Malignancies Of Female Reproductive System Research Articles

Abstract 4639: Unraveling the oncogenic network of USP37 and USP14 in gynecological cancers: Decrypting the molecular landscape of chemoresistance

Abstract Background: Gynecological cancers (GC) involve female reproductive system malignancies, and acquired chemoresistance is a challenge in the treatment of GC. Protein deubiquitination, mediated by deubiquitinating enzymes (DUBs) like ubiquitin-specific proteases (USPs), holds therapeutic promise in cancer treatment. This study delves into the mechanistic understanding of DUBs, particularly in acquired chemoresistance in GC. Methodology: We initially examined TCGA database to assess the impact of Ubiquitin Specific Proteases (USPs), specifically USP37 and USP14, on prognosis in Gynaecological Cancers (GCs). Subsequently, we evaluated their expression in various GC cell lines at both protein and RNA levels. Cell proliferation and metastasis assays were performed to analyze the effect of depleting these USPs on survival and metastasis in GC cells under replication stress. Proteomics analysis was conducted on cells with altered expression of USP37 and USP14 to identify interacting proteins regulating proliferation and metastasis. To investigate DUBs role in chemoresistance, we generated chemoresistant (CR) cell lines with cisplatin exposure, characterized their viability and proliferation, conducted cell cycle and apoptosis analyses, and performed proteomic profiling to explore the USP37 and USP14 specific interactome in chemoresistant cell lines. Results: Examination of TCGA database revealed an association between elevated USP37 and USP14 expression and poor Overall Survival (OS) and Disease-free Survival (DFS) in Gynaecological Cancers (GC) cohort. Increased expression of USP37 and USP14 at RNA and protein levels was observed in GC cell lines. Inhibiting USP37 and USP14 reduced GC cell proliferation under replication stress and hindered metastasis. Proteomics analysis identified proteins linked to replication (PCNA), DNA damage (Chk-1), cell cycle, and metastasis. Cisplatin-resistant GC cell lines were successfully established, demonstrating prolonged survival and increased proliferative capacity after cisplatin treatment compared to chemosensitive (CS) cell lines. FACS analysis indicated altered cell cycle distribution and increased proliferation in CR cells. Comparative interactome analysis revealed altered protein sets associated with USP37 and USP14 in CR and CS GC cells. Conclusion: This study provides evidence that supports the participation of USP37 and USP14 in the onset of gynecological cancers (GC). We present evidence of alterations in the oncogenic network linked to USP37 and USP14 in GC. Additionally, we elucidate the roles of these deubiquitinating enzymes (DUBs) in chemoresistant cell lines. Citation Format: Ravi Chauhan, Ashna Gupta, Gunjan Dagar, Lakshay Malhotra, Ekta Rai, Muzafar A Macha, Ajaz A Bhat, Ethayathulla A Samath, Mayank Singh. Unraveling the oncogenic network of USP37 and USP14 in gynecological cancers: Decrypting the molecular landscape of chemoresistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4639.

Niraparib and Advanced Ovarian Cancer: A Beacon in the Non-BRCA Mutated Setting.

Ovarian cancer (OC) is the eighth most common cancer among the female population and the most lethal of all the female reproductive system malignancies. Poly (ADP-ribose) polymerase inhibitors (PARPis) have reshaped the treatment scenario of metastatic OC in the maintenance setting post platinum-based chemotherapy. Niraparib is the first Food and Drug Administration (FDA)- and European Medical Agency (EMA)-approved PARPi as maintenance therapy for platinum-sensitive OC, regardless of BReast CAncer gene (BRCA) status, in first-line patients, with a recent restriction to germline BRCA mutations in second-line patients. In this review, we comprehensively summarized the pharmacological properties of niraparib, alongside the efficacy and safety data of the main trials leading to the current approvals, and discussed the future development of this agent.

Olaparib and advanced ovarian cancer: Summary of the past and looking into the future.

Ovarian cancer (OC) is women's eighth most common cancer, bearing the highest mortality rates of all female reproductive system malignancies. Poly (ADP-ribose) polymerase inhibitors (PARPis) have reshaped the treatment scenario of metastatic OC as a maintenance post platinum-based chemotherapy. Olaparib is the first PARPi developed for this disease. Results from Study 42, Study 19, SOLO2, OPINION, SOLO1, and PAOLA-1 clinical trials, led to the FDA and EMA approval of olaparib for the maintenance treatment of women with high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer without platinum progression: in the platinum-sensitive recurrent OC; in the newly diagnosed setting in case Breast Cancer (BRCA) mutations and, in combination with bevacizumab, in case of BRCA mutation or deficiency of homologous recombination genes. In this review, we synthetized olaparib's pharmacokinetic and pharmacodynamic properties and its use in special populations. We summarized the efficacy and safety of the studies leading to the current approvals and discussed the future developments of this agent.

Coicis Semen for the treatment of malignant tumors of the female reproductive system: A review of traditional Chinese medicinal uses, phytochemistry, pharmacokinetics, and pharmacodynamics.

Coicis Semen is an important food product and traditional Chinese medicine (TCM) derived from the dried and mature seeds of Coix lacryma-jobi L.var.ma-yuen (Roman.) Stapf. An increasing number of studies have investigated its use, either alone or in combination with other botanical drugs, to treat female reproductive system malignancies, and its pharmacological effects have been confirmed clinically. This review aims to provide an overview of Coicis Semen's historical role in treating female reproductive system malignancies based on TCM theory, to summarize clinical trials results, and to analyze information pertaining to the main phytochemical components, pharmacokinetics, related anti-cancer pharmacological effects, and toxicology of Coicis Semen. Information on Coicis Semen was collected from internationally accepted scientific databases. Seventy-four clinical trials were identified that used Coicis Semen in combination with other Chinese medicine to treat female reproductive system malignancies, most of which demonstrated good anti-tumor efficacy and few adverse reactions. To date, more than 80 individual compounds have been isolated from this botanical drug. In terms of anti-tumor effects, Coix seed oil has been studied the most. Pharmacokinetic data suggest that the active ingredients in Coicis Semen are widely distributed after administration, and Coicis Semen and its active compounds play a beneficial role in treating female reproductive system malignancies. Mechanistically, the anti-cancer effects may be related to inhibition of tumor cell proliferation and promotion of apoptosis, inhibition of tumor angiogenesis, suppression of the chronic inflammatory microenvironment of tumors, modulation of immune function, and regulation of the female reproductive system. Most acute toxicity and genotoxicity studies have shown that Coicis Semen is non-toxic. However, the existing studies have many limitations, and the future research direction should emphasize 1) the relationship between drug concentration and pharmacological action as well as toxicity; 2) the structural modification or the synthesis of analogues led by the active ingredients of Coicis Semen to enhance pharmacological activities and bioavailability; 3) accurately revealing the anti-cancer pharmacological effects of Coicis Semen and its compounds through multi-omics technology. We hope that this review can determine future directions and inform novel drug development for treating female reproductive malignancies.

An Integrative Analysis Revealing ZFHX4-AS1 as a Novel Prognostic Biomarker Correlated with Immune Infiltrates in Ovarian Cancer.

Ovarian cancer (OC) is the main cause of deaths worldwide in female reproductive system malignancies. Growing studies have indicated that eRNAs could regulate cellular activities in various tumors. Yet the potential roles of eRNAs in OC progression have not been elucidated. Thus, comprehensive assays were needed to screen the critical eRNAs and to explore their possible function in OC. We used Kaplan–Meier methods to identify survival-associated eRNAs in OC based on TCGA datasets. The levels of ZFHX4-AS1 were examined using TCGA datasets. Further exploration was carried out based on the following assays: clinical and survival assays, GO terms, and KEGG assays. TIMER was applied to delve into the relationships between ZFHX4-AS1 and tumor immune infiltration. In this research, we observed 71 survival-related eRNAs in OC patients. ZFHX4-AS1 was highly expressed in OC specimens and predicted a poor prognosis of OC patients. In addition, high ZFHX4-AS1 expression was positively related to the advanced stages of OC specimens. Multivariate assays revealed that ZFHX4-AS1 was an independent prognostic factor for overall survival of OC patients. KEGG analysis indicated that ZFHX4-AS1 may play a regulatory effect on TGF-beta signaling, PI3K-Akt signaling, and proteoglycans in cancer. The pan-cancer validation indicated that ZFHX4-AS1 was related to survival in eight tumors, namely, UCEC, STAD, SARC, OV, ACC, KICH, KIRC, and BLCA. The expression of ZFHX4-AS1 was correlated with the levels of B cells, T cell CD8+, neutrophil, macrophage, and myeloid dendritic cells. Simultaneously, ZFHX4-AS1 may be a prognostic biomarker and a distinctly immunotherapy-related eRNA in OC.

Calcineurin Gamma Catalytic Subunit PPP3CC Inhibition by miR-200c-3p Affects Apoptosis in Epithelial Ovarian Cancer.

Epithelial ovarian cancer (EOC) outpaces all the other forms of the female reproductive system malignancies. MicroRNAs have emerged as promising predictive biomarkers to therapeutic treatments as their expression might characterize the tumor stage or grade. In EOC, miR-200c is considered a master regulator of oncogenes or tumor suppressors. To investigate novel miR-200c-3p target genes involved in EOC tumorigenesis, we evaluated the association between this miRNA and the mRNA expression of several potential target genes by RNA-seq data of both 46 EOC cell lines from Cancer Cell line Encyclopedia (CCLE) and 456 EOC patient bio-specimens from The Cancer Genome Atlas (TCGA). Both analyses showed a significant anticorrelation between miR-200c-3p and the protein phosphatase 3 catalytic subunit γ of calcineurin (PPP3CC) levels involved in the apoptosis pathway. Quantitative mRNA expression analysis in patient biopsies confirmed the inverse correlation between miR-200c-3p and PPP3CC levels. In vitro regulation of PPP3CC expression through miR-200c-3p and RNA interference technology led to a concomitant modulation of BCL2- and p-AKT-related pathways, suggesting the tumor suppressive role of PPP3CC in EOC. Our results suggest that inhibition of high expression of miR-200c-3p in EOC might lead to overexpression of the tumor suppressor PPP3CC and subsequent induction of apoptosis in EOC patients.

FOXP4-AS1 is a favorable prognostic-related enhancer RNA in ovarian cancer.

Ovarian cancer (OV) is the main cause of deaths worldwide in female reproductive system malignancies. Enhancer RNAs (eRNAs) are derived from the transcription of enhancers and has attracted increasing attention in cancers recently. However, the biological functions and clinical significance of eRNAs in OV have not been well described presently. We used an integrated data analysis to identify prognostic-related eRNAs in OV. Tissue-specific enhancer-derived RNAs and their regulating genes were considered as putative eRNA–target pairs using the computational pipeline PreSTIGE. Gene expression profiles and clinical data of OV and 32 other cancer types were obtained from the UCSC Xena platform. Altogether, 71 eRNAs candidates showed significant correlation with overall survival (OS) of OV samples (Kaplan–Meier log-rank test, P<0.05). Among which, 23 were determined to be correlated with their potential target genes (Spearman’s r > 0.3, P<0.001). It was found that among the 23 prognostic-related eRNAs, the expression of forkhead box P4 antisense RNA 1 (FOXP4-AS1) had the highest positive correlation with its predicted target gene FOXP4 (Spearman’s r = 0.61). Moreover, the results were further validated by RT-qPCR analysis in an independent OV cohort. Our results suggested the eRNA FOXP4-AS1 expression index may be a favorable independent prognostic biomarker candidate in OV.

Tubulin Beta 2C Chain (TBB2C), a Potential Marker of Ovarian Cancer, an Insight from Ovarian Cancer Proteome Profile.

Ovarian cancer (OC) is the most lethal among female reproductive system malignancies. Depending upon the stage at presentation, the five year survival ratio varies from ∼92 to ∼30%. The role of biomarkers in early cancer diagnosis, including OC, is well understood. In our previous study, through an initial screening, we have analyzed eleven proteins that exhibited differential expression in OC using two-dimensional gel electrophoresis (2D-GE) and matrix-assisted laser desorption/ionization-time of flight mass spectrometric (MALDI-TOF MS) analysis. In continuation of our previous study, the present work describes analysis of twenty more proteins that showed aberrant expression in OC. Among these, six showed consistent significant deregulation in the OC false discovery rate [FDR ≤ 0.05]. Upon MS analysis, they were identified as vimentin, tubulin beta 2C chain, tubulin alpha 1C chain, actin cytoplasmic 2, apolipoprotein A-I, and collagen alpha 2(VI) chain [peptide mass fingerprint (PMF) score ≥ 79]. One of the differentially regulated proteins, tubulin beta 2C chain, was found to be significantly (fold change, 2.5) enhanced in OC. Verification by western blot and enzyme-linked immunosorbent assay (ELISA) demonstrated that the tubulin beta 2C chain may serve as a valuable marker for OC (ANOVA p < 0.0001). The assessment of the likely association of TBB2C with OC in a larger population will not only help in developing clinically useful biomarkers in the future but also improve our understanding of the progression of OC disease.

Human recombinant arginase I [HuArgI (Co)-PEG5000]-induced arginine depletion inhibits ovarian cancer cell adhesion and migration through autophagy-mediated inhibition of RhoA

Ovarian carcinoma is the second most common malignancy of the female reproductive system and the leading cause of death from female reproductive system malignancies. Cancer cells have increased proliferation rate and thus require high amounts of amino acids, including arginine. L-arginine is a non-essential amino acid synthesized from L-citrulline by the Arginosuccinate synthetase (ASS1) enzyme. We have previously shown that the ovarian cancer cells, SKOV3, are auxotrophic to arginine, and that arginine deprivation by treatment with the genetically engineered human arginase I (HuArgI (Co)-PEG5000) triggers the death of SKOV3 cells by autophagy. In this study we examine the effect of HuArgI (Co)-PEG5000 on ovarian cancer cell migration and we dissect the mechanism involved. Wound healing assays, 2D random cell migration assays and cell adhesion analysis indicate that arginine deprivation decreases SKOV3 cell migration and adhesion. This effect was mimicked when autophagy was induced through rapamycin and reversed with the autophagy inhibitor chloroquine when autophagy was inhibited. This proved that arginine deprivation leads to the inhibition of cancer cell migration through autophagy, in addition to cell death. In addition, we were able to establish through pull-down assays and reversal experiments, that arginine deprivation-mediated autophagy inhibits cell migration through a direct inhibition of RhoA, member of the Rho family of GTPases. In conclusion, here we identify, for the first time, an autophagy-mediated inhibition of RhoA that plays an important role in regulating ovarian cancer cells motility and adhesion in response to arginine depletion.

Upregulated CXCL14 is associated with poor survival outcomes and promotes ovarian cancer cells proliferation.

Ovarian cancer is one of the common malignant tumours of female reproductive organs. Due to early diagnosis difficulties and lack of effective treatment in the late stage, ovarian cancer has the highest mortality rate in female reproductive system malignancies. Therefore, finding reliable early diagnosis indicators and new therapeutic targets for ovarian cancer is an urgent problem to be solved. Chemokine (C-X-C motif) ligand 14 (CXCL14) is a small cytokine belonging to the CXC chemokine family, which has been found to possess multi-effects in tumourigenesis and development. Here, we reported that CXCL14 was preferentially expressed in ovarian cancer. By analysing the TCGA database, we found that CXCL14 was highly expressed in advanced ovarian cancer patients and correlated with poor prognosis. In addition, the abnormal high CXCL14 levels were observed in serum and ovarian tissue of ovarian cancer patients by qRT-PCR and ELISA. In vitro and in vivo experiments both confirmed that overexpression of CXCL14 promoted the ovarian cancer cell proliferation. Moreover, transfection of CXCL14 increased the phosphorylation level of signal transducer and activator of transcription 3 (STAT3), and administration of STAT3 inhibitor III inhibited the tumour-promoting effects of CXCL14. Therefore, our study suggests that CXCL14 could be utilised as a novel adjunct biomarker for early diagnosis of ovarian cancer and provides new targets and ideas for the treatment of advanced ovarian cancer. SIGNIFICANCE PARAGRAPH: CXCL14 could be utilised as a novel adjunct biomarker for early diagnosis of ovarian cancer and provides new targets and ideas for the treatment of advanced ovarian cancer.

RACK1 promotes the invasive activities and lymph node metastasis of cervical cancer via galectin-1.

Cervical cancer remains the first leading cause of cancer-related mortality among female reproductive system malignancies worldwide, and invasion and lymph node metastasis of cervical cancer represent the major reason for its poor prognosis. In this study, we found that RACK1 facilitated tumor cell invasion and lymphatic tube formation in vitro, as well as promoted lymphangiogenesis and lymph node metastasis in vivo in a galectin-1-dependent manner. Mechanism studies revealed that RACK1 promoted the expression and secretion of galectin-1 by reducing miR-1275 levels. Additionally, RACK1 also augmented galectin-1-induced downstream MEK/ERK, FAK, and AKT signaling via integrin-β1 in cervical cancer cells. Tissue microarray confirmed that RACK1 was upregulated in squamous intraepithelial lesion and cancer, and RACK1 was positively correlated with invasion/metastasis phenotype, galectin-1 expression, and unfavorable prognosis in cervical cancer cases. Human papillomavirus E6 oncogene contributes to increased expression of RACK1 via the enhancement of its O-GlcNAcylation and protein stability. Together, our results demonstrate that RACK1 stimulates tumor invasion and lymph node metastasis of cervical cancer via galectin-1 and imply that targeting RACK1/galectin-1 axis provides promising means for cervical cancer treatment.

An integrated analysis reveals the oncogenic function of lncRNA LINC00511 in human ovarian cancer.

Ovarian cancer is one of the most common female reproductive system malignancies worldwide. Recently, the aberrant long noncoding RNAs (lncRNAs) expression has been identified in multiple cancers. Emerging evidence has highlighted the critical roles of lncRNAs in carcinogenesis and tumor progression, including ovarian cancer. The objective of this study is to comprehensively analyze lncRNAs expression pattern, and explore their clinical significance and underlying mechanism in human ovarian cancer. In this study, we found hundreds of dysregulated lncRNAs in ovarian cancer by performing genome‐wide analysis using RNA sequencing data from Genotype‐Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) project, and three microarray datasets from Gene Expression Omnibus (GEO). Moreover, our results revealed that up‐ or down‐regulation of some lncRNAs expression in ovarian cancer is accompanied by their genomic loci copy number amplification or deletion. Importantly, some lncRNAs expression levels are significantly associated with ovarian cancer patients’ poor prognosis. Further experimental validation and mechanistic investigation indicate that LINC00511 exerts oncogenic function in ovarian cancer cells through interacting with EZH2 and repressing P21 expression. Taken together, the findings in the current study may provide a useful resource of novel ovarian cancer associated lncRNAs and potential diagnostic biomarker and therapeutic targets for ovarian cancer.

Adenocarcinoma of the fallopian tube and malignancies of the female reproductive system – a review of the literature

There has been a paradigm shift in the understanding of the role played by the fallopian tube in the development of malignancies involving the female reproductive system. In particular, malignancies affecting the ovaries, such as high-grade serous ovarian carcinoma and serous peritoneal carcinoma, are presently thought to originate from malignant seedlings derived from the fallopian tube. However, the literature on adenocarcinoma of the fallopian tube is limited despite the strategic role this malignancy plays in the pathogenesis of malignancies of the female reproductive system. In this review we discuss current knowledge of adenocarcinoma of the fallopian tube, including management. The role of adenocarcinoma of the fallopian tube in the development of other female reproductive system malignancies is also described, with the aim of identifying aspects of the condition that will need further study. A search of PubMed, using the keywords ‘adenocarcinoma’, ‘fallopian tube’, ‘treatment’ and ‘salpingectomy’, yielded 179 articles over the past 15 years, of which 40 were relevant to the review. The role played by adenocarcinoma and malignant precursor lesions of the fallopian tube in malignancies affecting other parts of the female reproductive system needs to be further researched to provide more understanding and possibly better management of these conditions.

Polymorphisms of the anti-inflammatory IL-10 gene associated with malignancy in female reproductive system.

Association of three polymorphisms (1082G/A, 819C/T, and 592C/A) of the promotor region of the anti-inflammatory IL-10 gene with malignancy of female reproductive organs was revealed by SNP (single nucleotide polymorphism) method in ethnic groups of Adygei Republic. Breast cancer, cervical cancer, and cancer of the uterine corpus are associated with allele 592A (р=0.042) in Circassians and with polymorphism 819T in Russians (р=0.046). Irrespective of the ethnicity, allele 819T was signifi cantly more often (р<0.05) detected in prevalent forms of breast cancer involving regional lymph nodes. 1082G polymorphism is associated with low-differentiated adenocarcinoma. In women of Adygei Republic, ATA/GCA gaplotypes are associated with high risk factors for breast cancer.

P29 Expression of proliferation biomarkers in female reproductive system malignancies

P29 Expression of proliferation biomarkers in female reproductive system malignancies