Frontiers in Bioscience-Landmark

Molecular Subtypes of Ovarian Cancer Based on Lipid Metabolism and Glycolysis Reveals Potential Therapeutic Targets

Background: Ovarian cancer (OC) is one of the most lethal gynecological malignant neoplasms. The aim of this study was to use high-throughput sequencing data to investigate the molecular and clinical characteristics of OC subtypes related to lipid metabolism and glycolysis, thus providing a theoretical basis for clinical decision-making. Methods: Molecular data and clinicopathological characteristics of OC patients were extracted from the Cancer Genome Atlas (TCGA), Genotype-Tissue Expression Project (GTEx), and the Gene Expression Omnibus (GEO). Following analysis of genes involved in lipid metabolism and glycolysis, OC was classified into subtypes by unsupervised clustering. The molecular features and clinical outcomes of these subtypes were then evaluated. Results: OC patients were divided into five subtypes based on the analysis of nine genes of interest. Amongst these, patients in subtype D had longer overall survival and more benign clinical features. Subtypes B and E had shorter overall- and progression-free survival, respectively. Both the B and E subtypes were closely related to lipid metabolism and to the glycolytic process. Subtype D was positively correlated with the infiltration of CD8+ T cells, CD4+ T cells, and macrophages, all of which play essential anti-tumor roles. Several risk models for selected subtypes were also constructed based on the expression of select genes. Conclusions: The present work revealed that irregular metabolism in OC tissues was an indicator of poor clinical outcome and altered homeostasis in cancer-related pathways. Moreover, aberrant gene expression signatures associated with lipid metabolism and glycolysis were also correlated with an immunosuppressive tumor microenvironment. Based on lipid metabolism and glycolysis, we have therefore identified several OC molecular subtypes that may prove useful for the development of potential therapeutic targets.

PGAM1 Promotes Glycolytic Metabolism and Paclitaxel Resistance via Pyruvic Acid Production in Ovarian Cancer Cells

Background: Enhanced glycolysis occurs in most human cancer cells and is related to chemoresistance. However, detailed mechanisms remain vague. Methods: Using proteinomics analysis, we found that the glycolytic enzyme Phosphoglycerate mutase 1 (PGAM1) was highly expressed in the paclitaxel-resistant ovarian cancer cell line SKOV3-TR30, as compared to its parental cell line SKOV3. Cell Counting Kit-8 proliferation experiment, plasmids and siRNA transfection, pyruvic acid and lactic acid production detection, immunofluorescence staining of functional mitochondria and oxygen consumption rate and extracellular acidification rate measurement were uesd to assess the glycolytic metabolism and paclitaxel resistance in ovarian cancer cells. The expression and prognostic effect of PGAM1 in 180 ovarian cancer patients were analyzed. Results: SKOV3-TR30 cells display higher glycolytic flux and lower mitochondrial function than SKOV3 cells. Down-regulation of PGAM1 in SKOV3-TR30 cells resulted in decreased paclitaxel resistance. Up-regulation of PGAM1 in SKOV3 cells led to enhanced paclitaxel resistance. Analysis of the glycolytic flux revealed that PGAM1-mediated pyruvic acid or lactic acid production could modulate the capabilities of ovarian cancer cell resistance to paclitaxel. Our data also show high expression of PGAM1 as significantly correlated with reduced overall survival and reduced progression free survival in ovarian cancer patients. Conclusions: PGAM1 acts to promote paclitaxel resistance via pyruvic acid and/or lactate production in ovarian cancer cells. Inhibiting PGAM1 may provide a new approach to favorably alter paclitaxel resistance in ovarian cancer.

Therapeutic Potential of CLDN Family Proteins in Ovarian Cancer: Emerging Biomarkers and Targets

Background: Claudins (CLDNs), key components of tight junctions, are dysregulated in various cancers. However, the roles and therapeutic potential of specific CLDN family members-particularly CLDN6, CLDN9, and CLDN10-in ovarian cancer (OC) remain incompletely defined. To address this gap, we conducted a comprehensive analysis of the CLDN family to identify novel diagnostic and prognostic biomarkers as well as potential therapeutic targets for OC. Methods: Gene expression profiles and corresponding clinical data from The Cancer Genome Atlas ovarian cancer cohort (TCGA-OV) and two Gene Expression Omnibus (GEO) datasets (GSE18520, GSE26712) were analyzed. Differential expression of CLDN genes between OC and normal tissues was evaluated using R with appropriate bioinformatics packages (e.g., limma). Logistic regression models were employed to calculate odds ratios (ORs), and receiver operating characteristic (ROC) curves were generated across all datasets to identify consistently dysregulated CLDNs associated with OC. Prognostic hazard ratios (HRs) for these CLDNs were extracted from the Kaplan-Meier Plotter (KM Plotter) database and synthesized using a random-effects model to assess their associations with overall survival. Intersection analysis was performed to identify CLDNs exhibiting both significant differential expression and prognostic significance. Candidate targets underwent comprehensive validation, including single-cell RNA sequencing (scRNA-seq) to characterize cell-type-specific expression patterns. Notably, Key findings regarding CLDN6 were further validated by immunohistochemistry (IHC) on an independent tissue microarray (TMA), as well as functional assays in OC cell lines following siRNA-mediated knockdown. These included transwell invasion, wound healing (scratch) test, and measurements of mitochondrial depolarization, reactive oxygen species (ROS) accumulation, cell cycle arrest, and apoptosis. Results: CLDN6, CLDN9, and CLDN10 were consistently and significantly upregulated in OC compared to normal tissues across all datasets. Single-cell RNA sequencing revealed that CLDN6 and CLDN10 were predominantly expressed in malignant epithelial cell subsets, a pattern associated with aggressive tumor phenotypes. Meta-analysis of HRs showed that HR >1 in CLDN6 and HR <1 in CLDN10. Although CLDN10 is highly expressed in tumor cells, its hazard ratio (HR) is less than 1, and the underlying mechanism of this gene remains unclear. Experiments have confirmed that CLDN6 is closely associated with tumor invasion. Computational analysis, meta-analysis, and single-cell data collectively confirm that only CLDN6 is a clearly defined gene closely associated with tumor progression, a finding subsequently validated by experimental results. Notably, the combined signature comprising CLDN6, CLDN9, and CLDN10 exhibited superior diagnostic performance, with higher area under the curve (AUC) values in ROC analysis, compared to individual CLDNs or established OC biomarkers such as carbohydrate antigen 125 (CA125), human epididymis 4 (HE4), carcinoembryonic antigen (CEA), and alpha-fetoprotein (AFP). The signature also showed enhanced prognostic discrimination, as indicated by time-dependent ROC analysis. Protein overexpression of these targets was validated by IHC and Western blot. Functional assays further demonstrated that siRNA-mediated knockdown of CLDN6 significantly inhibited the proliferation of OC cells, promoted cell apoptosis, increased production of ROS, induced G1 phase arrest, inhibited cell invasion and migration in vitro. Furthermore, western blot analysis identified that knockdown of CLDN6 repressed the Wnt/β-catenin pathway. Nude mice experiments indicated that CLDN6 knockdown in OC cells dramatically suppresses the tumor growth and lung metastasis in vivo. Conclusions: CLDN6, CLDN9, and CLDN10 are critically involved in the pathogenesis and progression of OC. A biomarker panel combining these three claudins demonstrates superior diagnostic and prognostic performance compared to individual markers and established clinical biomarkers such as CA125 and HE4. Notably, functional evidence indicates that CLDN6 plays a pivotal role in regulating malignant phenotypes, highlighting its potential as a novel therapeutic target. These findings collectively support the clinical utility of the CLDN6/9/10 axis as both a non-invasive biomarker signature and a promising avenue for targeted intervention in ovarian cancer.

Reviewing the Developing Significance of the Serine Protease PRSS23

The serine protease 23 (PRSS23) is a highly conserved member of trypsin-like serine proteases, which are associated with numerous essential processes, including digestion, blood coagulation, fibrinolysis, development, fertilization, apoptosis, and immunity. Original reports on PRSS23 unfolded not earlier than 2006 when a molecular biology study characterized and described PRSS23 as an ovarian protease. Then, in 2012, another important study was published linking PRSS23 with proliferation of breast cancer cells by an estrogen receptor 1 (ESR1)-dependent transcriptional activation of the serine protease. Thereafter, a developmental study in zebrafish reported the implication of PRSS23 in endothelial-to-mesenchymal transition (EndMT) during cardiac valve formation. Although these early studies on PRSS23 have revealed its involvement in some critical or fundamental processes, only in recent years an increasing number of studies have evolved describing the expression and functions of PRSS23 in various normal physiological conditions, diseases, and experimental configurations. Besides breast cancer, PRSS23 has been shown to be involved in different types of malignancies, e.g., in gastric cancer, where drug screening found that the protease inhibitor tipranavir impedes cancer-promoting PRSS23 expression. New innovative techniques such as single cell RNA-sequencing (scRNA-seq) and bioinformatics studies accelerated the discovery of gene expression changes in smaller cell populations, which, e.g., led to the identification of marked PRSS23 expression in a myofibroblast-like subpopulation in localized scleroderma. This review compiles major and significant research results that have contributed to our current knowledge of PRSS23 and briefly discusses where prospective studies could add to our understanding of this versatile serine protease.

Iron Fist in a Velvet Glove: Class IV Ferroptosis Inducers as a Novel Strategy to Target Ovarian Cancer

Epithelial ovarian cancer (EOC) is a highly lethal gynecological malignancy characterized by frequent late-stage diagnosis, high rates of chemoresistance, and poor long-term survival. Emerging evidence underscores the central role of iron metabolism dysregulation in EOC pathogenesis, progression, and treatment resistance. Ovarian cancer cells and cancer stem cells exhibit an “iron-addicted” phenotype, characterized by increased iron uptake, reduced export, and enhanced storage, which sustains proliferative signaling, redox imbalance, and metastatic potential. Recent advances have illuminated ferroptosis, a regulated form of iron-dependent cell death driven by lipid peroxidation, as a promising therapeutic target for overcoming resistance to platinum-based chemotherapy. This review provides a comprehensive synthesis of the mechanisms governing iron metabolism and ferroptosis in EOC, with a particular focus on Class IV ferroptosis inducers (FINs). These agents act by disrupting iron homeostasis and promoting labile iron pool accumulation, thereby triggering oxidative stress and ferroptotic death. Preclinical studies demonstrate that Class IV FINs, including iron nitroprusside, superparamagnetic iron oxide nanoparticles, ferric ammonium citrate, and Ferlixit, exhibit potent antitumor activity in EOC models, particularly in chemoresistant and stem-like tumor subpopulations. Furthermore, Class IV FINs show synergistic effects when combined with other ferroptosis modulators or immunotherapeutic agents. Despite their promise, clinical translation remains limited by challenges in bioavailability, delivery specificity, and potential systemic toxicity. Ongoing efforts in nanotechnology, biomarker discovery, and tumor stratification offer new avenues for refining ferroptosis-based interventions. Ultimately, this review highlights Class IV FINs as a mechanistically distinct and clinically actionable strategy to target metabolic vulnerabilities in EOC, with the potential to reshape therapeutic paradigms and improve patient outcomes.

Splicing Factor PTBP1 Silencing Induces Apoptosis of Human Cervical Cancer Cells via PI3K/AKT Pathway and Autophagy

Background: Cervical cancer is the most common gynecological malignancy in the world and seriously threatens to women’s lives and health. Polypyrimidine tract binding protein 1 (PTBP1), as an important splicing factor, has been identified as a proto-oncogene in several cancers, but its role and mechanism in cervical cancer remain poorly understood. Thus, our aim is to explore the impact of PTBP1 on proliferation, migration, apoptosis of cervical cancer cells, and its underlying mechanisms. Methods: The biological functions in cervical cancer cells were determined using small interfering RNA (siRNA), agonist, Cell Counting Kit-8 (CCK-8), transwell, migration test, western blot, real-time-PCR, immunohistochemistry and immunofluorescence, respectively. Results: The results indicated that PTBP1 was highly expressed in cervical cancer patients and cervical cancer cell lines compared to the normal group. Moreover, PTBP1 silencing significantly inhibited cell proliferation, and migration in both HeLa and SiHa cells. The PTBP1 silencing also induced mitochondrial apoptosis through upregulating Bax and mitochondrial apoptotic protein Cytochrome C, and downregulating B-Cell Leukemia/Lymphoma 2 (Bcl2) protein. Additionally, PTBP1 silencing induced autophagy by downregulating Sequestosome I (p62) and upregulating the ratio of Light chain 3-Ⅱ/Light chain 3-Ⅰ (LC3-Ⅱ/LC3-Ⅰ). Mechanistically, we found that the Phosphoinositide 3-kinase (PI3K) agonist reversed the changes induced by PTBP1 silencing. Conclusions: Overall, PTBP1 silencing can induce cervical cancer cells apoptosis mainly through PI3K/AKT pathway and protective autophagy. This study provides preliminary evidence for PTBP1 as a therapeutic target or prognostic marker for cervical cancer.

SPC25 Functions as a Prognostic-Related Biomarker, and Its High Expression Correlates with Tumor Immune Infiltration and UCEC Progression

Background: Most tumor tissues expressed spindle pole body component 25 (SPC25), one of the four subunits of the NDC80 complex, at greater levels compared to surrounding normal tissues. According to earlier researches, this subunit strongly encouraged tumor cell proliferation and tumor growth, which resulted in worse prognoses in patients with hepatocellular, breast, lung, and prostate cancer. Precisely because SPC25’s role in uterine corpus endometrial carcinoma (UCEC) is understudied, we chose to concentrate on UCEC for gaining a more scientific and thorough understanding of SPC25. Methods: Along with examining SPC25’s differential expression, prognostic significance, and biological function in UCEC, our research sought to clarify the underlying mechanism by which SPC25 influences the course of UCEC and patient prognosis from the viewpoints of methylation and immune infiltration. Results: We observed differential expression of SPC25 gene in different clinicopathological features of UCEC and identified SPC25 as a hazard factor for poorer overall survival (OS), disease-specific survival (DSS), and progress free interval (PFI) in UCEC, particularly in its multiple clinical subtypes. In addition, we also discovered that SPC25 and its co-expressed genes mostly engaged in biological processes and signal transduction routes linked to cell cycle and cell division in UCEC. After investigating SPC25’s methylation status, we discovered that patients with UCEC had elevated SPC25 expression and a poor prognosis due to hypomethylation of CpG sites in the SPC25 gene sequence. Finally, we investigated SPC25’s potential role in immunotherapy and discovered that SPC25 might alter the major immune cell infiltration levels in the tumor microenvironment (TME) by regulating the expression of immunoregulatory molecules and chemokines, which would be beneficial for SPC25 to control the progression of UCEC. Conclusions: In conclusion, SPC25 was a useful predictive biomarker as well as a possible therapeutic target for UCEC.

Integrative Analysis of Glycine, Serine, and Threonine Metabolism and the Immune Microenvironment in Endometrial Cancer: A Prognostic Model and Metabolic-Immune Framework for Precision Oncology

Background: Metabolic reprogramming is a hallmark of the pathogenesis and progression of endometrial carcinoma (EC). This study comprehensively analyzed the expression profiles of glycine, serine, and threonine (Gly/Ser/Thr) metabolism–related genes in EC. We also established a robust prognostic model and developed a molecular subtyping framework that integrates metabolic and immune characteristics based on the identified prognostic genes. The aims of this work are to enhance diagnostic precision and improve clinical management strategies for patients with EC. Methods: Untargeted metabolomic analysis was performed on 35 EC and 15 normal tissues. The Cancer Genome Atlas (TCGA) transcriptomic data were integrated with weighted gene co-expression network analysis (WGCNA) to identify EC-related metabolic genes and construct a prognostic model using Cox proportional hazards and least absolute shrinkage and selection operator (LASSO) regression analyses. The model was validated using an independent proteomic and single-cell dataset from our institution. Consensus clustering classified patients into three molecular subtypes, which were further characterized by gene set variation analysis (GSVA) and profiling of immune infiltration. Finally, key prognostic genes were validated by reverse transcription quantitative polymerase chain reaction (RT-qPCR) in EC and normal endometrial epithelial cells. Results: Metabolomic analysis revealed significant enrichment of the Gly/Ser/Thr metabolic pathways. WGCNA identified a tumor-associated metabolic module among 1741 pathway-related genes. A prognostic model comprising methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), ribosomal protein S6 kinase A1 (RPS6KA1), and cyclin-dependent kinase inhibitor 2A (CDKN2A) was subsequently established. Consensus clustering based on risk scores stratified EC patients into three molecular subtypes: immunometabolic-suppressed (C1), proliferative-immunobalanced (C2), and immune-activated (C3). The C1 subtype had the poorest prognosis and was characterized by metabolic suppression and immune evasion. The C2 subtype showed a favorable prognosis and was defined by a “proliferation–immune balance” in which high proliferative activity coexisted with strong anti-tumor immunity. The C3 subtype was also associated with a favorable outcome, driven by upregulated DNA repair and oxidative phosphorylation pathways alongside infiltration of immune-active cells. RT-qPCR confirmed significant differences in the mRNA expression of MTHFD2, RPS6KA1, and CDKN2A between normal and EC cells (p < 0.05). Conclusion: This study developed a Gly/Ser/Thr pathway–based prognostic model for EC, based on the expression of MTHFD2, RPS6KA1, and CDKN2A as novel biomarkers. The resulting patient stratification framework holds significant clinical potential for guiding precise and personalized management of EC.

A Primer on the Role of TP53 Mutation and Targeted Therapy in Endometrial Cancer

Endometrial Cancer (EC) is one of the most common gynecological malignancies, ranking first in developed countries and regions. The occurrence and development of EC is closely associated with genetic mutations. TP53 mutation, in particular, can lead to the dysfunction of numerous regulatory factors and alteration of the tumor microenvironment (TME). The changes in the TME subsequently promote the development of tumors and assist in immune escape by tumor cells, making it more challenging to treat EC and resulting in a poor prognosis. Therefore, it is important to understand the effects of TP53 mutation in EC and to conduct further research in relation to the targeting of TP53 mutations. This article reviews current research progress on the role of TP53 mutations in regulating the TME and in the mechanism of EC tumorigenesis, as well as progress on drugs that target TP53 mutations.

Long Non-Coding RNA RAB11B-AS1 Suppresses Cervical Cancer Progression by Upregulating RPL26 Expression

Background: Cervical cancer (CC) is one of the most prevalent gynecological malignancies. The expression and functional role of the long non-coding RNA (lncRNA) Ras-related protein Rab-11B antisense RNA 1 (RAB11B-AS1) in CC remain poorly understood. Methods: The expression profile of lncRNA RAB11B-AS1 across multiple cancer types was initially assessed using data from The Cancer Genome Atlas. Its expression in CC tissues and lesions of varying pathological grades was subsequently validated via RNA in situ hybridization. To investigate its functional role in CC, a combination of transcriptomic, proteomic, and functional assays was employed to delineate the molecular role of RAB11B-AS1. The effects of alterations in RAB11B-AS1 expression on cervical cancer growth were ultimately validated in vivo. Results: LncRNA RAB11B-AS1 was downregulated in CC and associated with a favorable patient prognosis. Functionally, RAB11B-AS1 promoted apoptosis while suppressing proliferation, migration, and invasion of CC cells in vitro, and inhibited tumor growth in vivo. Mechanistically, RAB11B-AS1 upregulated ribosomal protein L26 (RPL26) expression. Notably, RAB11B-AS1 suppressed cervical cancer progression by activating the p53 pathway via RPL26. Critically, in vitro and in vivo experiments confirmed that RPL26 knockdown abrogates the tumor-suppressive functions of RAB11B-AS1, establishing RPL26 as a pivotal downstream effector of RAB11B-AS1 in CC. Conclusions: Our findings demonstrate that lncRNA RAB11B-AS1 suppresses cervical cancer progression primarily through upregulation of RPL26 and suggest that RAB11B-AS1 may serve as a potential biomarker and therapeutic target in cervical cancer.

Excavation of Molecular Subtypes of Cervical Cancer Based on DNA Methylation Patterns

Background: Cervical cancer remains a major cause of cancer-related death among women worldwide. Despite advances in treatment, prognosis remains poor for many patients due to tumor heterogeneity. DNA methylation, an epigenetic modification, is known to influence tumor development, but its role in defining molecular subtypes and prognostic stratification in cervical cancer remains inadequately understood. Methods: We analyzed DNA methylation profiles from 287 cervical cancer samples obtained from the UCSC Xena database. Univariate and multivariate Cox regression analyses were applied to identify prognostic CpG sites, as these models allow evaluation of individual and combined effects of methylation sites on patient survival. Consensus clustering was performed to define robust molecular subtypes based on methylation patterns, providing insights into tumor heterogeneity. Differentially methylated regions were identified using the Quantitative Differentially Methylated Regions (QDMR) software, an entropy-based tool validated for detecting subtype-specific methylation markers. A Bayesian classifier was constructed and validated in training and test cohorts to evaluate the predictive accuracy of these markers for subtype classification. Additionally, immune cell infiltration was estimated using computational algorithms to assess tumor microenvironment differences, and chemosensitivity was predicted to explore potential clinical implications of the methylation subtypes. Results: Four distinct methylation-based subtypes differed in methylation patterns, histological types, clinical stages, and metastatic status. A total of 501 subtype-specific methylation sites were identified. The Bayesian classifier demonstrated strong predictive performance, with an area under the receiver operating characteristic (ROC) curve (AUC) of 0.824 based on 10-fold cross-validation, indicating high classification accuracy and robustness. The immune microenvironment composition varied markedly among subtypes. Notably, Cluster 1 had elevated infiltration of central memory CD8+ and effector memory CD4+ T cells, whereas Cluster 4 exhibited reduced immune activation and the lowest immune checkpoint expression. These findings indicate subtype-specific differences in potential responsiveness to immunotherapy. Conclusions: These DNA methylation-driven subtypes highlight the heterogeneity of cervical cancer and offer new insights for personalized therapy.

The Display between HPV Infection and Host Immunity in Cervical Cancer

Most cervical cancers are related to the persistent infections of high-risk Human Papillomavirus (HPV) infections. Increasing evidence has witnessed the immunosuppressive effectiveness of HPV in the oncogenesis steps and progression steps. Here we review the immune response in HPV-related cervical malignancies and discuss the crosstalk between HPVs and the host immune response. Furthermore, we describe the identification and development of current immunotherapies in cervical cancer. Above all, we hope to provide a novel insight of the display between HPV infections and the host immune system.

CENPA Promotes Endometrial Cancer Progression by Stabilizing YY1 and Enhancing Glycolytic Metabolism

Background: Centromere protein A (CENPA) is a histone H3 variant essential for centromere function and has been implicated in tumorigenesis in several cancers. However, its clinical significance and biological role in endometrial cancer (EC) remain poorly characterized. This study aimed to elucidate the oncogenic function and underlying mechanisms of CENPA in EC progression. Methods: CENPA expression and its correlation with patient survival were analyzed using clinical datasets and tissue samples. Gain- and loss-of-function assays were performed to evaluate the effects of CENPA on EC cell proliferation, migration, and invasion. Metabolic assays, protein interaction studies, and in vivo xenograft models were utilized to investigate the molecular mechanisms driving CENPA-mediated tumorigenesis. Results: CENPA was significantly upregulated in EC tissues compared to normal endometrium, and high expression correlated with poor overall survival. Functionally, CENPA overexpression promoted, while its silencing suppressed, EC cell growth and metastasis. Mechanistically, CENPA facilitated metabolic reprogramming by enhancing aerobic glycolysis. We identified Yin Yang 1 (YY1) as a direct binding partner of CENPA. CENPA stabilized YY1 protein levels by inhibiting its proteasomal degradation. Importantly, YY1 knockdown rescued the glycolytic and tumorigenic phenotypes induced by CENPA both in vitro and in vivo. Conclusions: Our findings establish CENPA as a critical oncogenic driver in EC that functions by stabilizing YY1 to promote metabolic reprogramming. The CENPA-YY1 axis may represent a potential therapeutic target for EC.

Role of SLC5A8 as a Tumor Suppressor in Cervical Cancer

Background: The SLC5A8 gene is silenced in various types of cancer, including cervical cancer; we recently demonstrated that the SLC5A8 gene is also silenced in cervical cancer by hypermethylation of the CpG island in the gene promoter. This study aims to analyze whether SLC5A8 could be a tumor suppressor in cervical cancer. Methods: After ectopic expressing SLC5A8 in the HeLa cell line, we evaluated its effects on cell behavior both in vitro and in vivo by Confocal immunofluorescence, cell proliferation, migration assays, and xenograft transplants. Results: Overexpression of SLC5A8 in the HeLa cell line decreased its proliferation by arresting cancer cells in the G1 phase and inhibiting cellular migration. Furthermore, we observed that pyruvate increased the SLC5A8 effect, inducing S-phase arrest and inhibiting the entry into mitosis. SLC5A8 decreased tumor growth in xenograft transplants, significantly reducing the volume and tumor weight at 35 days of analysis. Conclusions: In summary, our results indicate that SLC5A8 has a role as a tumor suppressor in cervical cancer.

Anoikis Patterns in Cervical Cancer: Identification of Subgroups and Construction of a Novel Risk Model for Predicting Prognosis and Immune Response

Background: Cervical cancer has high morbidity and intratumor heterogeneity. Anoikis, a form of programmed cell death preventing detached cancer cells from readhering, may serve as a potential prognostic signature for cervical cancer. This study aimed to assess the predictive performance of anoikis patterns in cervical cancer prognosis. Methods: Differentially expressed anoikis-related genes (DEARGs) were identified between normal and cancer samples using data from the Gene Expression Omnibus database with the elucidation of mutation status and bio-function. Novel anoikis molecular subtypes were defined in The Cancer Genome Atlas (TCGA) cohort with consensus clustering analysis. A multigene prognostic signature was constructed through least absolute shrinkage and selection operator (LASSO) Cox analysis with internal and external validation. The nomogram-based survival probability of cervical cancer over 3 and 5 years was predicted and assessed with calibration, receiver operating characteristic, decision curve analysis, and Kaplan-Meier curves. Additionally, mutation, function, and immune analysis were conducted among different risk groups. Results: We identified 77 DEARGs between normal and cervical cancer tissues and explored their mutation status and functions. The TCGA cohort could be categorized into two subtypes based on these genes. Furthermore, seven prognostic signature genes were constructed, and the nomogram involving DEARGs and clinicopathological characteristics showed satisfactory predictive performance. Functional analysis indicated that immune-related genes were enriched, and immune status, as well as sensitivity of chemotherapies and targeting drugs, were correlated with the risk model. Conclusions: Anoikis patterns play important roles in tumor immunity and can be used to predict the prognosis of cervical cancers.

Advances in Etiopathological Role and Control of HPV in Cervical Cancer Oncogenesis

The human papillomavirus (HPV) is a well-known oncovirus whose causal link in the occurrence and development of several cancers, such as cervical cancer (CC), has been well established. Indeed, numerous researches depicted the etiological role of HPV in CC pathogenesis in such a way as to develop efficient strategies, including early diagnoses and HPV vaccination, to mitigate HPV infection and CC occurrence. Despite the effectiveness of these strategies in preventing HPV infection, its persistence, and the progression to precancerous lesions and cancers, extensive work that could give a better understanding of other unknown factors favoring oncogenesis is much more needed. In this last decade, scarce or few but crucial and strategic studies have been carried out to improve and deepen our understanding of the etiopathological role of HPV in the progression towards the development of CC. In this review, we highlighted the recent findings on the pathological role of HPV in CC occurrence and the advances in novel adopted strategies to reduce HPV infection and prevent CC occurrence more effectively.

ARID1A-mutated cervical cancer depends on the activation of YAP signaling

Background: Cervical cancer is a prevalent female malignancy with poor survival rates. ARID1A is frequently mutated or deleted in a variety of tumors and YAP signaling is widely activated in human malignancies. Nevertheless, the mechanism of YAP signaling in ARID1A-mutated cervical cancer remains unknown. Methods: The cell viability was determined by MTT assay. The expression of ARID1A, YAP1 and CTGF were evaluated by western blot. The cell proliferation was detected by colony formation. Results: The bioinformatics analysis suggested that mutation of ARID1A was associated with the activation of YAP1 signaling. In addition, knockdown of YAP1 inhibited ARID1A-mutated cervical cancer cells growth. Verteporfin is an inhibition of YAP1 signaling. Interestingly, knockdown of ARID1A decreased ARID1A-wildtype cervical cancer cells resistance to verteporfin. Meanwhile, overexpression of ARID1A increased ARID1A-mutated cervical cancer cells resistance to verteporfin. Similarly, blocking YAP1 signaling inhibited the tumor formation caused by ARID1A-mutated cervical cancer cells in vivo. Conclusion: Inhibition of YAP1 signaling suppresses ARID1A-mutated-induced tumorigenesis of cervical cancer, providing a novel therapeutic strategy for cervical cancer.

RIPK4 Promotes Cell Invasion and the Epithelial–Mesenchymal Transition in Ovarian Cancer

Objective: To investigate the clinical role and biological function of receptor-interacting protein kinase 4 (RIPK4) in ovarian cancer (OC). Methods: We conducted a comprehensive analysis of the expression and prognostic role of RIPK4 in OC using various public databases including The Cancer Genome Atlas, Oncomine, and Kaplan–Meier plotter. In vitro studies included wound healing, cell migration and invasion, cell proliferation, and cell apoptosis assays as well as vascular mimicry experiments. In vivo studies were conducted using subcutaneous and intraperitoneal xenografts. Results: Our findings revealed that RIPK4 was significantly overexpressed in OC tissue compared to normal ovarian tissue. Moreover, the overexpression of RIPK4 was associated with advanced-stage disease and a poor prognosis in OC patients. RIPK4 silencing resulted in significant inhibition of intraperitoneal tumor growth, invasion, and vascular mimicry in OC cells. Furthermore, downregulation of RIPK4 inhibited the epithelial–mesenchymal transition of OC cells both in vitro and in vivo by promoting the expression of E-cadherin and inhibiting the expression of N-cadherin. Conclusion: The results of this study suggest that RIPK4 may function as an oncogene in the development and prognosis of OC.

ARHGAP10, Transcriptionally Regulated by Sodium Butyrate, Promotes Ferroptosis of Ovarian Cancer Cells

Background: Ovarian cancer is a highly lethal gynecologic malignancy. ARHGAP10, a member of Rho GTPase-activating proteins, is a potential tumor suppressor in ovarian cancer. However, its role and the involved mechanism need further examination. Here, we investigated whether ARHGAP10 is also associated with ferroptosis. Methods: Lentivirus infection was used for gene overexpression or silencing. Real-time polymerase chain reaction (RT-PCR) and Western blot were used to assess mRNA and protein levels, respectively. Cell viability was assessed by Cell Counting Kit-8 (CCK-8) assay. Lipid reactive oxygen species level was measured by flow cytometry. A tumorigenicity assay was performed to evaluate tumor growth in vivo, and sections of mouse tumor tissues were examined by immunofluorescence microscopy. Chromatin Immunoprecipitation (ChIP) assay was used to assess the binding of H3K9ac to the promoter region of ARHGAP10. Results: ARHGAP10 overexpression promoted ferroptosis in ovarian cancer cells, resulting in decreased cell viability, and increased lipid reactive oxygen species (ROS) level. Further, it decreased and increased GPX4 and PTGS2 expression, respectively, and also induced suppression of tumor growth in mice. Fer-1, a potent inhibitor of ferroptosis, suppressed the above effects of ARHGAP10. Contrarily, ARHGAP10 silencing alleviated ferroptosis in ovarian cancer cells, which was reversed by RSL3, a ferroptosis-inducing agent. Lastly, sodium butyrate (SB) was found to transcriptionally regulate ARHGAP10, thereby also contributing to the ferroptosis of ovarian cancer cells. Conclusions: Our results suggest that SB/ARHGAP10/GPX4 is a new signaling axis involved in inducing ferroptosis in ovarian cancer cells and suppressing tumor growth, which has potential clinical significance.

Optical Genome Mapping Reveals the Landscape of Structural Variations and Their Clinical Significance in HBOC-Related Breast Cancer

Background: Structural variations (SVs) are common genetic alterations in the human genome. However, the profile and clinical relevance of SVs in patients with hereditary breast and ovarian cancer (HBOC) syndrome (germline BRCA1/2 mutations) remains to be fully elucidated. Methods: Twenty HBOC-related cancer samples (5 breast and 15 ovarian cancers) were studied by optical genome mapping (OGM) and next-generation sequencing (NGS) assays. Results: The SV landscape in the 5 HBOC-related breast cancer samples was comprehensively investigated to determine the impact of intratumor SV heterogeneity on clinicopathological features and on the pattern of genetic alteration. SVs and copy number variations (CNVs) were common genetic events in HBOC-related breast cancer, with a median of 212 SVs and 107 CNVs per sample. The most frequently detected type of SV was insertion, followed by deletion. The 5 HBOC-related breast cancer samples were divided into SVhigh and SVlow groups according to the intratumor heterogeneity of SVs. SVhigh tumors were associated with higher Ki-67 expression, higher homologous recombination deficiency (HRD) scores, more mutated genes, and altered signaling pathways. Moreover, 60% of the HBOC-related breast cancer samples displayed chromothripsis, and 8 novel gene fusion events were identified by OGM and validated by transcriptome data. Conclusions: These findings suggest that OGM is a promising tool for the detection of SVs and CNVs in HBOC-related breast cancer. Furthermore, OGM can efficiently characterize chromothripsis events and novel gene fusions. SVhigh HBOC-related breast cancers were associated with unfavorable clinicopathological features. SVs may therefore have predictive and therapeutic significance for HBOC-related breast cancers in the clinic.

LncRNA PART1 Regulates Ovarian Carcinoma Development via the miR-150-5p/MYB Axis

Background: Over the past few years, there have been many reports on the abnormal expression and functional relevance of long non-coding RNAs (lncRNAs) in tumors. The role played by lncRNAs in epithelial ovarian carcinoma (EOC) remains poorly understood, however the goal of the present work was to study molecular mechanisms that underlie involvement of prostate androgen-regulated transcript 1 (PART1) lncRNA in EOC development. Methods: A total of 25 tumor and 17 normal specimens were obtained from women undergoing surgery between 2015 and 2019 in the Second Affiliated Hospital, Nanjing Medical University. Expression levels for PART1 in EOC tissue and EOC cell lines were assessed using qRT-PCR. Assays for CCK-8, trans-well, colony forming and western blotting were used to investigate PART1, miR-150-5p and MYB (MYB proto-oncogene) for their invovement in EOC cell proliferation, migration and invasion. Luciferase reporter gene assay was also performed to investigate biological functions of PART1, miR-150-5p and MYB in EOC, and an animal xenograft model was employed to test tumorigenicity. Results: PART1 expression was increased in EOC relative to normal cells and correlated with EOC cell proliferation, migration and invasion. PART1 can sponge miR-150, thereby inhibiting growth of EOC by targeting MYB. The xenograft mouse model revealed that PART1 can regulate tumorigenesis in vivo. Conclusions: The PART1/miR-150/MYB axis is involved in EOC pathogenesis and could represent a new target to use in diagnosis and therapy.

ACSL1-Mediated Fatty Acid β-Oxidation Enhances Metastasis and Proliferation in Endometrial Cancer

Background: Gynecological malignancies, such as endometrial cancer (EC) and uterine cancer are prevalent. Increased Acyl-CoA synthetase long-chain family member 1 (ACSL1) activity may contribute to aberrant lipid metabolism, which is a potential factor that contributes to the pathogenesis of endometrial cancer. This study aimed to elucidate the potential molecular mechanisms by which ACSL1 is involved in lipid metabolism in endometrial cancer, providing valuable insights for targeted therapeutic strategies. Methods: Xenograft mouse models were used to assess the effect of ACSL1 on the regulation of endometrial cancer progression. ACSL1 protein levels were assessed via immunohistochemistry and immunoblotting analysis. To assess the migratory potential of Ishikawa cells, wound-healing and Transwell invasion assays were performed. Changes in lipids in serum samples from mice with endometrial cancer xenotransplants were examined in an untargeted lipidomic study that combined multivariate statistical methods with liquid chromatography‒mass spectrometry (LC/MS). Results: Patient sample and tissue microarray data suggested that higher ACSL1 expression is strongly associated with the malignant progression of EC. Overexpression of ACSL1 enhances fatty acid β-oxidation and 5′-adenylate triphosphate (ATP) generation in EC cells, promoting cell proliferation and migration. Lipidomic analysis revealed that significant changes were induced by ACSL1, including changes to 28 subclasses of lipids and a total of 24,332 distinct lipids that were detected in both positive and negative ion modes. Moreover, pathway analysis revealed the predominant association of these lipid modifications with the AMPK/CPT1C/ATP pathway and fatty acid β-oxidation. Conclusions: This study indicates that ACSL1 regulates the AMPK/CPT1C/ATP pathway, which induces fatty acid β-oxidation, promotes proliferation and migration, and then leads to the malignant progression of EC.

Increased expression of PD-L1 in endometrial cancer stem-like cells is regulated by hypoxia

Background: The expression levels of the programmed cell death ligand 1 (PD-L1), known as an immune-inhibitory molecule, are closely associated with cancer stem cell (CSCs) immune escape. Recently, PD-L1 has also been reported to be able to regulate the self-renewal of cancer stem cells. However, The expression and intrinsic role of PD-L1 in endometrial cancer stem-like cell (ECSC) maintenance and its underlying mechanism of action remain unclear. Methods: Using flow cytometry and western blot assays, we have demonstrated that PD-L1 expression is higher in ECSCs derived from endometrial cancer than in nonstem-like cancer cells. Using mouse xenograft assays for ECSC tumorigenicity. Using gene reporter assay for uncovering the regulation mechanism of PD-L1 in the hypoxia. Results: We revealed the high expression levels of PD-L1 in ECSCs and its correlation with self-renewal. We further found that PD-L1 knockdown reduced expression of several pluripotency-related genes (aldehyde dehydrogenase 1 (ALDH1), CD133, OCT4, SOX2, NANOG), impaired ECSC proliferation and undifferentiated colonies and decreased the number of CD133 positive ECSCs and the number of stem-like spheres. Furthermore, we found that PD-L1 knockdown inhibited ECSC tumorigenicity and the PD-L1 induced self-renewal capability of ECSCs was dependent upon hypoxia HIF-1α and HIF-2α activation. Conclusions: These data link ECSC maintenance to PD-L1 expression through hypoxia and suggest a promising target for PD1/PD-L1 immunotherapy.

N6-methyladenosine Methyltransferase METTL3 Enhances PTGER2 Expression to Increase Ovarian Cancer Stemness and Chemoresistance

Background: Ovarian cancer is the second leading cause of gynecologic cancer-associated deaths. Cancer stemness and chemoresistance are responsible for ovarian cancer metastasis and the poor prognosis of patients. In this study, we determined the function of N6-methyladenine (m6A) RNA methylation and prostaglandin E receptor 2 (PTGER2) in ovarian cancer progression. Methods: The m6A RNA methylation-associated PTGER2 in ovarian cancer was identified using bioinformatics analysis. The role of PTGER2 in ovarian cancer was elucidated in cell lines and clinical samples with cellular and molecular experiments. Results: In this investigation, bioinformatics analysis based on a public cancer database was used to elucidate the impact of m6A modification on the prognosis of patients with ovarian cancer. Moreover, PTGER2 was identified as a potential oncogene associated with the distant metastasis of ovarian cancer and poor patient prognosis. Interestingly, PTGER2 expression was experimentally shown to be enhanced by N6-adenosine-methyltransferase 70 kDa subunit (METTL3)-mediated m6A modification. In addition, PTGER2 enhanced cancer stem cell self-renewal properties, the epithelial-mesenchymal transition, and DNA damage repair, thus potentiating cell stemness, therapy resistance to carboplatin, proliferation, and metastasis of ovarian cancer. Importantly, PTGER2 expression in clinical samples was associated with distant metastasis, predicted poor patient prognosis, and independently served as a prognostic predictor in ovarian cancer. Conclusions: Our work defines PTGER2 as an oncogene and reveals that PTGER2 is a prognostic predictor and novel therapeutic target for the management of ovarian cancer.

NOTCH Pathway Genes in Ovarian Cancer: Clinical Significance and Associations with Immune Cell Infiltration

Background: Activation of the NOTCH signaling pathway is associated with tumorigenesis. The aim of this study was to investigate NOTCH pathway gene functions and regulatory mechanisms in ovarian cancer (OC). Methods: We conducted a bioinformatics analysis of publicly available datasets in order to identify potential NOTCH-related mechanisms, associated genes, biological pathways, and their relation to immune function. Results: Significant differential expression of the NOTCH pathway genes DLL1, DLL3, DLL4, HES1, HEY1, JAG1, NOTCH2, NOTCH3, and NOTCH4 was observed between OC samples and normal controls. Low expression of DLL4 and of NOTCH4 in OC patients was associated with International Federation of Gynecology and Obstetrics (FIGO) stage (p <0.001 and p = 0.036, respectively), while high expression of NOTCH3 was associated with race (p = 0.039) and age (p = 0.044). JAG2 and NOTCH1 expression were significantly associated with progression-free interval (PFI) (p = 0.011 and p = 0.039, respectively). DLL1 (Hazard Ratio (HR): 2.096; 95% CI: 1.522–2.886, p < 0.001) and NOTCH1 (HR: 0.711; 95% CI: 0.514–0.983, p = 0.039) expression were independently associated with PFI in multivariate analysis. DLL1, DLL3, JAG1, JAG2, NOTCH3 and NOTCH4 expression could significantly differentiate OC from non-cancer samples. Genes associated with the NOTCH pathway were mainly enriched in five signaling pathways: the NOTCH signaling pathway, breast cancer, endocrine resistance, Th1 and Th2 cell differentiation, and oxidative phosphorylation. The expression of NOTCH pathway genes was significantly associated with immune cell infiltration. Conclusions: NOTCH pathway genes appear to play an important role in the progression of OC by regulating immune cells, endocrine resistance, Th1 and Th2 cell differentiation, and oxidative phosphorylation. JAG2 and NOTCH1 are potential biomarkers and therapeutic targets for the treatment of OC.

A Comprehensive Analysis of Prognostic Indicators in Serous Ovarian Cancer Based on Leukocyte Migration and Immune Microenvironment

Background: High-grade serous ovarian cancer (HGSOC) treatment is facing clinical challenges. The tumor immune microenvironment (TME) has recently been shown to perform a critical function in the prediction of clinical outcomes as well as the effectiveness of treatment. Leukocyte migration is enhanced in malignant tumors and promotes immunity. However, its role in how to underlie the migration of immune cells into the TME remains to be further explained in HGSOC. Methods: We built a prognostic multigene signature with leukocyte migration-related differentially expressed genes (LMDGs), which is associated with TME by single-sample gene set enrichment analysis (ssGSEA), in the The Cancer Genome Atlas (TCGA) cohort. Furthermore, we systematically correlated risk signature with immunological characteris-tics in TME, mutational profiles of HGSOC, and potential value in predicting efficacy of platinum-based chemotherapy and immunotherapy. Screening of the most important prognostic factor among risk signatures by Friends analysis, and immunofluorescence was employed to examine both the expression of CD2 as well as its relationship with CD8 and PD-1. Results: LMDGs-related prognostic model showed good prediction performance. Patients who had high-risk scores exhibited significantly reduced progression-free survival (PFS) and overall survival (OS) than those with low-risk scores, according to the results of the survival analysis (p < 0.001). In the TCGA cohort, the risk signature was found to have independent prognostic sig-nificance for HGSOC (HR =1.829, 95% CI = 1.460–2.290, p < 0.001) and validated in the Gene Expression Omnibus (GEO) cohort. Samples with high-risk scores had lower levels of CD8+ T cells infiltration. The low-risk signature shapes an inflamed TME in HGSOC. Furthermore, immune therapy might be effective for the low-risk subtype of HGSOC patients (p < 0.001). Friends analysis revealed that CD2 was the most important prognostic gene among risk signatures. Real-time quantitative PCR analysis showed the expression of CD2 was greater in tumor cells as opposed to normal ovarian cells. CD8, PD-1, and CD2 were shown to be co-localized in HGSOC tissues, according to immunofluorescence analyses. CD2 was significantly correlated with CD8 (r = 0.47). Conclusions: Our study identified and validated a promising LMDGs signature associated with inflamed TME, which might offer some prospective clinical implications for the treatment of SOC. CD2 might be a novel biomarker to predict immune efficacy.

LRG1 Is Involved in the Progression of Ovarian Cancer via Modulating FAK/AKT Signaling Pathway

Background: Rapid progression and early metastasis remain the main cause of high mortality in epithelial ovarian cancer (EOC) patients. The objective of this study was to explore the mechanisms of EOC progression and detect the function of leucine-rich alpha-2-glycoprotein 1 (LRG1) in modulating the pathologic process. Methods: Ultracentrifugation was initially performed to extract exosomes from the urine samples of EOC patients and healthy female subjects. Mass spectrometry (MS) was employed to analyze differentially expressed proteins. Survival analysis was performed to examine the association between LRG1 levels and the prognosis of EOC patients. LRG1 silencing ovarian cancer cell lines were built and cell migration was further evaluated via wound healing and transwell assays. Immunoblot, immunofluorescence and immunohistochemistry analyses were performed. A subcutaneous tumor model was established to study the function of LRG1 in vivo. Results: Exosomal LRG1 was specifically expressed in urine samples of EOC patients and high LRG1 levels were significantly associated with poor prognosis. Function analyses showed that LRG1 was associated with ovarian cancer migration and progression. Mechanistically, LRG1 was significantly related to the focal adhesion kinase/protein kinase B (FAK/AKT) signaling pathway. Conclusions: LRG1 participated in progression and metastasis of ovarian cancer via activation of the FAK/AKT pathway probably.

Long Noncoding RNAs in Ovarian Cancer—Functions and Clinical Applications

Long noncoding RNAs (lncRNAs) are RNA molecules with a length of more than 200 nt that have been discovered in recent years. LncRNAs can participate in regulating gene expression and various biological activities through multiple pathways, such as at the epigenetic level, transcriptional level, and posttranscriptional level. In recent years, with the increasing understanding of lncRNAs, a large number of studies have shown that lncRNAs are closely related to ovarian cancer and participate in its occurrence and development, providing a new method to investigate ovarian cancer. In this review, we analyzed and summarized the relationship between various lncRNAs and ovarian cancer in terms of occurrence, development, and clinical significance, in order to provide a theoretical basis for basic research and clinical application of ovarian cancer.

Construction of an Immunity and Ferroptosis-Related Risk Score Model to Predict Ovarian Cancer Clinical Outcomes and Immune Microenvironment

Background: Ovarian cancer (OV) is a severe and common gynecological disease. Ferroptosis can regulate the progression and invasion of tumors. The immune system is a decisive factor in cancer. The present study aimed to use gene expression data to establish an immunity and ferroptosis-related risk score model as a prognostic biomarker to predict clinical outcomes and the immune microenvironment of OV. Methods: Common gene expression data were searched from the Gene Expression Omnibus and The Cancer Genome Atlas databases. Immunity-related genes and ferroptosis-related genes were searched and downloaded from the ImmPort and FerrDb databases, followed by the analysis of the overall survival of patients with OV and the identification of genes. Subsequently, the status of the infiltration of immune cells and the association between immune checkpoints and risk score were assessed. Results: A total of 10 prognostic genes (C5AR1, GZMB, IGF2R, ISG20, PPP3CA, STAT1, TRIM27, TSHR, RB1, and EGFR) were included in the immunity and ferroptosis-related risk score model. The high-risk group had a higher infiltration of immune cells. The risk score, an independent prognostic feature of OV was negatively associated with each immune checkpoint. The risk score may thus help to predict the response to immunotherapy. Conclusions: The immunity and ferroptosis-related risk score model is an independent prognostic factor for OV. The established risk score may help to predict the response of patients to immunotherapy.

N-acetyltransferase 10 Promotes Cervical Cancer Progression Via N4-acetylation of SLC7A5 mRNA

Introduction: N-acetyltransferase 10 (NAT10) mediates N4-acetylcytidine (ac4C) mRNA modification and promotes malignant tumor progression. However, there has been limited research on its role in cervical cancer. This study aimed to decipher the role of NAT10 in cervical cancer. Methods: The prognostic value of NAT10 was explored using the cancer genome atlas (TCGA) database and immunohistochemistry of cervical cancer tissue. The biological actions of NAT10 in cervical cancer were investigated by cell proliferation, transwell, wound healing, and chicken chorioallantoic membrane assays. The therapeutic action of remodelin (a NAT10 inhibitor) was verified in a nude mouse model. Mechanistic analyses were conducted by RNA sequencing, ac4C dot blotting, acetylated RNA immunoprecipitation, quantitative PCR, and RNA stability experiments. Results: NAT10 was overexpressed in cervical carcinoma and its overexpression was associated with poor prognosis. NAT10 knockout impaired proliferative and metastatic potentials of cervical cancer cells, while its overexpression had the opposite effects. Remodelin impaired cervical cancer proliferation in vivo and in vitro. NAT10 acetylated solute carrier family 7 member 5 (SLC7A5) enhanced mRNA stability to regulate SLC7A5 expression. Conclusions: NAT10 exerts a critical role in cervical cancer progression via acetylating SLC7A5 mRNA and could represent a key prognostic and therapeutic target in cervical cancer.

Potential Therapeutic Targets in Ovarian Cancer: Autophagy and Metabolism

Ovarian cancer (OC) is characterized by high mortality rates owing to late diagnosis and resistance to chemotherapy. Autophagy and metabolism play essential roles in the pathological process of cancer and have recently been proposed as potential targets for anticancer therapies. Autophagy is responsible for the catabolic clearance of functionally misfolded proteins and plays different roles depending on the stage and type of cancer. Thus, understanding and controlling autophagy is relevant for treating cancer. Autophagy intermediates can communicate with each other by providing substrates for glucose, amino acid, and lipid metabolism. Metabolites and metabolic regulatory genes modulate autophagy and influence the immune response. Therefore, autophagy and the functional manipulation of metabolism during starvation or overnutrition are being investigated as potential therapeutic targets. This review discusses the role of autophagy and metabolism in OC and highlights effective therapeutic strategies targeting these processes.

Metabolic cross-talk between ovarian cancer and the tumor microenvironment—providing potential targets for cancer therapy

Conventional treatments for ovarian cancer, including debulking cytoreductive surgery combined with carboplatin/paclitaxel-based chemotherapy, are insufficient, as evidenced by the high mortality rate, which ranks first among gynecological tumors. Therefore, there is an urgent need to develop new and effective treatment strategies. Recent evidence has shown that metabolic processes and cell behaviors in ovarian cancer are regulated by intracellular factors as well as metabolites in the tumor microenvironment (TME), which determine occurrence, proliferation, and metastasis. In this review, we describe the comprehensive landscape of metabolic cross-talk between ovarian cancer and its TME with a focus on the following four aspects: (1) intracellular metabolism based on the Warburg effect, (2) metabolism in non-tumor cells in the ovarian TME, (3) metabolic communication between tumor cells and non-tumor cells in the TME, and (4) metabolism-related therapeutic targets and agents for ovarian cancer. The metabolic cross-talk between ovarian cancer and its microenvironment involves a complex network of interactions, and interrupting these interactions by metabolic interventions is a promising therapeutic strategy.

Endostar Synergizes with Radiotherapy to Inhibit Angiogenesis of Cervical Cancer in a Subcutaneous Xenograft Mouse Model

Background: To investigate the synergic effect and underlying mechanism of Endostar, a recombinant human endostatin used for anti-angiogenesis, in radiotherapy for cervical cancer. Methods: The Cell Counting Kit-8 (CCK-8) assay and plate cloning experiment were first employed to analyze the proliferation of HeLa and SiHa cervical cancer cells and human umbilical vein vascular endothelial cells (HUVECs). Flow cytometry was used to detect apoptosis and cell cycle progression. A tube formation assay was used to assess angiogenesis in vitro. The expression of gamma H2A histone family member X (γ-H2AX) and activation of the vascular endothelial growth factor receptor (VEGFR) signaling pathway were detected by immunofluorescence and western blotting, respectively. In a HeLa xenograft model, tumor tissue expression of CD31 and alpha smooth muscle actin and serum expression of VEGF-A were detected by immunohistochemistry (IHC) and enzyme-linked immunosorbent assay, respectively. Results: The CCK-8 and plate cloning assays showed that Endostar and radiotherapy synergistically inhibited the growth of HUVECs but not HeLa and SiHa cells. The flow cytometric results showed that Endostar only promoted radiotherapy-induced apoptosis and G2/M phase arrest in HUVECs (p < 0.05). Endostar combined with radiotherapy also significantly inhibited tube formation by HUVECs (p < 0.05). Furthermore, Endostar inhibited the radiotherapy-induced expression of γH2AX (p < 0.05) and phosphorylation of VEGFR2/PI3K/AKT/DNA-PK in HUVECs (p < 0.05). IHC showed that Endostar enhanced the inhibitory effect of radiotherapy on the microvessel density in xenograft tumor tissues (p < 0.05), as well as serum VEGF-A expression (p < 0.05). The tumor volume in the combination therapy groups (1200 mm3) was significantly lower than in the control group (2500 mm3; p < 0.05). Conclusions: Our findings provide experimental evidence and a theoretical basis for the application of Endostar in combination with irradiation for anti-cervical cancer treatment.

The Prognostic and Immune Significance of BZW2 in Pan-Cancer and its Relationship with Proliferation and Apoptosis of Cervical Cancer

Background: Basic leucine zipper and W2 domains 2 (BZW2), a member of the basic domain leucine zipper superfamily of transcription factors, has been implicated in the development and progression of various cancers. However, the precise biological role of BZW2 in pan-cancer datasets remains to be explored. This study aimed to assess the prognostic significance of BZW2 and its immune-related signatures in various tumors. Methods: Our study investigated the expression, epigenetic modifications, and clinical prognostic relevance of BZW2 using multi-omics data in different cancer types. Additionally, the immunological characteristics, tumor stemness, drug sensitivity, and correlation of BZW2 with immunotherapy response were explored. Finally, in vitro experiments were conducted to assess the impact of BZW2 knockdown on Hela cells, a cell line derived from cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC). Results: BZW2 exhibited elevated expression levels in various tumor tissues and significantly impacted the prognosis of different cancer types. BZW2 emerged as an independent prognostic factor in CESC. We found that copy number amplification and methylation levels of BZW2 were associated with its mRNA expression. Immunological analyses revealed that BZW2 shapes a non-inflamed immunosuppressive tumor microenvironment across multiple cancers. Furthermore, our cell experiments demonstrated that BZW2 knockdown reduced proliferation, migration, and apoptosis activities in CESC cells. Conclusions: BZW2 promotes cancer progression by shaping a non-inflamed immunosuppressive tumor microenvironment. Additionally, BZW2 was shown to significantly influence the proliferation, migration, and apoptosis of CESC cells.

Tumor-Suppressor Gene Transmembrane Protein 98 Promotes Proliferation and Inhibits Apoptosis in Ovarian Cancer

Background: Ovarian cancer (OC) is the most deadly tumor in gynecology and there is no effective biomarker for diagnosis and treatment. The role of Transmembrane Protein 98 (TMEM98) in ovarian cancer is still unclear. Methods: The expression and prognostic effect of TMEM98 in OC were analyzed using the public database. Cell Counting Kit-8 proliferation experiment, scratch experiment, Transwell invasion experiment, flow cytometry, TUNEL staining, and in vivo and vitro experiment were used. Results: TMEM98 was significantly downregulated in OC tissues and cell lines compared to the normal ovarian tissue and cells lines. In addition, patients with lower TMEM98 levels exhibited inferior survival. Low expression of the TMEM98 promoted proliferation, migration, invasion, vasculogenic mimicry, and inhibited apoptosis in OC cells. The expression of Caspase-3 was significantly downregulated and the expression of Bcl-2 was significantly increased in the silencing-TMEM98 group. Moreover, low expression of TMEM98 promotes OC development in vivo. Bioinformatics analysis showed that TMEM98 expression was negatively correlated with poly ADP-ribose polymerase expression. Conclusions: This study demonstrates that TMEM98 is low expressed in OC and impacts the prognosis of OC patients. TMEM98 inhibits proliferation and promotes apoptosis and finally exerts a certain tumor-suppressor effect on OC.

Ferroptosis Induction is Insufficient to Ensure NK Cell Activation in High-Grade Ovarian Cancer

Background: High-grade ovarian cancer (HGOC) is a heterogeneous and aggressive malignancy with a tumor microenvironment (TME) that suppresses immune responses, limiting immunotherapy efficacy. Ferroptosis, an iron-dependent form of regulated cell death, has emerged as a potential therapeutic target. Methods: We investigated the immunomodulatory effects of the ferroptosis inducer RAS-Selective Lethal 3 (RSL3) in four HGOC cell lines (ES-2, OVCAR-5, HEY, PEO-1) using flow cytometry and lactate dehydrogenase (LDH) release assays. Results: RSL3 modulated Natural Killer (NK) ligand expression in a cell line-dependent manner, resulting in differential susceptibility to NK cell-mediated cytotoxicity. OVCAR-5 cells became more susceptible to NK cell killing after treatment, whereas HEY cells showed reduced susceptibility, and ES-2 and PEO-1 cells exhibited minimal changes. Conclusions: Ferroptosis induction alone does not consistently enhance NK cell-mediated cytotoxicity in HGOC cells. These findings underscore the heterogeneity of tumor responses and highlight the need for further studies, particularly in in vivo models, to elucidate mechanisms linking ferroptosis to immune recognition and thereby inform therapeutic development.