ-induced PD-L1 expression in OC cells is regulated by JAK1, STAT1, and IRF1 signaling, and suggest that targeting the JAK1/ STAT1/IRF1 pathway may provide a leverage to regulate the PD-L1 levels in ovarian cancer.

Aberrant angiogenic signaling pathways: Accomplices in ovarian cancer progression and treatment

Ovarian cancer is one of the most common malignant tumors in women, and treatment options are limited. Despite efforts to adjust cancer treatment models and develop new methods, including tumor microenvironment (TME) therapy, more theoretical support is needed. Increasing attention is being given to antiangiogenic measures for TME treatment. Another important concept in ovarian cancer TME is angiogenesis, where tumor cells obtain nutrients and oxygen from surrounding tissues through blood vessels to support further expansion and metastasis. Many neovascularization signaling pathways become imbalanced and hyperactive during this process. Inhibiting these abnormal pathways can yield ideal therapeutic effects in patients, even by reversing drug resistance. However, these deep TME signaling pathways often exhibit crosstalk and correlation. Understanding these interactions may be an important strategy for further treating ovarian cancer. This review summarizes the latest progress and therapeutic strategies for these angiogenic signaling pathways in ovarian cancer.

CXXC5 drove inflammation and ovarian cancer proliferation via transcriptional activation of ZNF143 and EGR1

CXXC5, a zinc-finger protein, is known for its role in epigenetic regulation via binding to unmethylated CpG islands in gene promoters. As a transcription factor and epigenetic regulator, CXXC5 modulates various signaling processes and acts as a key coordinator. Altered expression or activity of CXXC5 has been linked to various pathological conditions, including tumorigenesis. Despite its known role in cancer, CXXC5's function and mechanism in ovarian cancer are unclear. We analyzed multiple public databases and found that CXXC5 is highly expressed in ovarian cancer, with high expression correlating with poor patient prognosis. We show that CXXC5 expression is regulated by oxygen concentration and is a direct target of HIF1A. CXXC5 is critical for maintaining the proliferative potential of ovarian cancer cells, with knockdown decreasing and overexpression increasing cell proliferation. Loss of CXXC5 led to inactivation of multiple inflammatory signaling pathways, while overexpression activated these pathways. Through in vitro and in vivo experiments, we confirmed ZNF143 and EGR1 as downstream transcription factors of CXXC5, mediating its proliferative potential in ovarian cancer. Our findings suggest that the CXXC5-ZNF143/EGR1 axis forms a network driving ovarian cell proliferation and tumorigenesis, and highlight CXXC5 as a potential therapeutic target for ovarian cancer treatment.

E3 ubiquitin ligase RNF180 impairs IPO4/SOX2 complex stability and inhibits SOX2-mediated malignancy in ovarian cancer

RING finger protein 180 (RNF180), an E3 ubiquitin ligase, is thought to be a tumor suppressor gene. However, the detailed mechanism of its effect on ovarian cancer (OV) has not been elucidated. Importin 4 (IPO4) which belongs to transport protein is reported to have cancer-promoting effects on OV. Here, we explored the potential signaling pathways related to RNF180 and IPO4. It was first verified that RNF180 is downregulated and IPO4 is upregulated in OV. By overexpressing or knocking down RNF180 in OV cells, we confirmed that RNF180 inhibited the malignant behaviors of OV cells both in vitro and in vivo. Bioinformatics analysis and proteomics experiments found that RNF180 could interact with IPO4 and promote the degradation of IPO4 through ubiquitination. In addition, overexpression of IPO4 removed the inhibitory effect of RNF180 on OV. We subsequently found that IPO4 could bind to the oncogene Sex determining Region Y-box 2 (SOX2). Knockdown of IPO4 in OV cells decreased SOX2 protein level in nucleus and promoted cyclin-dependent kinase inhibitory protein-1 (p21) expression. Overexpression of RNF180 also inhibited the expression of SOX2 in nucleus. All these results indicated that RNF180 inhibited the nuclear translocation of SOX2 by promoting ubiquitination of IPO4, which ultimately promoted the expression of p21 and then suppressed the progression of OV. This study verified the tumor suppressor effect of RNF180 on OV, elucidated the mechanism of the molecule network related to RNF180 and IPO4 in OV and identified for OV.

CENPA promotes glutamine metabolism and tumor progression by up-regulating SLC38A1 in endometrial cancer

Glutamine addiction is a significant hallmark of metabolic reprogramming in tumors and is crucial to the progression of cancer. Nevertheless, the regulatory mechanisms of glutamine metabolism in endometrial cancer (EC) remains elusive. In this research, we found that elevated expression of CENPA and solute carrier family 38 member 1 (SLC38A1) were firmly associated with worse clinical stage and unfavorable outcomes in EC patients. In addition, ectopic overexpression or silencing of CENPA could either enhance or diminish glutamine metabolism and tumor progression in EC. Mechanistically, CENPA directly regulated the transcriptional activity of the target gene, SLC38A1, leading to enhanced glutamine uptake and metabolism, thereby promoting EC progression. Notably, a prognostic model utilizing the expression levels of CENPA and SLC38A1 genes independently emerged as a prognostic factor for EC. More importantly, CENPA and SLC38A1 were significantly elevated and positively correlated, as well as indicative of poor prognosis in multiple cancers. In brief, our study confirmed that CENPA is a critical transcription factor involved in glutamine metabolism and tumor progression through modulating SLC38A1. This revelation suggests that targeting CENPA could be an appealing therapeutic approach to address pan-cancer glutamine addiction.

TRIM35 inhibits endometrial cancer progression via ubiquitination and degradation of EIF3E

Endometrial carcinoma (EC), recognized as the predominant gynecologic malignancy, is associated with substantial mortality rates. While chemotherapy serves as a critical component in adjuvant and primary treatments, existing pharmacological interventions demonstrate limited efficacy in significantly extending overall survival. Consequently, deciphering the molecular mechanisms driving EC pathogenesis is essential for developing innovative therapies. Existing evidence implicates TRIM35 in tumor proliferation, invasion, and metastatic processes across multiple cancers. To investigate TRIM35's role in EC, we performed integrated bioinformatics analysis followed by experimental validation via RT-qPCR and western blotting, which confirmed its significant downregulation in EC tissues. Subsequently, we transfected endometrial cancer cells with lentiviral plasmids overexpressing TRIM35 to investigate its Impact on cellular proliferation, cell cycle, invasion, and migration. We found that overexpressing TRIM35 significantly inhibited proliferation, invasion, and migration. Further research revealed that TRIM35 regulates the ubiquitination of EIF3E. Additionally, TRIM35 modulates the CDK4/Cyclin D1 signaling pathway, suppressing EC cell proliferation. Intriguingly, overexpressing EIF3E reversed the inhibitory effects of TRIM35 in EC cells. In conclusion, our study demonstrates that TRIM35 regulates the ubiquitination of EIF3E and inhibits the CDK4/Cyclin D1 signaling pathway, thereby suppressing the malignant proliferation of EC. These findings suggested that TRIM35 has potential as a therapeutic target for EC.

Unraveling the secrets of UBE2S in endometrial cancer: Potential targets for diagnosis, prognostic assessment, and ferroptosis therapy

UBE2S exhibits elevated expression in various cancers. Its overexpression is positively correlated with poor prognosis in endometrial cancer (UCEC) patients. However, the role and underlying mechanisms of UBE2S in UCEC progression remain to be fully elucidated. Utilizing TCGA data, we initially identified UBE2S as a prognostically significant gene. Subsequently, We evaluated UBE2S expression levels in UCEC tumor tissues and cell lines using immunohistochemistry (IHC), qRT-PCR and Western blotting. Following shRNA-mediated knockdown of UBE2S, we systematically assessed its effects on cell proliferation and migration through CCK-8, EdU staining, colony formation, wound healing, and Transwell migration assays. These findings were further validated through in vivo experiments. RNA sequencing (RNA-seq) and TCGA data analysis revealed the cellular biological functions mediated by UBE2S. Flow cytometry and FerroOrange staining were used to examine the effects of UBE2S knockdown on the cell cycle, apoptosis, and ferroptosis. Western blotting was utilized to confirm changes in the expression of proteins associated with these pathways. A prediction model based on five core UBE2-genes demonstrated significant prognostic value. Notably, UBE2S exhibited significantly elevated expression in UCEC tissues, which was strongly correlated with adverse prognosis and tumor immunosuppressive microenvironment. Additionally, UBE2S knockdown resulted in the suppression of malignant phenotypes in UCEC cells, characterized by reduced cell proliferation and migration both in vitro and in vivo. Furthermore, downregulation of UBE2S induced cell cycle arrest, enhanced apoptosis, and increased ferroptosis. As a potential oncogene and therapeutic target in UCEC, UBE2S may play a critical role in UCEC cell malignancies.

ACSL4 coordinates metabolic and cell cycle reprogramming to promote endometrial cancer progression

Endometrial cancer (EC) is a common gynecologic malignancy associated with lipid metabolic reprogramming. We identified ACSL4, a fatty acid-activating enzyme, as significantly upregulated in EC and inversely correlated with tumor differentiation. Functional assays revealed that ACSL4 promotes EC cell proliferation, migration, and G1/S progression, while its knockdown exerts suppressive effects. Mechanistically, ACSL4 activates the PPARα-CPT1C axis to enhance fatty acid β-oxidation and upregulates E2F2 to drive cell cycle progression. Inhibition of ACSL4 with PRGL493 suppressed tumor growth in vitro and in vivo. These findings highlight ACSL4 as a dual regulator of lipid metabolism and cell proliferation and a potential therapeutic target in EC.

Machine learning combined with single-cell analysis reveals predictive capacity and immunotherapy response of T cell exhaustion-associated lncRNAs in uterine corpus endometrial carcinoma

The exhaustion of T-cells is a primary factor contributing to immune dysfunction in cancer. Long non-coding RNAs (lncRNAs) play a significant role in the advancement, survival, and treatment of Uterine Corpus Endometrial Carcinoma (UCEC). Nevertheless, there has been no investigation into the involvement of lncRNAs associated with T-cell exhaustion (TEXLs) in UCEC. The goal of this work is to establish predictive models for TEXLs in UCEC and study their related immune features. Using transcriptome and single-cell sequencing data from The Cancer Genome Atlas and Gene Expression Omnibus databases, we employed co-expression analysis and univariate Cox regression to identify prognostic-associated TEXLs (pTEXLs). The prognostic model was developed using the Least Absolute Contraction and Selection Operator. The immunotherapy characteristics of the prognostic model risk score were studied. Then molecular subgroups were identified through non-negative Matrix Factorization based on pTEXLs. The identification of co-expressed genes was done using a weighted correlation network analysis. Subsequently, a diagnostic model for UCEC was created. In-depth investigations, both in vitro and in vivo, were carried out to elucidate the molecular mechanism of the key gene within the diagnostic model. Receiver operating characteristic curve, calibration curve, and decision curve analysis proved the validity of the predictive models established according to pTEXLs. The subgroup with lower risk scores in the prognostic model has better responses to blocking immune checkpoint therapy. Single-cell analysis suggests that the expression level of MIEN1 is relatively high in immune cells among diagnostic genes. Furthermore, the targeted suppression of MIEN1 via sh-MIEN1 diminishes the proliferative, migratory, and invasive capacities of UCEC cells, potentially associated with CD8 The association between TEXLs and UCEC was methodically elucidated by our investigation. A stable pTEXLs risk prediction model and a diagnosis model for UCEC were also established.

IL-6/KIAA1429 promotes ferroptosis resistance in endometrial cancer through m6A modification of DDIT3

Endometrial cancer (EC) exhibits significant resistance to ferroptosis. Interleukin (IL)-6 is a pleiotropic cytokine that is a regulator of the expression of various oncogenes and tumour suppressor genes. Notably, N6-methyladenosine (m6A) modification has been demonstrated to play a significant role in tumour occurrence and development. However, IL-6 regulatory role in ferroptosis during carcinogenesis and whether it affects m6A modification in EC remain unclear. The present study aimed to investigate the effect of IL-6 on m6A modification in EC. The degree of ferroptosis of EC in vitro and in vivo was evaluated using a cell proliferation assay, western blotting, total reactive oxygen species (ROS) detection, a lipid peroxidation assay, and a subcutaneous xenograft tumour model. The regulation of downstream molecules by KIAA1429 was confirmed using dot blot, RNA and methylated RNA immunoprecipitation (RIP), a RNA stability assay, and fluorescence in situ hybridisation (FISH). IL-6 upregulated overall m6A levels in EC cells, with the KIAA1429 expression upregulation being the most significant. Functionally, IL-6 inhibited EC cell ferroptosis and promoted proliferation. The downregulation of KIAA1429 triggered ferroptosis, subsequently suppressing the proliferation of EC cells in vitro and tumour growth in vivo. Mechanistically, IL-6 activated KIAA1429 expression through the JAK1/STAT3 pathway. KIAA1429 regulated DDIT3 expression and promoted its degradation through m6A modification. IL-6 is crucial in EC cell ferroptosis resistance. Overall, the IL-6/KIAA1429/DDIT3 axis is a novel pathway that promotes EC progression and provides novel directions for targeted EC therapy.

SOX12 promotes serine synthesis and tumor progression in endometrial cancer

Studies have demonstrated that the sex-determining region Y-box 12 (SOX12), a key oncogene, is highly expressed in various tumors and is associated with poor prognosis. Unfortunately, the effect of SOX12 in endometrial cancer (EC) remains unclear. Here, we discovered that SOX12 expression was significantly elevated in EC tissues from advanced-stage patients and patients who died. Additionally, high expression of SOX12 was shown to predict poor overall survival (OS) and recurrence-free survival (RFS), indicating that SOX12 is an independent prognostic factor for patients with EC. Furthermore, the overexpression or knockdown of SOX12 significantly enhanced or inhibited the activity, proliferation, migration, invasion ability, serine synthesis pathway (SSP) activity and metabolism, respectively, of EC cells. Moreover, overexpression of SOX12 significantly promoted the growth and malignant progression of subcutaneously transplanted tumors, facilitated the formation of lung metastatic nodules, and ultimately reduced the survival time of nude mice. In contrast, stable suppression of SOX12 markedly inhibited the growth of subcutaneous grafts and the formation of lung metastatic nodules in introduced via the tail vein, while also increasing the survival time of nude mice. Mechanistically, SOX12 directly binds to the promoter of the target gene 3-phosphoglycerate dehydrogenase (PHGDH), activating its transcription and enhancing the SSP and metabolism, which ultimately contributes to the malignant progression of EC. Surprisingly, we found that the combination of serine deprivation and SOX12 knockdown had a more pronounced effect on inhibiting the malignant progression of EC in vivo and in vitro. In summary, our study not only enhances the understanding of the carcinogenic mechanisms associated with SOX12 but also presents a potential strategy for molecularly targeted therapy in EC.

LLGL2 targets the Hedgehog signaling pathway to influence malignant progression of endometrial cancer

Endometrial cancer (EC) is a malignant tumor of the endometrial epithelium, with endometrial adenocarcinoma being the most common type. It has a good overall prognosis, but recurrence and metastasis are often associated with poorer outcomes. LLGL2 is closely linked to tumorigenesis; however, its in endometrial carcinoma is unknown. This study investigated the biological function of LLGL2 in endometrial cancer and its intrinsic molecular mechanisms in promoting the malignant progression of the disease. The expression of LLGL2 in endometrial cancer was analyzed using the TCGA database via UALCAN and validated through western blot analysis, RT-qPCR, and immunohistochemistry. Additionally, the correlation between LLGL2 and the clinicopathological features of patients was examined. The effects of LLGL2 on the proliferation and migration of endometrial cancer cells were assessed using EdU proliferation assay, clone formation assay, Transwell assay, scratch assay, and the detection of proliferation and metastasis markers. Furthermore, the impact of LLGL2 on key genes of the Hedgehog signaling pathway, including SHH, PTCH1, SMO, and GLI1, was explored using western blot analysis and RT-qPCR. The expression of SHH, PTCH1 and GLI1 was also detected in cells treated with the Hedgehog signaling pathway inhibitor (JK184) in endometrial cancer cells overexpressing LLGL2. Finally, the role of LLGL2 in tumor growth was investigated in vivo using sh-LLGL2 and OE-LLGL2 nude mouse tumorigenic model. LLGL2 expression was upregulated in endometrial cancer tissues compared to normal endometrium. LLGL2 expression was significantly correlated with tumor histological grading (p < 0.01). LLGL2 promoted proliferation, migration, and invasive abilities of endometrial cancer cells. In the nude mouse tumorigenic model, LLGL2 deficiency inhibited the growth of subcutaneously transplanted tumors, and overexpression of LLGL2 promoted the growth of tumors. At the molecular level, LLGL2 may promote the transduction of the Hedgehog signaling pathway in endometrial cancer cells. LLGL2 may be involved in the development of endometrial cancer as an oncogene, leading to aberrant activation of the Hedgehog signaling pathway. Therefore, LLGL2 is a potential new target for the treatment of endometrial cancer.

Activated PARP1/FAK/COL5A1 signaling facilitates the tumorigenesis of cholesterol-resistant ovarian cancer cells through promoting EMT

Cancer cells require plentiful cholesterol for membrane biogenesis and other functional needs due to fast proliferating, leading to the interaction of cholesterol or its metabolites with cancer-related pathways. However, the impact of long-lasting high cholesterol concentrations on tumorigenesis and its underlying mechanisms remains largely unexplored. To the best of our knowledge, this study is the first to establish a cholesterol-resistant ovarian cancer cells, whose intracellular total cholesterol level up to 6-8 mmol/L. We confirmed that high cholesterol facilitated the progression of ovarian cancer in vitro and in vivo. Notably, our findings revealed significant upregulation of collagen type V alpha 1 chain (COL5A1) expression in cholesterol-resistant ovarian cancer cells and human ovarian cancer tissue, which was depended on FAK/Src activation. Mechanistically, PARP1 directly bound to FAK in response to activate FAK/Src/COL5A1 signaling. Intriguingly, COL5A1 depletion significantly impeded the tumorigenesis of these cells, concomitant with a decrease in epithelial-mesenchymal transition (EMT) progression. In conclusion, PARP1/FAK/COL5A1 signaling activation facilitated progression of cholesterol-resistant ovarian cancer cells by promoting EMT, thereby broadening a new therapeutic opportunity.