Gene

miRNAs in oral cancer; diagnostic and prognostic roles

Suppressing effects of green tea extract and Epigallocatechin-3-gallate (EGCG) on TGF-β- induced Epithelial-to-mesenchymal transition via ROS/Smad signaling in human cervical cancer cells

Transforming growth factor-β (TGF-β)-induced Epithelial-to-mesenchymal transition (EMT) process is a fundamental target for preventing cervical cancer cells' progression and invasion. Green tea and its principal active substance, Epigallocatechin-3-gallate (EGCG), demonstrate anti-tumor activities in various tumor cells. The cell viability of two cervical cancer cell lines, Hela and SiHa, in the experimental groups was examined employing the MTT method, and ROS generation was probed applying 2',7'-dichlorofluorescein diacetate-based assay. The Smad signaling and EMT process was evaluated utilizing western blot analysis and quantitative real-time polymerase chain reaction (qRT-PCR). Chromatin immunoprecipitation (ChIP) and Smad binding element (SBE)-luciferase assays were employed to measure Smad-DNA interaction and Smad transcriptional activity, respectively. EGCG (0-100 μmol/L) and green tea extract (0-250 μg/ml) suppressed the viability of cancer cells in a dose-dependent manner (p < 0.01). Our conclusions affirmed that pre-incubation with green tea extract (80 μg/ml) and EGCG (60 μmol/L) significantly reversed the impacts of TGF-β in Hela and SiHa cells by decreasing Vimentin, ZEB, Slug, Snail, and Twist and increasing E-cadherin expression. The molecular mechanism of green tea extract and EGCG for TGF-β-induced EMT inhibition interfered with ROS generation and Smad signaling. Green tea extract and EGCG could significantly decrease ROS levels, the phosphorylation of Smad2/3, the translocation, DNA binding, and activity of Smads in cervical cancer cell lines treated with TGF-β1 (p < 0.01). EGCG and green tea extract suppressed TGF-β-induced EMT in Hela and SiHa cells, and the underlying molecular mechanism may be related to the ROS generation and Smad signaling pathway.

Hsa_circ_0061140 promotes endometrial carcinoma progression via regulating miR-149-5p/STAT3

Circular RNAs (circRNAs) are reported to participate in many diseases including tumorigenesis, which can modulate gene expression post-transcriptionally. Up to now, the detailed function of circRNAs in endometrial carcinoma (EC) progression are to be well established. hsa_circ_0061140 has been revealed to act as crucial regulators in several cancers. This current study was carried out to explore the function of hsa_circ_0061140 in EC development. Here, hsa_circ_0061140 expression was modulated using functional assays and we found loss of hsa_circ_0061140 significantly restrained EC cells progression. Moreover, we revealed hsa_circ_0061140 could act as a molecular sponge for miR-149-5p. STAT3 was predicted as a downstream target gene of miR-149-5p. As well known, miR-149-5p is reported to be involved in tumor growth and metastasis. Then, dual luciferase reporter experiment and RIP assay were carried out to evidence the direct binding association between hsa_circ_0061140 and miR-149-5p. miR-149-5p was able to negatively modulate STAT3 expression. Additionally, we proved hsa_circ_0061140 exhibited its oncogenic role due to the modulation of miR-149-5p and STAT3 axis. Taken these together, we suggested that hsa_circ_0061140 might act as an effective therapy to treat EC through functioning as a molecular sponge of miR-149-5p.

The impacts of dipeptidyl- peptidase 4 (DPP-4) inhibitors on common female malignancies: A systematic review

The inhibition of dipeptidyl- peptidase 4 (DPP-4) is an essential therapy for controlling hyperglycemia in patients with type 2 diabetes (T2DM). However, the role of DPP-4 in cancer is not yet clear, with some studies suggesting that it may either promote or suppress tumors. This makes it crucial to have personalized treatment for diabetic women with cancer to effectively manage their diabetes whilst and preventing cancer mortality. To address this issue, we conducted an integrative in-silico analysis and systematic review of the literature to comprehensively examine the relationship between DPP-4 expression and the effects of its inhibitors on prevalent female malignancies. We specifically chose studies that examined the effects of DPP-4 expression and DPP-4 inhibition (DPP-4i) on prevalent cancers in women, such as breast cancer (BC), ovarian cancer (OV), cervical cancer (CC), and endometrial cancer (EC). These studies comprised those conducted both in vivo and in vitro. The review of the literature indicated that DPP-4i may worsen aggressive traits such as metastasis, Epithelial-to-mesenchymal transition (EMT), and chemotherapy resistance in BC cells. However, cohort studies on diabetic and BC patients did not confirm these findings. In vitro studies indicate that on OV, DPP-4 upregulation has been shown to prevent metastasis, while CCappears to be influenced by DPP-4 expression in terms of cell migration. sitagliptin, a pharmaceutical inhibitor of DPP-4, had a significant impact on reducing adhesion in CC cells in vitro. Overexpression of DPP-4 increased cell migration and proliferation in CC and EC cells, and hence the application of sitagliptin is expected to prevent this effect. On the other hand, the result of in-silico data confirmed that a significant correlation exists between DPP-4 expression and immune cell infiltration in breast, ovarian, cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) as well as downregulated in these cancers compared to their normal tissue samples. Furthermore, a significant (p < 0.05) effect on OS of BC and CESC patients has been reported due to the elevation of DPP-4 methylation on a specific CPG Island. These findings could aid in creating specialized treatments for diabetic women with specific malignancies, but caution should be exercised when considering the patient's medical history and cancer type.

Association of intronic variants (Apal and Bsml) of vitamin D receptor gene with uterine leiomyoma among North Indian women

Understanding the genetic factors involved in the Uterine Leiomyoma (UL) development is crucial for exploring the complexities of UL disorders. This study aimed to examine genetic association between UL incidence and intronic polymorphisms of vitamin D receptor gene in north Indian population. Total 200 subjects (100 healthy women and 100 with uterine leiomyomas) of age- and gender-matched control subjects, were genotyped for BsmI (rs1544410) and ApaI (rs7975232) polymorphisms in the VDR gene using TETRA ARMS PCR, followed by Sanger sequencing validation. Levels of VDR mRNA and vitamin D were also assessed through quantitative real-time PCR and ELISA respectively. The association of these variants with leiomyomas was analyzed, along with clinico-pathological (obesity) association. ApaI revealed a significant association with UL, especially for the TG genotype (OR = 2.38; 95 % CI, 1.26---4.51; p = 0.003). In a similar manner, ApaI is associated with an increased risk for UL with all three genetic models. Comparing VDR ApaI polymorphism between obese and non-obese patients revealed that AC genotype was significantly (OR = 3.71; 95 % CI, 1.53--9.11; p = 0.002) associated with a reduced risk of UL in non-obese patients. The expression of VDR mRNA was two times lower in patients with UL (p < 0.001), along with decreased serum vitamin D levels (p < 0.001). A significant association was also observed between VDR ApaI variant with reduced mRNA expression, vitamin D level and obesity. However, no associations were observed amongBsm1VDR genotypes and ULs. This study found significant association between the VDR intronic ApaI polymorphism (rs7975232) and the incidence of UL. This VDR variant showed significant association with reduced VDR mRNA expression and serum vitamin D levels in UL patients. However, no significant association was observed between BsmI VDR polymorphism (rs1544410) and UL in North Indian women.

Prostaglandin E2 suppresses KCNH1 gene expression and inhibits the proliferation of CaSki cervical cells through its four prostanoid PTGER subtypes

The main risk factor for cervical cancer is the persistent infection of high-risk HPV subtypes, notably HPV16. Another contributing factor is proinflammatory prostaglandin E

circCUL3 drives malignant progression of cervical cancer by activating autophagy through sponge miR-223-3p upregulation of ATG7

Circular RNA (circRNA) has emerged as a pivotal regulatory factor in cancer biology, yet its exact role in cervical cancer remains incompletely understood. In this study, we investigated the functional role of circCUL3 in cervical cancer and explored its potential as a therapeutic target. Functional gain and loss experiments were conducted in Hela and Siha cell lines to elucidate the biological functions of circCUL3 in cervical cancer. The results revealed that circCUL3 overexpression significantly enhanced cell viability, migration, and invasion while suppressing apoptosis, while circCUL3 knockout displayed the opposite effects. Mechanistically, we identified hsa-miR-223-3p as a target of circCUL3, with its expression being negatively regulated by circCUL3. Furthermore, we discovered that circCUL3 could sequester miR-223-3p, leading to the upregulation of ATG7 expression, and this was linked to the regulation of autophagy in cervical cancer cells. In vivo validation using a xenograft mouse model further supported our in vitro findings. Notably, we found that chloroquine (CQ), an autophagy inhibitor, restored miR-223-3p expression and counteracted the oncogenic effect of circCUL3 overexpression. In conclusion, circCUL3 potentially contributes to the malignant progression of cervical cancer by acting as a sponge for miR-223-3p, resulting in the upregulation of ATG7 and the activation of autophagy.

Novel strategies in HPV‑16‑related cervical cancer treatment: An in vitro study of combined siRNA-E5 with oxaliplatin and ifosfamide chemotherapy

Cervical cancer, primarily caused by HPV infection, remains a global health concern. Current treatments face challenges including drug resistance and toxicity. This study investigates combining E5-siRNA with chemotherapy drugs, Oxaliplatin and Ifosfamide, to enhance treatment efficacy in HPV-16 positive cervical cancer cells, targeting E5 oncoprotein to overcome limitations of existing therapies. The CaSki cervical cancer cell line was transfected with E5-siRNA, and subsequently treated with Oxaliplatin/Ifosfamide. Quantitative real-time PCR was employed to assess the expression of related genes including p53, MMP2, Nanog, and Caspases. Cell apoptosis, cell cycle progression, and cell viability were evaluated using Annexin V/PI staining, DAPI staining, and MTT test, respectively. Furthermore, stemness ability was determined through a colony formation assay, and cell motility was assessed by wound healing assay. E5-siRNA transfection significantly reduced E5 mRNA expression in CaSki cells compared to the control group. The MTT assay revealed that monotherapy with E5-siRNA, Oxaliplatin, or Ifosfamide had moderate effects on cell viability. However, combination therapy showed synergistic effects, reducing the IC50 of Oxaliplatin from 11.42 × 10 The study demonstrates that combining E5-siRNA with Oxaliplatin or Ifosfamide enhances the efficacy of chemotherapy in HPV-16 positive cervical cancer cells. This synergistic approach effectively targets multiple aspects of cancer cell behavior, including proliferation, apoptosis, migration, and stemness. The findings suggest that this combination strategy could potentially allow for lower chemotherapy doses, thereby reducing toxicity while maintaining therapeutic efficacy. This research provides valuable insights into targeting HPV E5 as a complementary approach to existing therapies focused on E6 and E7 oncoproteins, opening new avenues for combination therapies in cervical cancer treatment.

LINC01605 promotes malignant phenotypes of cervical cancer via miR-149-3p/WNT7B axis

Long non-coding RNAs (LncRNA) play a pivotal role in the progression of various malignancies. Despite recent identification as an oncogene associated with tumorigenesis. The precise role of LINC01605 in cervical cancer (CC) remains unclear. Therefore, the objective of this study was to investigate the influence of LINC01605 on proliferation and invasion of CC cells, while also exploring its potential underlying mechanisms. The expression of LINC01605 in CC cell lines was analyzed using the TCGA database and qRT-PCR. Various assays, including CCK-8 and transwell analysis, were conducted on CC cells to assess the influence of LINC01605 on their proliferation, migration, and invasion capabilities. Bioinformatics and dual luciferase reporter gene assays were employed to analyze the target genes of LINC01605 and miR-149-3p. To further investigate the mechanism of action, transfection and investigation were performed using specific siRNA, miRNA mimics, or inhibitors. The expression of LINC01605 exhibited a significant increase in CC cell lines, and this upregulation was associated with an unfavorable prognosis. Modulating the expression of LINC01605, either by down-regulating or up-regulating it, exerted suppressive or stimulatory effects on the growth and invasion of HeLa and Siha cells. LINC01605 functioned as a competitive endogenous RNA (ceRNA) for miR-149-3p, with WNT7B being identified as a target gene of miR-149-3p. The involvement of LINC01605 in CC development is facilitated by its ability to regulate the expression of WNT7B through sequestering miR-149-3p. Our study demonstrates that LINC01605 acts as a competitive endogenous RNA in modulating the effects of WNT7B on the proliferation and invasion of CC cells by sequestering miR-149-3p. This research provides novel insights into the involvement of LINC01605 in the advancement of CC.

In vitro study of HPV18-positive cervical cancer HeLa cells based on CRISPR/Cas13a system

The E6 protein is a known oncogene in cervical cancer and plays a key role in the development and progression of cervical cancer by reducing the expression level of the tumor suppressor protein P53 and ultimately leading to enhanced cell proliferation and reduced apoptosis. Therefore, antiviral agents that inhibit the expression of E6 oncoprotein are expected to be potential therapies for human cervical cancer. Here we developed CRISPR/Cas13a: crRNA dual plasmid system and demonstrated that CRISPR/Cas13a could effectively and specifically knock down human papillomavirus 18 E6 mRNA, downregulate the expression level of E6 protein, and restore the expression of the tumor suppressor gene P53 protein, thereby inhibiting the growth of cervical cancer cells and increasing their apoptosis, the E6-2, E6-3, and E6-5 groups resulted in apoptosis rates of 25.4%, 22.4%, and 22.2% in HeLa cells. Moreover, CRISPR/Cas13a enhances the proliferation inhibition and apoptosis induction of cisplatin in cervical cancer HeLa cells. The CRISPR/Cas13a system targeting HPV E6 mRNA may be a promising therapeutic approach for the treatment of human papillomavirus-associated cervical cancer.

Association between dense PAX1 promoter methylation and HPV16 infection in cervical squamous epithelial neoplasms of Xin Jiang Uyghur and Han women

DNA methylation is an epigenetic alteration that may lead to carcinogenesis by silencing key tumor suppressor genes. Hypermethylation of the paired box gene 1 (PAX1) promoter is important in cervical cancer development. Here, PAX1 methylation levels were compared between Uyghur and Han patients with cervical lesions. Data on PAX1 methylation in different cervical lesions were obtained from the Gene Expression Omnibus (GEO) database, whereas data on survival and PAX1 mRNA expression in invasive cervical cancer (ICC) were retrieved from the Cancer Genome Atlas (TCGA) database. MassARRAY spectrometry was used to detect methylation of 19 CpG sites in the promoter region of PAX1, whereas gene mass spectrograms were drawn by Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry. Human papillomavirus (HPV) 16 infection was detected by polymerase chain reaction. PAX1 methylation in high-grade squamous intraepithelial lesion (HSIL) and ICC was significantly higher than in normal tissues. PAX1 hypermethylation was associated with poor prognosis and reduced transcription. ICC-specific PAX1 promoter methylation involved distinct CpG sites in Uyghur and Han patients HPV16 infection in HSIL and ICC patient was significantly higher than in normal women (p < 0.05). Our study revealed a strong association between PAX1 methylation and the development of cervical cancer. Moreover, hypermethylation of distinct CpG sites may induce HSIL transformation into ICC in both Uyghur and Han patients. Our results suggest the existence of ethnic differences in the genetic susceptibility to cervical cancer. Finally, PAX1 methylation and HPV infection exhibited synergistic effects on cervical carcinogenesis.

Fatty acid synthase (FASN) inhibits the cervical squamous cell carcinoma (CESC) progression through the Akt/mTOR signaling pathway

Cervical cancer is a malignant tumor that affects females and remains the cause of the highest morbidity and mortality among women worldwide. Currently, gene-targeted therapy is a novel treatment option for clinicians. Furthermore, fatty acid synthase (FASN) plays a therapeutic role in various cancers. Nonetheless, the mechanism of action of this enzyme in cervical squamous cell carcinoma and cervical duct adenocarcinoma (CESC) has not yet been reported. RNA (ribonucleic acid) sequencing data and clinical information were obtained from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx). The expression levels of FASN were obtained from Gene Expression Profiling Interactive Analysis 2 (GEPIA2) and Human Protein Atlas (HPA). Univariate and multivariate Cox regression analyses were utilized to assess independent prognostic factors associated with survival. A nomogram and receiver operating characteristic curve (ROC) were employed to evaluate survival and predictive power. In vitro experiments and real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) were conducted to identify cell interference efficiency. MTS, monoclonal formation, and EDU assays were used to determine cell viability. Wound healing and invasion assays (transwell assay) were used to evaluate cell migration and invasion. Finally, Hoechst 33342, propidium iodide (PI) staining and Annexin V-FITC staining were used to assess apoptosis and the cell cycle, while western blotting was utilized to determine the protein expression levels. FASN was aberrantly expressed in various cancers, including CESC, where it was highly expressed. Kaplan-Meier, univariate, multivariate Cox regression analyses and ROC curve indicated that FASN is a potential key indicator of survival prognosis among CESC patients and demonstrated good predictive ability and efficacy. Complementary in vitro experiments confirmed that FASN is an important target for CESC therapy. The current study validated the biological and clinical significance of FASN in CESC prognosis, suggesting that FASN knockdown may exert antitumor activity against cervical cancer through the Akt/mTOR signaling pathway.

Role of MLH1 and MSH2 deficiency in the development of tumorigenesis and chemo-tolerance of cervical Carcinoma: Clinical implications

Cervical cancer (CACX) is one of the top causes of cancer death in women globally. The involvement of several cellular pathways in carcinogenesis is still poorly understood. Here, we focused to evaluate the contributory role of Mismatch Repair (MMR) pathway genes-MLH1 and MSH2 in CACX and their association with chemo-tolerance of the disease. For this purpose, molecular profiles (expression/promoter methylation/deletion) of the genes were analysed in both normal cervical epithelium and tumour tissue, also validated in in-silico dataset as well. Later on, prognostic importance of the genes was identified through analysis of their methylation/expression status in plasma DNA of circulating tumour cells (CTCs) and cisplatin-tolerant CACX cell lines respectively. It was found that the expression profile of MLH1 and MSH2 genes was considerably reduced from undifferentiated basal-parabasal layers of normal cervical epithelium towards progression of the disease. Further analysis showed that frequent deletion [34-48%] and promoter methylation events [28-46%] of the genes were the plausible reasons for their reduced expression during tumorigenesis. Incidentally, the prevalence of MLH1 [32%] and MSH2 [27%] promoter methylation found in CTCs of plasma of the clinically advanced CACX patients implicated their prognostic importance of the disease. In addition, the patients having high alterations of those genes resulted in poor patient outcomes even after the therapy. In in-depth analysis of this result in cisplatin-tolerant CACX cell lines, we discovered that increased promoter methylation frequency of those genes at higher concentrations of cisplatin and gradual accumulation of the cells in the G2/M phase of the cell cycle were the rational causes for their reduced expression and MMR deficiency in the system. Hence, it is possible to conclude that the gradual down-regulation of MLH1 and MSH2 proteins may be a key event for MMR pathway inactivation in CACX. This might also be associated with chemo-tolerance and overall poor survival among the patients.

Vitamin D receptor Fok1 polymorphism and invasive ovarian carcinoma risk – A case-control study

ARID3A and ARID3B induce stem promoting pathways in ovarian cancer cells

ARID3A and ARID3B are paralogs from the AT-Rich interactive Domain (ARID) family. ARID3A and ARID3B associate to regulate genes in B-cells and cancer. We were the first to demonstrate that ARID3B regulates stem cell genes and promotes the cancer stem cell phenotype. Importantly, different knockout phenotypes in mice and distinct patterns of expression in adult animals suggests that ARID3A and ARID3B may have unique functions. In addition, high levels of ARID3B but not ARID3A induce cell death. Our goal was to express ARID3A, ARID3B, or both genes at a moderate level (as can be observed in cancer) and then identify ARID3 regulated genes. We transduced ovarian cancer cells with ARID3A-GFP, ARID3B-RFP, or both. RNA-sequencing was conducted. ARID3A and ARID3B regulated nearly identical sets of genes. Few genes (<5%) were uniquely regulated by ARID3A or ARID3B. ARID3A/B induced genes involved in cancer and stem cell processes including: Twist, MYCN, MMP2, GLI2, TIMP3, and WNT5B. We found that ARID3A and ARID3B also induced expression of each other, providing evidence of the cooperativity. While ARID3A and ARID3B likely have unique functions in distinct contexts, they are largely capable of regulating the same stem cell genes in cancer cells. This study provides a comprehensive list of genes and pathways regulated by ARID3A and ARID3B in ovarian cancer cells.

Multi-omics profiling links enhancer-associated MSH6 downregulation to platinum resistance, prognosis, and immune features in ovarian cancer

Platinum resistance is a major cause of poor outcome in ovarian cancer (OC), but biomarkers that reflect the proteomic and epigenetic basis of resistance remain limited. We aimed to develop a multi-omics signature associated with prognosis and to explore molecular features linked to chemoresistance in OC. Proteomic, transcriptomic, single-cell, spatial transcriptomic, and epigenomic data were integratively analyzed. A risk model was built using LASSO and Random Forest methods and validated across seven GEO datasets combined into a metavalidation cohort (n = 1049). MSH6 was further examined by ChIP-qPCR and immunohistochemistry in 71 OC samples. Immune-related associations were evaluated using IOBR and the IMvigor210 cohort. A five-protein signature (ARAF, ATM, MSH6, ASNS, SETD2) was associated with platinum resistance and survival in OC. The model consistently stratified patients into prognostically distinct risk groups across multiple cohorts. Single-cell and spatial analyses indicated that the high-risk group was enriched for stem-like epithelial features and showed reduced immune infiltration. Additional analyses supported an association between lower MSH6 expression and reduced H3K27ac enrichment at a putative enhancer locus. In the clinical cohort, low MSH6 protein expression was associated with platinum resistance and poor prognosis. Low MSH6 expression was also linked to immune-cold features and less favorable immunotherapy-related associations in external datasets. This study identifies a proteomics-derived multi-omics signature associated with platinum resistance and prognosis in OC and highlights MSH6 as a candidate marker linked to chemoresistant and immune-related features. Further mechanistic and clinical validation is needed.

Inhibitory role of oleanolic acid and esculetin in HeLa cells involve multiple signaling pathways

The global burden of cervical cancer from low and middle-income groups is increasing at alarming rates with more than half a million women being diagnosed every year. Although the disease is largely preventable when screened and diagnosed in earlier stages, the development of resistance and relapse had resulted in a poor prognosis. Therefore, a comprehensive approach needs to be put forward to understand and develop new preventive and therapeutic strategies to effectively combat cancer. Recently, much attention has been diverted to plant-derivatives for the treatment as they exhibit potent anti-cancer properties and side-effects caused by chemotherapeutic agents can also be prevented. Oleanolic acid and Esculetin are natural compounds known for their anti-cancer properties. Hence, the present study investigates the effect and mechanism of these compounds on cervical carcinoma, using HeLa cells. Posttreatment, it was observed that these compounds inhibited proliferation by both arresting the cells in the sub G1 phase and inducing senescence. Also, a marked reduction in the migration and cell survival was observed, as evidenced by results obtained from wound healing assay and Annexin V-FITC/PI staining. Furthermore, studies on the expression pattern of genes involved in major signaling pathways demonstrated a profound effect of these compounds. Taken together, the results of our study suggest that both Oleanolic acid and esculetin serve as a plausible therapeutic agent.

Boric acid as a promising agent in the treatment of ovarian cancer: Molecular mechanisms

The aim of this study is to determine the therapeutic effects of boric acid cell proliferation, invasion, migration, colony formation, cell cycle and apoptosis mechanisms in ovarian cancer cell line under in vitro conditions. MDAH-2774 ovarian cancer cells were employed. Real-time PCR test was used to investigate changes in genes and proteins of cell cycle and apoptosis and identified miRNAs under the addition of boric acid. The apoptosis rates were calculated by TUNEL assay. Matrigel invasion, colony formation and Wound healing tests were used to determine invasion and migration. Oxidative stress index value was calculated for oxidative stress. Boric acid inhibited cell proliferation, invasion, migration and colony formation, but induces apoptosis and oxidative stress. Also, the expression of miRNA-21, miRNA-200a, miRNA-130a and mi-RNA-224 (which are indicators of poor prognosis of ovarian cancer) decreased significantly. The potential of boric acid as a natural molecule may supports its effectiveness in reducing adverse effects arising from conventional ovarian cancer treatments.

Multi-omics analysis of the prognosis and therapeutic significance of circadian clock in ovarian cancer

Ovarian cancer (OV) is one of the most common female malignancies with high morbidity and mortality, but its mechanism is not fully understood. The circadian clock is involved in the regulation of the immune system and the tumor microenvironment, regulating biological processes and behaviors in multiple ways. Circadian rhythm disorders are considered a risk factor for tumorigenesis. Multi-omics analysis was performed to comprehensively illustrate the roles of circadian clock genes in OV, we found that most of circadian clock genes undergo epigenetic alterations in OV and are strongly correlated with overall and progression-free patient survival. These clock genes are mainly involved in the inhibition of Apoptosis pathway, Cell Cycle pathway and DNA Damage Response pathway, as well as the activation of RAS/MAPK pathway and RTK pathway. Drug sensitivity model indicate that the expression of core clock genes may associate with drug resistance. Further, immune infiltrates analysis shows that different mutant forms of core genes can not only suppress immune infiltration, but also affect clinical outcome of ovarian cancer patients. Overall, our results may provide novel insights for the potential selection of immunotherapeutic targets.

Identification of novel exonic variants contributing to hereditary breast and ovarian cancer in west Indian population

Breast and ovarian cancers are the most common cancer types in females worldwide and in India. Patients with these cancers require an early diagnosis which is essential for better prognosis, treatment and improved patient survival. Recently, the utilization of next-generation sequencing (NGS)-based screening has accelerated molecular diagnosis of various cancers. In the present study, we performed whole-exome sequencing (WES) of 30 patients who had a first or second-degree relative with breast or ovarian cancer and are tested negative for BRCA1/2 or other high and moderate-risk genes reported for HBOC. WES data from patients were analyzed and variants were called using bcftools. Functional annotation of variants and variant prioritization was performed by Exomiser. The clinical significance of variants was determined as per ACMG classification using Varsome tool. The functional analysis of genes was determined by STRING analysis and disease association was determined by open target tool. We found novel variants and gene candidates having significant association with HBOC conditions. The genes identified by exomiser (phenotype score > 0.75) are associated with various biological processes such as DNA integrity maintenance, transcription regulation, cell cycle regulation, and apoptosis. Our findings provide novel and prevalent gene variants associated with the HBOC condition in the West Indian population which could be further studied for early diagnosis and better prognosis of HBOC.

Association of a genetic variant in Interleukin-10 gene with increased risk and inflammation associated with cervical cancer

Cervical-cancer is among the most commonly diagnosed cancers in women, and infection with human papillomavirus (HPV) is associated with an increased risk of cervical cancer and altered serum concentrations of inflammatory cytokines. We have explored the association between a genetic variation in the Interleukin-10 (IL-10) gene (rs1800896) and cervical cancer risk and its relationship with tissue Interferon gamma (IFN-γ), Transforming growth factor beta (TGF-β), Tumor necrosis factor alpha (TNF-α) concentrations in women with cervical cancer. A total of 315 women with, or without cervical cancer, were recruited into the study. DNA was extracted from cervical cells, and genotyping was undertaken using Taq-man real-time PCR. The genotype frequency and allele distribution were analyzed together with their association with pathological data. The association of the rs1800896 gene variation with tissue levels of the inflammatory cytokines was also investigated. Our data showed a significant association between the A allele of the rs1800896 gene variant and the presence of cervical cancer. In particular, patients with AG/AA genotypes had an increased risk of cervical cancer with an odds ratio of 1.929 (95% confidence interval [CI]: 0.879-4.23, P < 0.001) in a recessive model, compared with the GG genotype. Also, the tissue concentrations of IFN-γ, TGF-β, and TNF-α in cervical tissues were significantly higher in women with cervical cancer (P < 0.001) and were associated with the AA genotype. We have found an association between the polymorphism rs1800896 in the IL-10 gene and an increased risk of cervical cancer as well as a higher level of tissue inflammatory cytokines. Further investigations are necessary on the value of emerging biomarkers for the risk stratification for the management of cervical cancer patients.

LncRNA GAS5 regulates apoptosis in ovarian cancer cells by regulating O-GlcNAcylation of GOLGA8B

Ovarian cancer therapy faces significant challenges, including late diagnosis, high recurrence rates, and chemoresistance. The long non-coding RNA GAS5 acts as a tumor suppressor and is downregulated in ovarian cancer, but the mechanism by which it regulates apoptosis remains unclear. This study aimed to reveal the molecular mechanism of GAS5-mediated apoptosis in ovarian cancer cells. We found that GAS5 expression was lower in ovarian cancer tissues and cell lines. Low GAS5 expression was related to worse prognosis. Functional experiments showed that increasing GAS5 expression promoted apoptosis in ovarian cancer cells. Mechanistically, increasing GAS5 raised the mRNA level of the Golgi protein-GOLGA8B. But it reduced the GOLGA8B protein level. Furthermore, GAS5 overexpression shortened the protein half-life and decreased the stability of GOLGA8B, suggesting the involvement of post-transcriptional regulation. Further investigation revealed that GAS5 inhibits O-GlcNAc transferase (OGT), thereby reducing O-GlcNAcylation of GOLGA8B.Ser58 was found to be the key modification site of GOLGA8B. Functionally, GOLGA8B was shown to activate the STAT3 signaling pathway.GAS5 inhibits STAT3 phosphorylation by downregulating GOLGA8B, thereby inducing cell apoptosis. In vivo animal experiments confirmed that GAS5 overexpression suppresses tumor growth. In summary, this study reveals that GAS5 regulates ovarian cancer cell apoptosis by modulating the O-GlcNAcylation of GOLGA8B, which in turn affects the STAT3 signaling pathway, providing a new potential therapeutic target for ovarian cancer.

Construction of circRNA-associated ceRNA network reveals the regulation of fibroblast proliferation in cervical cancer

Cervical cancer is one of the major cancers that threaten the health of women. CircRNA is an important factor in the regulation of cancer development and progression. The role of circRNA in cervical cancer is less well studied. The aim of this study was to explore the mechanism of circRNA effects on cervical cancer using circRNA-seq technology to study the expression profile data of 9 pairs of primary cervical cancer and paracancerous tissues. DESeq2 was used to analyse differentially expressed circRNA and mRNA in cervical cancer and paracancerous tissues. MiRanda and TargetScan are used to predict miRNAs that interact with circRNAs and mRNAs and to construct circRNA-miRNA-mRNA regulatory networks. KEGG and GO are used for functional annotation of differentially expressed genes. TIDE, TIMER2.0 was used to assess the status of the tumour immune microenvironment in cervical cancer. GEPIA2 was used to validate the results of differential expression analysis. We eventually obtained 22 differentially expressed circRNAs (7 up-regulated and 15 down-regulated) and 1834 differentially expressed genes (613 up-regulated and 1221 down-regulated). The results of the KEGG analysis showed that the differentially expressed genes were mainly enriched in cell cycle and cancer-related signalling pathways. The new circRNA: circZNF208 was identified to promote fibroblast proliferation by interfering with its downstream hsa-miR-324-3p regulating four downstream genes LPHN3. The level of fibroblast infiltration is implicated in the poor prognosis of cervical cancer. We have identified a novel circRNA: circZNF208 that can interfere with fibroblast proliferation in cervical cancer through a ceRNA regulatory network, thereby promoting fibroblast proliferation in cervical cancer and affecting the prognosis of cancer patients.

Gene expression profiling of HPV-associated cervical carcinogenesis in formalin-fixed paraffin-embedded (FFPE) tissues using the NanoString nCounterTM platform

Infection by high-risk human papillomavirus (HPV) causes genetic alterations in host cervical cells with consequent changes in gene expression affecting downstream molecular pathways, leading to the development of cervical cancer. In this exploratory study, we aimed to identify the perturbed cellular pathways during the various stages of cervical carcinogenesis. Total RNA was extracted from three formalin-fixed paraffin-embedded (FFPE) samples each of normal cervix, HPV-infected low-grade squamous intraepithelial lesion (LSIL), high-grade SIL (HSIL) and squamous cell carcinoma (SCC). Gene expression profiling was performed using the 770-gene panel from NanoString nCounter® PanCancer Pathways Panel to identify differentially expressed genes (DEGs) and significantly associated pathways in each stage of cervical cancer development. We identified 121 DEGs involved in cervical carcinogenesis. In the transformation from normal cells to LSIL, the MAPK, transcriptional misregulation and JAK-STAT pathways are implicated, while IL1B may promote inflammation and indirectly activates MMP9, resulting in collagen breakdown and cell migration. The cell cycle - apoptosis pathway with upregulation of E2F1 and MCM2, and DNA repair genes BRCA2-BRIP1 and FANCA are crucial during the progression from LSIL to HSIL. In the final stage of progression to SCC, the cell cycle and signaling pathways, as well as upregulation of c-MYC appear essential. In conclusion, archived FFPE-derived tissue samples are a valuable resource for gene expression profiling. The postulated dysregulated pathways and genes provide a guide of the molecular mechanisms that may be involved in the development of HPV-associated cervical cancer, for further investigation and validation studies.

Integrated case–control and in silico analysis of DNA double-strand break repair gene variants (RAD51, XRCC2, XRCC3, XRCC4, and LIG4) for ovarian cancer susceptibility

The contribution of low-penetrance DNA repair genes (DRGs) to ovarian cancer (OC) risk remains poorly understood. Variants in homologous recombination repair (HRR) and non-homologous end joining (NHEJ) pathway genes may influence genomic stability and modulate OC susceptibility. This population-based case-control study (474 subjects; 237 OC patients and 237 controls) evaluated polymorphisms in RAD51, XRCC2, XRCC3 (HRR), and XRCC4, LIG4 (NHEJ) to assess their role in OC predisposition. Genotyping was performed using PCR-RFLP, and logistic regression estimated risk associations. Multifactor Dimensionality Reduction (MDR) analysis examined SNP-SNP interactions, while in silico tools and electrostatic surface mapping predicted structural and functional effects. Significant associations were observed for RAD51 (rs1801320), where individuals with the mutant CC genotype showed a 2.8-fold higher OC risk (OR = 2.85; 95 % CI = 1.15-7.06; p = 0.049), and the CT genotype of LIG4 (rs1805388) conferred a 1.85-fold increased risk (OR = 1.85; 95 % CI = 1.11-3.07; p = 0.0097). Conversely, CT genotype carriers of XRCC3 (rs861539) exhibited reduced OC risk (OR = 0.49; 95 % CI = 0.32-0.75; p = 0.003). XRCC2 and XRCC4 showed no significant associations. However, XRCC2 variants correlated with tumor grade and menopausal status, and XRCC3 with tumor histology. MDR analysis revealed strong interactions between XRCC3 and RAD51, followed by combinations involving XRCC2, suggesting synergistic HRR gene effects. In silico predictions indicated XRCC2 R188H is destabilizing, XRCC3 T241M has mixed effects, and LIG4 T9I is stabilizing. Overall, RAD51 and LIG4 polymorphisms may contribute to OC susceptibility in South Indian women. Larger, multi-center studies are warranted to validate these findings and explore their potential as predictive biomarkers for OC.

Heritable Genetic Variability in Ovarian Tumours: Exploring Venous Thromboembolism Susceptibility and Cancer Prognosis in a Hospital-Based Study

Venous thromboembolism (VTE) is a frequently encountered paraneoplastic syndrome in patients with ovarian cancer (OC), an inflamm-aging entity. VTE is known to exacerbate their already poor prognosis, which is partially attributed to the contribution of the haemostatic system to ovarian tumourigenesis. In the past decade, numerous single-nucleotide polymorphisms (SNPs) implicated in VTE pathways have been proposed to influence tumour susceptibility and progression. These SNPs represent potential tools to improve the prognosis accuracy of OC patients. Hence, this study explored the influence of 12 haemostasis-associated SNPs on the risk for VTE, risk of OC progression and related death among 98 OC patients. The findings revealed a 20.5 % incidence of VTE, which was associated with more rapid disease progression and shorter survival times (log-rank test, p < 0.05). PROCR rs10747514 (AA/AG vs. GG; odds ratio (OR) = 3.67, p = 0.037) and SERPINE1 rs2070682 (CC/CT vs. TT; OR = 9.28, p = 0.040) were predictors of OC-related VTE development. Regarding patients' prognosis regardless of venous thrombogenesis, RGS7 rs2502448, F3 rs1361600, FGG rs2066865, and SERPINE1 rs2070682 were the most relevant biomarkers in different patient groups. These genetic variants might constitute attractive prognostic indicators among OC patients, offering insights to refine disease management strategies. However, due to the small cohort size and the study's retrospective nature, external validation is necessary to assess the generalisation of the findings.

Overcoming drug resistance in ovarian cancer through PI3K/AKT signaling inhibitors

Ovarian cancer has been identified as the eighth most typical gynaecological malignancy and cause of health problems in women. For almost forty years, platinum doublet chemotherapy has usually been the cornerstone of first-line treatment regimens. The effectiveness of conventional chemotherapy is severely hampered by relapse rates and mortality from chemotherapy resistance, which lead to the spread and recurrence of malignant cancers as well as poor outcomes in terms of quality of life in patients. Drug resistance has been linked to several mechanisms, including increased drug efflux, decreased apoptosis, increased autophagy, and changed drug metabolism. Further, the dysregulation of tumor suppressors or oncogenes plays a crucial role in chemoresistance. Additionally, PI3K/AKT/mTOR signaling has been implicated in several in vitro as well as clinical studies as a significant contributor to chemotherapy resistance in case of ovarian cancer. This review discusses the potential of various crude extracts, synthetic molecules, and nanoformulations for targeting PI3K/AKT/mTOR pathway. Moreover, a range of clinical studies involving PI3K/AKT/mTOR inhibitors have been summed up, addressing both the promises and complexities associated with their use. Overall, the review aims to provide a roadmap for future investigations that could lead to improved therapeutic outcomes for patients suffering from ovarian cancer, emphasizing the urgent need for continued exploration of novel pathways and strategies to combat drug resistance.

From diagnosis to therapy: The role of LncRNA GAS5 in combatting some cancers affecting women

Long non-coding RNAs (lncRNAs) are a collection of non-coding RNA molecules that consist of more than 200 nucleotides. In human malignancies, these lncRNAs exhibit abnormal expression patterns and play a significant role in either suppressing or promoting tumor growth. They achieve this by modulating various functions and mechanisms within cancer cells, including proliferation, invasion, metastasis, apoptosis, and resistance to different therapeutic approaches. The downregulation of long non-coding RNA growth arrest‑specific transcript 5 (GAS5) has been observed in multiple tumor types, indicating its role as a tumor suppressor in cancer. GAS5 exhibits interactions with various proteins, DNA, and microRNAs (miRNAs), leading to the upregulation of several mRNAs encoding suppressor proteins like PTEN. Consequently, this upregulation inhibits tumor growth. In this review, we have examined the existing literature concerning the expression of GAS5 and its diagnostic significance in female tissue-specific cancers, including breast, cervical, ovarian, and endometrial cancers. Additionally, we have explored its interactions with different miRNAs and its impact on cancer progression and resistance to therapy in these malignancies.

Cross-disease drug discovery based on bioinformatics and virtual screening: Study of key genes in Alzheimer’s disease and ovarian cancer

Alzheimer's disease (AD) and cancer, both age-related diseases, are characterized by abnormal cellular behavior. Epidemiological data indicate an inverse relationship between AD and various cancers. Accordingly, this study seeks to analyze the negatively correlated genes between AD and ovarian cancer and identify closely related compounds through virtual screening technology to explore potential therapeutic drugs. Microarray data were downloaded from the Gene Expression Omnibus database, and negatively correlated genes between AD and ovarian cancer were identified using bioinformatics analysis. Clinical prognostic and survival analyses were performed to identify genes most negatively associated with these diseases. The top ten compounds with the strongest binding to the target genes were screened from the ChemDiv database using virtual screening technology, considering the blood-brain barrier. Molecular dynamics simulations were used to identify potential sites for the binding of these compounds to the target protein MX1. Additionally, point mutation analysis of the target protein was performed. Finally, the binding site was verified in vitro. The MX1 gene was most significantly negatively associated with AD and ovarian cancer. Molecular dynamics simulations revealed intersection sites at Glu-227 and Gly-188, where MX1 binds tightly to the head compound. This study successfully identified MX1 as being negatively associated with AD and ovarian cancer and assessed the potential drug compounds that bind most closely to it. Our findings provide important rationale and candidate targets for the development of novel therapeutic strategies for AD and ovarian cancer.

FHOD3 shows clinical significance in progression of ovarian cancer through regulation of caspase-3 signaling pathway

Ovarian cancer is a malignant disease threatening women's life. Traditional therapies bring little benefits for the patients with distant metastasis or recurrence. FHOD3 gene was reported to promote progression in cancer. However, the role of FHOD3 in ovarian cancer is not known yet. To investigate the role of FHOD3 gene in the progression of ovarian cancer and its molecular mechanism, FHOD3 gene was successfully knocked down in ovarian cancer cell lines. Then cell behaviors includes proliferation, migration, invasion, and apoptosis were detected. The data demonstrated that cell proliferation, migration, and invasion ability were suppressed after FHOD3 knockdown. Cell apoptosis was induced reversely. Moreover, caspase-3-mediated signaling pathway was activated after FHOD3 knockdown, and activity of caspase-3 further supported this finding. In addition, PARP inhibitor, Olaparib showed much more potent inhibition in ovarian cancer cells with FHOD3 knockdown. In clinical ovarian cancer tissues, FHOD3 gene showed increased expression compared to adjacent normal tissues. And FHOD3 gene expression level was negatively correlated to the patients' survival. Overall, these findings shed light on the significance of FHOD3 gene in progression of ovarian cancer. This study showed that FHOD3 gene might be exploited as a new target to improve the clinical outcome of ovarian cancer.

MUL1 identified as mitochondria-linked biomarker promoting cisplatin resistance in OC cells

Ovarian cancer (OC) ranks among the prevalent tumors affecting the female reproductive system. The aim of this study was to evaluate mitochondria-associated platinum resistance genes using organoid models. Univariate Cox regression, LASSO and multivariate Cox regression analyses were performed on The Cancer Genome Atlas (TCGA) database to construct 2-gene prognostic signature (MUL1 and SSBP1), and GSE26712 dataset was used for external validation. In addition, the relationship between MUL1 and platinum resistance was examined by organoid culture, lentiviral transduction, CCK8 assay, and Western blot. The results showed that patients in the high-risk group exhibited significantly worse OS (P = 0.002, P = 0.017). Drug sensitivity analysis revealed that platinum resistance increased with the upregulation of MUL1 expression (Cor = 0.5154, P = 0.02). Our experimental findings demonstrated that knockout of the MUL1 gene significantly increased apoptosis and enhanced the sensitivity of the OC cell line A2780 to cisplatin. Through this study, we have provided strong evidence for further research on prognostic risk factors and individualized treatment in OC patients, and provided new insights into addressing platinum resistance in OC.

Profiling and bioinformatics analyses reveal differential circular RNA expression in ovarian cancer

Ovarian cancer (OC) is the deadliest form of gynecologic malignancy, with the majority of patients being diagnosed only once the disease reaches an advanced stage owing to a lack of available biomarkers capable of accurately detecting the disease. Stable circular RNAs (circRNAs) can be found at high levels in exosomes, and there is evidence to suggest that they may be viable diagnostic biomarkers for certain cancers. However, circRNAs in the serum of OC patients have rarely been evaluated to date. We therefore sought to investigate serum circRNA profiles of OC patients, and to explore whether these sorts of circRNAs could be used to detect early OC, serving as biomarkers of disease that may allow for the earlier treatment thereof. Second-generation sequencing was used to screen differentially expressed circRNAs in OC patient serum and also in the serum obtained from healthy controls, and circRNA expression was confirmed by qPCR. A bioinformatics-based approach was then used to assess what biological functions might be affected be the altered regulation of these RNA molecules. We further conducted GO, KEGG, and network analyses to further explore the expression of circRNAs. We detected 178 differentially expressed circRNAs in OC patient serum, of which 175 were up-regulated and 3 were down-regulated. We validated 5 of these identified circRNAs by qPCR to confirm their expression, and further found these RNAs to be closely linked with FC gamma R-mediated phagocytosis, VEGF signaling, Transcriptional misregulation in cancer, Chemokine signaling, ErbB signaling, and TNF signaling based on conducted analyses. This study provides a profile of circRNAs in OC patient serum, revealing a pattern of dysregulation of these RNAs associated with OC. Our bioinformatics analysis suggested that these circRNAs are likely related to OC development, and as such they may be viable novel OC biomarkers.

Synergistic effects of green tea extract and paclitaxel in the induction of mitochondrial apoptosis in ovarian cancer cell lines

Green tea is a natural compound with anti-neoplastic properties. Paclitaxel (PTX) is a natural anti-tumor medication used to manage patients with advanced ovarian cancer. This manuscript evaluated the cytotoxic effects of green tea extract combined with PTX drug in two human ovarian cancer cell lines (p53-negative cell line, SKOV-3; and mutant type p53 cell line, OVCAR-3) and underlying mechanisms. The human ovarian cancer cell lines were treated with green tea extract, PTX, and green tea plus PTX for 24 h, and cell viability was assessed using the MTT method. Flow cytometric analyses were carried out to detect apoptosis. For the apoptotic process, quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting analysis were applied to study pAkt, Bax, Bcl-2, Cytochrome C (Cyt-C), cleaved-caspase-3, and cleaved-caspase-9 levels after drug treatments. Our results pointed out that various green tea (25 and 50 µg/ml) concentrations combined with PTX (20 and 40 µg/ml) synergistically inhibited cell viability of cancer cells more than green tea or PTX alone after 24 h of treatment. Also, green tea and PTX combination induced apoptosis in ovarian cancer cells by blocking the phosphorylation of Akt and the expression of Bcl-2 while inducing Bax, Cyt-C, cleaved-caspase 3, and cleaved-caspase 9. Our results showed that the combination of green tea and PTX could be more potent than the individual drug to induce cytotoxicity and apoptosis in ovarian cancer cells.

Genetic variation in progesterone receptor gene and ovarian cancer risk: A case control study

Previous studies examined the association of genetic variation in progesterone receptor (PR) gene (PGR) with ovarian cancer, possibly by altering the expression of PR-B isoform, but with mixed outcome. This study evaluated the association of PGR variants with ovarian cancer and associated features. This was a retrospective case-control study, which involved 82 women with ovarian cancer and 95 cancer-free women who served as controls. Genotyping was done by Taqman® SNP genotyping by qRT-PCR. The PGR variants tested were rs471767 (A > G), rs590688 (G > C), and rs10895068 (G > A). Stratification analyses were used for testing the correlation between the PGR variants with ovarian cancer susceptibility according to menstruation status, FIGO classification, pathological grade, and chemotherapy. Significantly lower minor allele frequency (MAF) of rs10895068 was seen among ovarian cancer patients, thereby imparting disease protective nature to this variant. Significant association of rs10895068 genotypes with ovarian cancer was seen under the dominant model, but not other genetic models. FIGO classification correlated positively with rs471767 and rs10895068, while rs10895068 correlated positively with lymph node positivity. Three-locus haplotype analysis identified ACA and HCG haplotypes to be negatively associated with the risk of ovarian cancer. This report confirms the contribution of PGR variants, specifically the rs10895068 (+331G/A) the etiology of ovarian cancer.

Innovative minicircle DNA vector encoding pri-miR-375 silences E6 and E7 oncoproteins in HPV16-positive CaSki cells

The infection by Human Papillomaviruses (HPV) has long been established as one of the main causes of cervical cancer, with HPV16/HPV18 high-risk types expressing E6/E7 oncoproteins that inhibit p53/pRB tumor suppressor proteins. Therefore, this work focuses on gene therapy, using the innovative minicircle DNA (mcDNA) vector to protect and express the pri-miR-375 in the cancer cell nucleus, ultimately originating the microRNA-375 (miR-375) in the cytoplasm. This miR-375, initially downregulated in cervical cancer cells, can silence HPV E6/E7 transcripts, thereby negatively regulating the expression of these oncoproteins. The mcDNA-pri-miR-375 vector was successfully constructed, biosynthesized in the host cell, extracted, and purified, followed by several in vitro transfection studies in CaSKi cells (HPV16-infected cervical cancer model) to evaluate the mcDNA-pri-miR-375 effect. FITC-stained-mcDNA-pri-miR-375 was present in cancer cell nucleus, confirmed by confocal microscopy. RT-PCR analysis showed a more intense band of miR-375 transcripts, and RT-PCR/ RT-qPCR confirmed that E6/ E7 transcript levels were nearly 80 % diminished 24 h after CaSki cells transfection. Also, western-blot showed a decreased band intensity for E6/ E7 proteins on transfected cells. Proliferation and cell invasion studies demonstrated growth and migration arrest for CaSki cells throughout 72 h. Cell viability study of these cells also revealed a gradual decrease for the same period, while the NHDF cell viability was not affected, indicating specificity towards CaSki. The consequent effect of silencing the E6/ E7 transcripts was also observed through an increase in p53 protein levels (determined by western blot and ELISA) and caspase-3 activity, after 48 h of CaSki cell transfection. These results suggest that mcDNA-pri-miR-375 vector has the potential to be further explored in gene therapy for the treatment of HPV-caused cervical cancer.

Suppressor of cytokine signaling 6 (SOCS6) mediates ubiquitination degradation of SLC7A11 to drive ferroptosis and block lipid metabolism in ovarian cancer cells

Ovarian cancer (OVCA) is a highly malignant gynecological tumor characterized by a dismal 5-year survival rate that is closely linked to aberrant ferroptosis regulation and lipid metabolic reprogramming. This study integrated bioinformatics analyses of TCGA and The Human Protein Atlas datasets, clinical validation in 30 pairs of OVCA tissues, in vitro functional assays using HO8910 and HEYT30 cell lines, and nude mouse xenograft models to explore the role of suppressor of cytokine signaling 6 (SOCS6) in OVCA prognosis. The results revealed that SOCS6 was significantly downregulated in OVCA tissues and cell lines, and low expression was strongly correlated with poor patient prognosis. Mechanistically, SOCS6 overexpression inhibited cellular proliferation, migration, and invasion and enhanced sensitivity to the ferroptosis inducer erastin. This effect occurs by promoting the ubiquitin-proteasomal degradation of the ferroptosis antagonist SLC7A11, reducing intracellular glutathione (GSH) levels, and augmenting reactive oxygen species (ROS) and Fe

Elevated expression of ECT2 as a diagnostic marker and prognostic indicator in endometrial cancer

The study aims to investigate genes associated with endometrial cancer (EC) progression to identify new biomarkers for early detection. Differentially expressed genes (DEGs), Series test of cluster (STC) and protein-protein interaction analyses identified hub genes in EC. Clinical samples were utilized to examine the expression pattern of ECT2, assess its prognostic value, and evaluate its diagnostic potential. Upregulated DEGs were significantly enriched in cancer-related processes and pathways. Validations across databases identified ASPM, ATAD2, BUB1B, ECT2, KIF14, NUF2, NCAPG, and SPAG5 as potential hub genes, with ECT2 exhibiting the highest diagnostic efficacy. The expression levels of ECT2 varied significantly across different clinical stages, pathological grades, and metastasis statuses in UCEC. Furthermore, ECT2 mRNA was upregulated in the p53abn group, indicating a poorer prognosis, and downregulated in the MMRd and NSMP groups, suggesting a moderate prognosis. In clinical samples, ECT2 expression increased from normal endometria and endometrial hyperplasia without atypia (EH) to atypical endometrial hyperplasia (AH) and EC, effectively distinguishing between benign and malignant endometria. High ECT2 expression was associated with an unfavourable prognosis. ECT2 expression significantly rises in AH and EC, showing high accuracy in distinguishing between benign and malignant endometria. ECT2 emerges as a promising biomarker for diagnosing endometrial neoplasia and as a prognostic indicator in EC.

SOGA1 drives ovarian cancer progression via regulation of GNAI1 and activation of the TNF/NF-κB pathway

Ovarian cancer (OC) poses a significant public health challenge due to its dismal prognosis and low survival rates. However, the mechanism of OC development remains unclear. Transcriptomic data from the Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases underwent analysis to identify hub programmed cell death (PCD) genes in OC samples compared to normal controls, utilizing weighted gene co-expression network analysis (WGCNA) and Machine learning models. Then, conduct pan-cancer analysis and nomogram on the hub gene Suppressor Of Glucose, Autophagy Associated 1 (SOGA1). The expression levels of the SOGA1 gene were assessed in clinical samples through Reverse Transcription-Quantitative Real-time Polymerase Chain Reaction (RT-qPCR) experiments. Subsequently, Western Blot (WB), Cell Counting Kit-8 (CCK8), Terminal Deoxynucleotidyl Transferase-Mediated dUTP Nick End Labeling (Tunel) wound healing tests, transwell, RNA sequencing, and subcutaneous tumorigenesis in C57BL/6 mice were conducted to investigate the correlation between SOGA1 and OC cell proliferation, invasion, migration, and other functions, as well as the underlying mechanisms. Through integrated bioinformatics analyses, SOGA1 emerged as a hub gene of PCD in OC. Overexpression of SOGA1 correlated with poor prognosis across multiple cancers, including OC, and served as an independent prognostic factor. The developed nomogram, incorporating SOGA1 expression, accurately predicted overall survival (OS) in OC patients. SOGA1 was significantly upregulated in OC tissues, and high expression of SOGA1 was significantly correlated with lymph node metastasis. Both in vitro and in vivo, modulation of SOGA1 expression led to changes in OC cell proliferation, and SOGA1 promoted OC cell invasion, migration and inhibit apoptosis and inhibit apopapoptosis in vitro. Mechanistically, we found that SOGA1 regulates the Guanine Nucleotide-Binding Protein G (I) Subunit Alpha-1 (GNAI1) protein and facilitates TNF-alpha / NFκB signaling. This study has confirmed that SOGA1 can regulate the progression of the disease by influencing the TNF signaling pathway according to regulate GNAI1 expression.

Deubiquitinating enzymes in endometrial cancer and cervical cancer

Endometrial cancer (EC) is one of the three most common malignancies of the female reproductive system, with its global incidence and disease-related mortality continuing to rise. Cervical cancer (CC), also known as uterine cervical cancer, refers to cancer occurring in the cervix. Despite the development of various therapeutic strategies, patient prognosis and survival rates remain poor due to high rates of metastasis and recurrence. Ubiquitination denotes the process by which ubiquitin is covalently attached to target proteins, while deubiquitinases (DUBs) catalyze the reverse process. Accumulating evidence indicates that dysregulation of deubiquitination plays significant roles in the pathogenesis and progression of both EC and CC. This review systematically summarizes recent research advances in DUBs, outlining their intrinsic characteristics, classification, catalytic mechanisms, and modes of activity regulation. Furthermore, it explores the potential mechanisms by which DUB dysregulation contributes to endometrial and cervical carcinogenesis. Additionally, we present the successful application of DUB inhibitors in the treatment of malignancies and provide an analysis of the current research status regarding targeted therapies for EC and CC.

Analysing the relevance of TGF-β and its regulators in cervical cancer to identify therapeutic and diagnostic markers

The role of transforming growth factor-beta (TGF-β) is dual, such that, it inhibits tumor development in initial stage and promotes metastasis in later stage. The present study is aimed to analyse the relevance of different types of TGF-β and their receptors on the overall survival (OS) and TGF-β driven gene expression in individuals with cervical cancer (CC) using ONCODB and GEPIA databases. The in-silico gene expression analysis showed, TGF-β1 and TGFβR2 are upregulated in cells infected with human papilloma virus (HPV)16, whereas, TGF-β2, TGFβR1 and TGFβR3 expression were downregulated. In HPV 18 infected cells, TGF-β1, TGF-β2 and TGFβR1 were downregulated, meanwhile, TGF-β3, TGFβR2 and TGFβR3 were upregulated. OS analysis of CC patients with different TGF-β expression revealed that, TGF-β1, TGF-β2, TGF-β3 and TGFβR2 were associated with reduced survival rate. Further, we identified four microRNAs (miRNAs) (hsa-miR-21-5p, hsa-miR-29b-3p, hsa-miR-101-3p and hsa-miR-130a-3p) interacted favorably with TGF-β in HPV 16 and 18 positive samples using MIENTURNET. This present review further emphasizes that, targeting TGF-β could be a novel and futuristic approach for CC management and therapeutics.

MCM10: A potential biomarker for cervical cancer and precancerous lesions

Cervical cancer remains a significant health burden worldwide, emphasizing the need for early detection and intervention. DNA replication is perturbed in cancer cells, and the minichromosome maintenance protein 10 plays an important role in origin firing. By analyzing the MCM10 mRNA expression in healthy controls, precancerous lesions, and cervical cancer using qRT-PCR, we can infer if it can be considered a biomarker. We collected cervical smear samples from patients and performed MCM10 expression analysis to set up thresholds for risk stratification. We also investigated the HPV status among the patient samples with precancerous lesions and cervical cancer and found 70 % of them to be positive. Our results demonstrated a significant upregulation of MCM10 mRNA expression in tumor samples (n = 40, 7.83 ± 1.2) and precancerous lesions (n = 54, 5.69 ± 1.4) compared to normal (n = 50, 4.27 ± 0.80) with a R

Inhibit ALDH3A2 reduce ovarian cancer cells survival via elevating ferroptosis sensitivity

Ovarian cancer (OC) is a malignant gynecologic tumor with high morbidity and mortality. As a newly discovered mode of programmed cell death, ferroptosis has been involved in various pathological processes of kinds of tumors in recent years. Aldehyde dehydrogenase 3 family member A2 (ALDH3A2) catalyzes the oxidation of long-chain aliphatic aldehydes to fatty acid. ALDH3A2 has been shown to be associated with ferroptosis in acute myeloid leukemia (AML), but the mechanism remains unclear. In this study, we analyzed the TCGA and GTEx databases and showed that high ALDH3A2 expression predicted poor prognosis in ovarian cancer. Further studies found that knockout or overexpression of ALDH3A2 correspondingly increased or attenuated the ferroptosis sensitivity of ovarian cancer cells. And sequencing revealed that ALDH3A2 knockout led to the activation of lipid metabolic, GSH metabolic, phospholipid metabolic, and aldehyde metabolic pathways, suggesting that ALDH3A2 induced changes in the sensitivity of ovarian cancer cells to ferroptosis by affecting these metabolic processes. Our results provide a new promising therapeutic strategy for the treatment of OC.

Identification of immunity- and ferroptosis-related genes for predicting the prognosis of serous ovarian cancer

Serous ovarian cancer (SOC) is the most common type of ovarian cancer (OC), with bad outcomes. To improve the prognosis of SOC patients, a novel risk signature was developed by combining immunity- and ferroptosis-related genes. By means of comparing SOC tissues with normal tissues, we screened the differential expression of immunity-related genes (DE-IRGs) and ferroptosis-related genes(DE-FRGs) with the standards of |log A risk signature constructed by totally four immunity- and ferroptosis-related DEGs (CXCL11, CX3CR1, FH, and DNAJB6) was developed, which distinguished the SOC patients as high-risk and low-risk groups. Patients in the high-risk group showed a lower overall survival (OS) than those in the low-risk group. Furthermore, the risk score was independent when analyzed with clinical augments, which was significantly associated with 13 KEGG signaling pathways. The gene signature showed favorable predictive performance according to Receiver operating characteristic (ROC) curves. Notably, the expression of immune-related markers or IPS indicated a negative connection with the risk score. SOC patients had a lower score of TIDE and T cell dysfunction than Whom had a higher score. Nonetheless, there were no significant differences in T cell exclusion scores between the two groups.Compared with normal ovarian cell line IOSE-80,QRT-PCR experiments exhibited that CXCL11, CX3CR1and FH were up-regulated in ovarian tumor cells lines(SK-OV-3,COC1,A2780),while DNAJB6 was down-regulated. Four-biomarker signature formed by immunity- and ferroptosis-related genes may be clinically used as risk stratifcation tool in serous ovarian cancer,which can help further clinical decision-making regarding prognostic prediction,individualized treatment and follow-up scheduling.

Overexpression of circular RNA hsa_circ_0001038 promotes cervical cancer cell progression by acting as a ceRNA for miR-337-3p to regulate cyclin-M3 and metastasis-associated in colon cancer 1 expression

Cervical cancer (CC) is a common cancer threatens women's health worldwide. Circular RNAs (circRNAs) is critically involved in carcinogenesis of various cancers. This work aimed to explore the expression pattern, functions and mechanisms of hsa_circ_0001038 in CC. RT-qPCR was performed to evaluate the levels of hsa_circ_0001038 in CC cell lines and tissues. Kaplan-Meier curves was applied to evaluate the overall survival rate of CC patients with high or low expression of hsa_circ_0001038. Fisher's exact test was analyzed to explore the relationship of hsa_circ_0001038 expression and CC patients' clinical features. Loss/Gain-of function assays were used to evaluate the role of hsa_circ_0001038 on the growth, apoptosis, migration and invasion of CC cell lines. The competing endogenous RNA (ceRNA) mechanism was predicted by bioinformatics databases and verified by dual-luciferase reporter assay. We found that hsa_circ_0001038 was highly expressed in CC cells and tissues and elevated hsa_circ_0001038 was closely related to the clinical severity including lymph node invasion and myometrial invasion. In addition, overexpressed hsa_circ_0001038 correlated with unfavorable outcome in CC patients. Knockdown of hsa_circ_0001038 attenuated cell growth, migration, and invasion but induced cell apoptosis. Ectopic expression of hsa_circ_0001038 increased cell oncogenic properties. For mechanism investigation, hsa_circ_0001038 could sponge miR-337-3p to release its suppression on cyclin-M3 (CNNM3) and metastasis-associated in colon cancer 1 (MACC1), thereby promoting CC cell growth and invasive potential, respectively. In conclusion, hsa_circ_0001038 plays an oncogenic role in CC cells partly by activating CNNM3 and MACC1.

Effect of alpha lipoic acid on epithelial mesenchymal transition in SKOV-3 cells

Ovarian cancer is the fifth leading cause of cancer-related death in women. Patients are usually diagnosed with advanced tumor metastass. Epithelial over cancer cells spread from primary tumor by undergoing epithelial mesenchymal transition (EMT). It has been suggested that alpha lipoic acid (ALA), a natural antioxidant lipophilic compound, reduces the oxidative stress by causing apoptosis and inhibition of proliferation of cell in cancer cells. The aim of our study was to establish a transforming growth factor β1 (TGF β1) dependent epithelial mesenchymal transition model in the SKOV-3 ovarian adenocarcinoma cell line which is an epithelial subtype of ovarian cancer and to investigate the effects of alpha lipoic acid on EMT and ovarian cancer migration. For establish an EMT model, SKOV-3 cells were treated with different dose of TGF β1 and XTT cell viability kit was used to find IC 50 dose of ALA. Four different groups that are control, TGF β1, ALA and ALA + TGF β1 were created. Changes in the expression of genes related to EMT markers that are E-cadherin, vimentin, Snail, Slug, Twist and Zeb were analyzed with quantitative real-time PCR. These proteins were determined with the immunocytochemistry method. The migration capacity was analyzed with wound healing assay. Matrigel invasion capacity test was used to show invasion and colonization test to show colonization. The dose of TGF β1 was determined 100 ng/ml at 72 h, the IC50 dose of ALA 219.033 µM at 48 h was determined. EMT markers in the TGF β1 group were compatible with EMT and it was shown to inhibit EMT in the groups given ALA. According to wound healing, colonization and invasion experiments, proliferation and invasion increased in TGF β1 group, but decreased in ALA and combined groups (p < 0.05). These results indicate that ALA suppresses the metastasis of ovarian cancer cells by regulating EMT, implying that ALA might be a potential therapeutic agent for the treatment of ovarian cancer.

Molecular Crosstalk by miR-449a and miR-34b in endometrial and ovarian cancer cells in vitro

Endometrial and ovarian cancers, the sixth and eighth most prevalent cancers in women globally, account for nearly 8% of all new female cancer cases annually. MicroRNAs (miRNAs) have emerged as a promising field in cancer treatment, offering new avenues for targeted therapies and diagnostic tools. Recent miRNA-based cancer research has uncovered various miRNAs commonly dysregulated in cancer and which possess tumor-suppressive functions. These miRNAs influence genes crucial for cellular differentiation, proliferation, apoptosis, and metabolism. In the present study, the researchers investigated the effect of dysregulation of two such miRNAs, miR-449a and miR-34b, on the oncogenes involved in the progression of endometrial and ovarian cancer using the respective RL95-2 and SKOV3 cell lines. The transcriptional gene expression analysis was done by Real-Time Quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR). It was found that the overexpression of miR-449a and miR-34b downregulated HIF-1α, VEGF, c-Myc, COX-2, and TNF-α while upregulating TP53 in both cancer types. Conversely, inhibiting these miRNAs increased the levels of HIF-1α, VEGF, c-Myc, COX-2, and TNF-α, and decreased TP53. However, co-transfection with both mimic and inhibitor had varying effects. The study demonstrated that these miRNAs could influence critical processes such as angiogenesis, proliferation, inflammation, tumorigenesis, and apoptosis in cancer cells, highlighting their potential as therapeutic targets. However, the varied effects observed with the co-transfection of mimics and inhibitors suggest a complex interplay that requires further investigation.

Altered cervicovaginal microbiota in premenopausal ovarian cancer patients

Nearly three hundred thousand female patients are diagnosed with ovarian cancer in the world annually, and this number shows an increasing trend. However, characteristic symptoms caused by ovarian cancer are so few that early diagnosis remains challenging, and an effective screening method has not yet been established. Here, we conducted a case-control study in Japan to analyze the association between cervicovaginal microbiome and ovarian cancer, using 16S rRNA amplicon sequencing. Analysis of DNA extracted from cervical smear samples revealed Lactobacillus-dominant and Lactobacillus-deficient, highly-diversified bacterial communities in premenopausal and postmenopausal healthy controls, respectively, as reported for vaginal microbiota previously. We found that cervicovaginal microbiota in ovarian cancer patients, regardless of their menopausal status, were frequently a diversified community and similar to those in healthy subjects at postmenopausal ages. The diverse microbiota was associated with the major histotypes of epithelial ovarian cancer, including serous ovarian cancer and ovarian clear cell cancer. The present study implies the potential of a cervicovaginal microbiome biomarker in screening ovarian cancer in premenopausal women.

Clinical and prognostic significance of FBXL6 expression in ovarian cancer

Growing evidence indicates that F-box and leucine-rich repeat protein 6 (FBXL6) is associated with the progression of various cancers, including gastric cancer, hepatocellular carcinoma, and colorectal cancer. This study focuses on the prognostic significance of FBXL6 in OC. Differential levels of FBXL6 in multiple cancers were evaluated using the TCGA and GSE26712 databases. We screened FBXL6-related differentially expressed genes using the GSE63885 dataset and conducted Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways analysis. The genes that associate with FBXL6 were screened using the "limma" package, the STRING database, and Cytoscape software, and the association was validated through Gene Expression Profiling Interactive Analysis. The potential substrates of FBXL6 were predicted using UbiBrowser2.0 database. FBXL6 protein levels in 84 OC samples were evaluated using immunohistochemistry. The prognostic significance of FBXL6 was explored using Kaplan-Meier and Cox regression analyses. Based on the Cox regression results, an FBXL6-based nomogram that can predict the overall survival (OS) rate were constructed. Moreover, we examined the net benefits and discriminative ability of the nomogram using the decision curve analysis (DCA), calibration plots, and receiver operating characteristic (ROC) curve. FBXL6 was elevated in OC tissues, and the overexpression of FBXL6 was linked to poor prognosis in OC patients. The ROC and DCA curves indicated that the prognostic value of the FBXL6-based nomogram model was superior to that of FBXL6, age, and FIGO stage alone. Elevated FBXL6 expression was an independent factor for OC, and an easily applied nomogram was developed to predict OS in OC patients.

WNT6 participates in the occurrence and development of ovarian cancer by upregulating/activating the typical Wnt pathway and Notch1 signaling pathway

Wnt/β-catenin pathway is associated with the progression of various cancers such as gastric cancer, colorectal cancer, and endometrial cancer. Using the Kaplan-Meier Plotter database, we found that WNT6 was associated with progression-free survival (PFS) outcomes. Immunohistochemical analysis of ovarian cancer samples and normal ovaries showed that the expression of WNT6 protein was significantly increased in ovarian cancer samples. Further, we explored the possible role of WNT6 in the occurrence and development of ovarian cancer. Our results showed that the mRNA and protein expression of WNT6 were significantly higher in CAOV3 and OVCAR3 cells compared with other ovarian cancer cell lines and normal ovarian cell line IOSE-80 as well. The transformation of CAOV3 and OVCAR3 cells with short interfering WNT6 (siWNT6) significantly inhibited their proliferation and lamellipodia formation, causing cell cycle arrest and promoting cell apoptosis. Western blot experiments confirmed that the down-regulation of WNT6 inhibited the expression of β-catenin and Notch1. These results suggest that WNT6 plays an important role in the occurrence and development of ovarian cancer.

Silibinin exerts anti-cancer activity on human ovarian cancer cells by increasing apoptosis and inhibiting epithelial-mesenchymal transition (EMT)

Silibinin, the principal flavonoid derived from milk thistle seeds, has been demonstrated to have strong inhibitory effects against human malignancies. The inhibitory function of silibinin on ovarian cancer, however, is not fully identified. In this essay, both in vivo and in vitro investigations were conducted to survey the silibinin's blocking effects on ovarian cancer. The impacts of silibinin on two ovarian cancer cell lines, SKOV-3 and A2870, were determined by evaluating cell viability, migration, invasion, and apoptosis. Q-RT-PCR and western blotting techniques were carried out to explore the protein levels of signaling pathway markers. A mouse xenograft model was utilized to determine the silibinin efficacy in inhibiting tumor growth. After cell treatment with silibinin, cell viability, migration, and invasion were appreciably inhibited in cancer cell lines, but cell apoptosis was promoted. Also, silibinin reversed the epithelial-mesenchymal transition (EMT) mechanism by inducing E-cadherin expression and reducing N-cadherin and vimentin expression, suppressing the levels of regulators related to EMT such as Snail, Slug, and ZEB1 transcription factors, and also decreasing PI3K/AKT, Smad2/3, and β-catenin intermediate molecules in vitro. Silibinin effectively ameliorated tumor growth in vivo. silibinin could be considered a potent agent against ovarian cancer based on the results.

Inherited rare and common variants in PTCH1 and PTCH2 contributing to the predisposition to reproductive cancers

PTCH1 and PTCH2 are associated with nevoid basal cell carcinoma syndrome and basal cell carcinoma. We determined the prevalence of their common and rare variants in 877 patients with various reproductive cancers and 296 healthy subjects. Using targeted next-generation sequencing, we found significantly statistical associations of the minor alleles at seven common variants of PTCH1 and PTCH2 with a decreased risk of reproductive cancers (P = 9.69 × 10

Rucaparib antagonize multidrug resistance in cervical cancer cells through blocking the function of ABC transporters

Upregulation of the ATP-binding cassette (ABC) transporter is one of the most important factors leading to multidrug resistance (MDR) in several types of cancer. In the present study, we investigated the ability of rucaparib, a Poly (ADP-ribose) polymerase (PARP) inhibitor which is currently in clinical development, on overcoming ABC transporters-mediated MDR in cervical cancer cell lines. Rucaparib significantly enhanced the cytotoxic effects of a series of conventional chemotherapeutic drugs in drug resistance cervical cancer cell lines. Moreover, rucaparib significantly increased the accumulation of rhodamine 123 in doxorubicin- and paclitaxel-resistance cervical cancer cell lines. In addition, rucaparib significantly increased the accumulation of tritium-labeled chemotherapeutic drugs in drug resistance cervical cancer cells, and decrease the efflux of tritium-labeled chemotherapeutic drugs. Molecular docking study indicated that rucaparib could bind to the active site of the ABC transporters. The present study indicated that rucaparib could antagonize MDR in cervical cancer cells by blocking the function of ABC transporters. The results obtained in the present study provide the potential possibilities that the combination of rucaparib with other chemotherapeutic agents may benefit patients with cervical cancer.

miR-214 down-regulates MKK3 and suppresses malignant phenotypes of cervical cancer cells

miRNA mediated genetic regulation is widely involved in carcinogenesis of cervical cancer. In this study, miR-214 was confirmed to directly regulate MKK3 via imperfect base-pairing to its 3'UTR, resulting down-regulation of its expression level. Compared to normal tissues, a down-regulated level of miR-214 was observed in cervical cancer, while MKK3 was up-regulated. Next, we demonstrated that over-expression of miR-214 or knockdown of MKK3 can inhibit the growth, proliferation, invasion and migration of cervical cancer in vitro and in vivo. Moreover, the effects of miR-214 in HeLa cells were rescued by the restoration of MKK3. In conclusion, our results laid new foundations for investigating the pathogenesis and diagnosis of cervical cancer.

Period circadian regulator 2 suppresses drug resistance to cisplatin by PI3K/AKT pathway and improves chronochemotherapeutic efficacy in cervical cancer

Chronotherapy, a promising therapy, may build up the chemotherapy efficacy through thinking about timing of therapy. Here, we observed the roles of period circadian regulator 2 (PER2) on cervical cancer progression and the therapeutic efficacy of cisplatin (DDP) based on the circadian rhythm of PER2. When Hela/DDP and SiHa/DDP transfected with pcDNA3.1-PER2 and/or treated with human epidermal growth factor (hEGF), viability, apoptosis, migration, and nuclear translocation of NF-κB p65 were detected by CCK-8, flow cytometry, transwell, immunofluorescence and western blot. Furthermore, the expression of circadian rhythm regulators, multidrug resistance, and epithelial-mesenchymal transition (EMT) proteins was detected by western blot. Hela/DDP cells-induced tumor formation in nude mice was constructed. The expression of PER2 was measured at different time point by RT-qPCR. Cisplatin was separately injected into mice with cervical cancer at the highest and lowest expression of PER2. After 5 weeks, tumor volume was measured and tumor proliferation was assessed by immunohistochemistry. Overexpression of PER2 significantly reduced proliferative and migrated capacities and nuclear translocation of NF-κB p65 as well as enhanced apoptosis in Hela/DDP and SiHa/DDP cells. Meanwhile, its overexpression elevated the expression of circadian rhythm regulators as well as lowered the expression of multidrug resistance proteins and EMT pathway activation by suppressing PI3K/AKT pathway. PER2 was rhythmically expressed in cervical cancer tissues. Compared to cisplatin treatment at the lowest expression of PER2, tumor growth and proliferation of tumor cells were distinctly suppressed in mice treated with cisplatin at the highest expression of PER2. Our findings confirmed the circadian rhythm of PER2 in cervical cancer and its overexpression restrained the resistance to cisplatin in cervical cancer by PI3K/AKT pathway. It may improve cisplatin efficacy through considering the circadian rhythm of PER2.

Exosomal miR-4516 derived from ovarian cancer stem cells enhanced cisplatin tolerance in ovarian cancer by inhibiting GAS7

Ovarian cancer (OC) is a devastating disease for women, with chemotherapy resistance taking the lead. Cisplatin has been the first-line therapy for OC for a long time. However, the resistance of OC to cisplatin is an important impediment to its efficacy. Mounting studies showed that ovarian cancer stem cells (OCSCs) affected chemotherapy resistance by secreting exosomes. MicroRNAs (miRNAs) play important roles in exosomes secreted by OCSCs. Here, through the analysis of GEO database (GSE107155) combined with RT-qPCR of OC-related cells/clinical tissues, it was found that hsa-miR-4516 (miR-4516) was significantly up-regulated in OCSCs. Then, OCSCs-derived exosomes were isolated and identified, and it was observed the influence of exosomes on the chemoresistance in SKOV3/cisplatin (SKOV3/DDP) cells. These results manifested that OCSCs-mediated exosomes facilitated the chemoresistance of SKOV3/DDP cells by delivering miR-4516 into them. Growth arrest-specific 7 (GAS7), a downstream target of miR-4516, was determined by bioinformatics prediction combined with molecular biological detection. Next, we up-regulated GAS7 expression and discovered that the promotion of chemoresistance in SKOV3/DDP cells by OCSCs-derived exosomes was significantly impaired. Finally, the mice tumor model of SKOV3/DDP cells was built to estimate the effect of GAS7 over-expression on OC growth. The results showed that GAS7 inhibited the chemoresistance of OC in vivo. In conclusion, our experiments suggested that OCSCs-derived exosomes enhanced OC cisplatin resistance by suppressing GAS7 through the delivery of miR-4516. This study provides a possible target for the treatment of OC DDP resistance.

Role of ERβ in the ovary and ovary related diseases

Estrogen and estrogen receptors (ERα and ERβ) regulate a multitude of complicated physiological and pathological processes. Jan-Ake Gustafsson's group discovered ERβ in 1996, this crucial finding gives us new insights into the understanding of estrogen signaling. ERβ is highly expressed in the ovary and particularly exists in granulosa cells (GCs). ERβ is a key transcription factor in the maintenance of ovarian granulosa cell growth, differentiation, and homeostasis, and the ovulation function of ovarian follicles and oocytes. Additionally, ERβ can modulate the steroidogenic transcriptional program through phosphorylation and regulate both gonadotropin response and FOXL2 expression within the ovary. In this review, we focus on the role of ERβ in regulating ovarian granulosa cell development and homeostasis, particularly its significance in ovarian cancer (OC), premature ovarian failure (POF), and polycystic ovary syndrome (PCOS). It also highlights the prospects of small molecule compounds targeting ERβ, providing a new strategy for the treatment of ovarian-related diseases.

OCIAD2 promotes pancreatic cancer progression through the AKT signaling pathway

Targeting TSPAN1 promotes ferroptosis in endometrial cancer cells, reduces energy metabolism and inhibits malignant behavior

This research endeavored to explore the significance of tetraspanin 1 (TSPAN1) in endometrial cancer, with a particular focus on its influence on ferroptosis and glycolytic activity. To achieve this, we established cell models that either overexpressed or silenced TSPAN1. We employed the CCK8 assay and EdU to assess the impact of TSPAN1 on cell proliferation. Additionally, scratch and Transwell assays were conducted to evaluate the cells' malignant biological behavior. The expression of ferroptosis-associated marker proteins was monitored. Further studies were conducted to investigate the effects of TSPAN1 on mitochondrial function, energy metabolism, and the cytoskeleton, and elucidated the interaction between TSPAN1 and SLC44A4. Our findings indicated that the downregulation of TSPAN1 markedly suppressed cell proliferation and the incidence of malignant biological behaviors. Moreover, the suppression of TSPAN1 was found to enhance ferroptosis and to reduce glycolytic activity. This study provides a comprehensive analysis of TSPAN1's role in endometrial cancer, shedding light on its potential as a key regulator of ferroptosis and glycolysis.

The role of BMI1 in endometrial cancer and other cancers

Endometrial cancer (EC) is the third leading gynecological malignancy, and its treatment remains challenging. B cell-specific Moloney murine leukemia virus integration site-1 (BMI1) is one of the core members of the polycomb group (PcG) family, which plays a promoting role in the occurrence and development of various tumors. Notably, BMI1 has been found to be frequently upregulated in endometrial cancer (EC) and promote the occurrence of EC through promoting epithelial-mesenchymal transition (EMT) and AKT/PI3K pathways. This review summarizes the structure and upstream regulatory mechanisms of BMI1 and its role in EC. In addition, we focused on the role of BMI1 in chemoradiotherapy resistance and summarized the current drugs that target BMI1.

Investigation of circular RNA transcriptome in obesity-related endometrial cancer

The present study has investigated the circular RNA (circRNA) transcriptome of twenty obese and postmenopausal women, recruited in Australia, with endometrial cancer (EC). This paper expands on previous findings which evaluated the circRNA transcriptome of a similar cohort of six women recruited in the United States of America. EC is the most common gynaecological malignancy and the fifth most common cancer in women worldwide with obesity as one of its major risk factors. CircRNAs, a class of non-coding RNAs, are involved in many human diseases including cancer. As such the objective of this study was to investigate the circRNA transcriptome of these twenty women and identify circRNAs of interest. We obtained paired samples (EC and adjacent normal tissue) from the cohort of twenty women. Samples were subjected to ribosomal RNA depletion and sequencing performed using Illumina sequencing technology. CircRNAs were identified through CIRI2 and CIRCexplorer2 and common circRNAs extracted for differential expression with edgeR which met the criteria of counts per million > 0.1 and expressed in ≥ 10. We found that the overall abundance of circRNAs was lower in EC compared to adjacent non-cancerous endometrial tissue. We also identified hotspot genes, genes expressing over 10 distinct circRNA isoforms. There were 82 hotspot genes in normal tissue and 23 hotspot genes in EC. There were 174 significantly differentially expressed circRNAs, of which 172 were down-regulated and 2 were up-regulated in EC. The circRNAs identified from this study may act as diagnostic or prognostic biomarkers for EC in obese women. While the circRNA transcriptome of obesity-related EC has been investigated further work is required to determine their functional significance.

Molecular characterization of the unusual peptide CORO1C-47aa encoded by the circular RNA and docking simulations with its binding partner

Circular RNAs, which have covalently closed ends, are in the class of non-coding RNAs. Recent studies reveal that they are associated with various biochemical pathways. One such involvement of circular RNAs is in the onset of different types of cancers. Though the circular RNAs are known as non-coding RNAs, some of them are found to possess the capacities to code for proteins. One such circular RNA is hsa-circ-0000437 which is known to code for a short peptide referred to as CORO1C-47aa. The peptide has anti-angiogenic activity and is associated with the prevention of endometrial cancer. The peptide binds to the PAS-B domain of the Aryl hydrocarbon Receptor Nuclear Translocator (ARNT). However, till date only the amino acid sequence of the peptide is known and no structural details of the peptide are available. Therefore, in this work, our aim was to predict how the peptide would fold and what could be its possible ligand binding sites. We used computational tools to determine the structure of the peptide refined further by molecular dynamics simulations. We then performed molecular docking simulations of the peptide with its known binding partner ARNT to gain an insight into the modes of binding as the process is associated with endometrial cancer. The possible ligand binding sites along-with the natures of the possible other different ligands of the peptide were analyzed further. From this structure function analysis study, we tried to elucidate the plausible mechanism of the involvements of the peptide in the onset of endometrial cancer. This is the first report on the structural characterization of the peptide and its modes of interactions with the partner protein ARNT. This study may therefore be useful in determining the structures of new drug candidates for the treatment of endometrial cancer.

Analysis of m6A methylation patterns and tumor microenvironment in endometrial cancer

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