Role of microRNAs in cancers of the female reproductive tract: insights from recent clinical and experimental discovery studies

Abstract

microRNAs (miRNAs) are small RNA molecules that represent the top of the pyramid of many tumorigenesis cascade pathways as they have the ability to affect multiple, intricate, and still undiscovered downstream targets. Understanding how miRNA molecules serve as master regulators in these important networks involved in cancer initiation and progression open up significant innovative areas for therapy and diagnosis that have been sadly lacking for deadly female reproductive tract cancers. This review will highlight the recent advances in the field of miRNAs in epithelial ovarian cancer, endometrioid endometrial cancer and squamous-cell cervical carcinoma focusing on studies associated with actual clinical information in humans. Importantly, recent miRNA profiling studies have included well-characterized clinical specimens of female reproductive tract cancers, allowing for studies correlating miRNA expression with clinical outcomes. This review will summarize the current thoughts on the role of miRNA processing in unique miRNA species present in these cancers. In addition, this review will focus on current data regarding miRNA molecules as unique biomarkers associated with clinically significant outcomes such as overall survival and chemotherapy resistance. We will also discuss why specific miRNA molecules are not recapitulated across multiple studies of the same cancer type. Although the mechanistic contributions of miRNA molecules to these clinical phenomena have been confirmed using in vitro and pre-clinical mouse model systems, these studies are truly only the beginning of our understanding of the roles miRNAs play in cancers of the female reproductive tract. This review will also highlight useful areas for future research regarding miRNAs as therapeutic targets in cancers of the female reproductive tract.

The role of MicroRNA molecules and MicroRNA-regulating machinery in the pathogenesis and progression of epithelial ovarian cancer

“…There are 14 studies that use only serous histotype samples (Supplemental Table 1) and 13 studies that mix histotypes in the same study (Supplemental Table 2). Since our two previous reviews (5, 25), the published studies for comprehensive microRNA profiling studies in EOC have expanded greatly in number and sophistication of experimental design. Clinical associations of specific microRNA molecules in EOC tissues are listed in Supplemental Table 3.…”

“…Improved screening approaches to detect early stage disease and novel histotype- or molecular-marker specific therapies for the treatment of late stage disease are urgently needed. This review highlights clinical associations of microRNA molecules and microRNA machinery, including DROSHA, DICER, and Argonaute proteins, in EOC identified since our last review (5). The clinical relevance of these potential new biomarkers as prognostic, diagnostic, and therapeutic molecules are discussed.…”

In vitro and in vivo activity of miR-92a–Locked Nucleic Acid (LNA)–Inhibitor against endometrial cancer

“…Recently endometrial oncogenesis was connected with alterations of microRNAs expression [2]. And a number of studies including our own research reported microRNAs as promising diagnostic and prognostic factors in EC [3–5].…”

Altered miRNA Expression in the Cervix During Pregnancy Associated with Lead and Mercury Exposure

“…Specifically, the gene subset enriched for abnormal morphology had mRNA targets predominantly regulated by let-7, miR-125b, and miR-24. For example, miR-205, miR-24, and miR-21 are highly expressed in cervical cancers compared to normal controls [49]; and miR-205 is thought to play a role in cervical cancer or serve as a diagnostic marker in plasma [22, 50]. Downregulation of miR-203 and upregulation of let-7 and miR-21 are associated with early stage and invasive cervical carcinoma [51].…”

“…The same investigators have linked these changes to reduced fetal growth [21]. Moreover, a number of miRNAs have been identified as associated with ovarian and cervical cancers (as reviewed in [22]) demonstrating that these biomarkers are biologically active in the reproductive system. Previously, we have shown that metal exposure affects the expression of specific miRNAs in blood from occupationally exposed individuals [23] and that miRNAs in the cervix during pregnancy are associated with subsequent gestational age at delivery [24], but metal-altered miRNA expression has not yet been investigated with respect to tissues involved in parturition and labor.…”