Role of microRNAs in Gynecological Pathology

Abstract

microRNAs (miRNAs) are 21-22 nucleotide non-coding RNAs that regulate gene expression and play fundamental roles in biological processes. These small molecules bind to target mRNAs, leading to translational repression and/or mRNA degradation. Aberrant miRNA expression is associated with several human diseases such as cancer, cardiovascular disorders, inflammatory diseases and gynecological pathology. The present article reviews the role of miRNAs in four gynecological disorders that affect the ovary or the uterus, one benign and frequent disease (endometriosis) that is classified as a tumor-like lesion and three malignant gynecological diseases (endometrial, cervical and ovarian cancers). Endometriosis, defined as the presence of endometrium outside the uterus, is one of the most frequent benign gynecological diseases. Similarly to tumor metastasis, endometriotic implants require neovascularization to proliferate, invade the extracellular matrix and establish an endometriotic lesion. Despite its high prevalence and incapacitating symptoms, the exact pathogenic mechanism of endometriosis remains unsolved. A relationship between endometriosis and gynecological cancer, especially ovarian cancer, has been reported. Endometriosis is a multifactorial and polygenic disease, and emerging data provide evidence that a dysregulation of miRNA expression may be involved. miRNAs appear to be potent regulators of gene expression in endometriosis, raising the prospect of using miRNAs as biomarkers and therapeutic tools in this disease. In cancer, miRNAs have an important role as regulatory molecules, acting as oncogenes (oncomiRs) or tumor suppressors. Endometrial cancer is one of the most frequent gynecological malignancies in the developed countries. Cervical cancer, also one of the most common cancers in women, is associated with high-risk human papillomaviruses although this infection alone may not be enough to induce the malignant transformation. Ovarian cancer is the fifth leading cause of all cancer-related deaths among women. Over 80% of cases are diagnosed at an advanced stage, with a reduced five-year survival rate. Recent studies have shown that miRNAs are aberrantly expressed in different human cancer types, including endometrial, cervical and ovarian cancer, and that specific dysregulated miRNAs may act as biomarkers of patients' outcome. Recently, miRNAs have been detected in serum and plasma, and circulating miRNA expression profiles have now been associated with a range of different tumor types. Their accessibility in peripheral blood and stability given the fact that miRNAs circulate confined within exosomes, make researchers foster hope in their role as emerging biomarkers of cancer and other disorders. The development of therapies that might block the expression or mimic the functions of miRNAs could represent new therapeutic strategies for any of the aforementioned gynecological disorders.

Biological markers with potential clinical value in endometrial cancer — review of the literature

“…Corresponding with these findings Torres et al reported a significant up-regulation of all miR-200 family members, mostly pronounced in the early phase of EEC [21]. Additionally, an over expression was found to encounter miR-205 and miR-210, suggesting them to be selected as biomarkers for the early diagnosis and prognosis of EC [22]. Xiong and colleges studied miRNAs in relation to early stage (stage I) EEC, and identified a deregulation of hsa-miR-196a-5p, hsa-miR-328-3p, hsa-miR-337-3p, and hsa-miR-181c-3p indicating their clinical value as potential diagnostic markers [18].…”

“…Several authors have implied that an up-regulation of AEG-1 enhances characteristics of malignant aggressiveness making it an independent prognostic factor for unfavourable clinical outcome. This suggests that AEG-1 is valuable as a prognostic biomarker of disease progression and survival in patients with EC [16][17][18].…”

“…MiRNA have aroused wide attention because of their suggested role as important regulators of gene expression in a broad spectrum of diseases, including solid and hematologic malignancies [18]. This is a family of small (21-22 nucleotides) non-protein-coding RNAs responsible for messenger-RNA (mRNA) stability and expression of proteins at a post-transcriptional level [18,19]. For that reason, miRNAs has become well-established group of markers for the development and progression in a wide range of malignancies.…”

“…Additionally, an over expression was found to encounter miR-205 and miR-210, suggesting them to be selected as biomarkers for the early diagnosis and prognosis of EC [22]. Xiong and colleges studied miRNAs in relation to early stage (stage I) EEC, and identified a deregulation of hsa-miR-196a-5p, hsa-miR-328-3p, hsa-miR-337-3p, and hsa-miR-181c-3p indicating their clinical value as potential diagnostic markers [18]. By comparing gene expression patterns in normal endometrium, atypical hyperplasia and EC tissue, Boren et al described a total of 13 miRNAs that demonstrated a significance difference in level of expression [23].…”

“…The set of miRNAs presented in this paragraph were all identified by means of microarray technology and/or next-generation sequencing (NGS) with further conformation using qRT-PCR. To investigate miRNA profiles, both plasma and tissue were collected form patients with EEC revealing their potential as future noninvasive biomarkers for early detection, diagnosis and prognosis of EC [18,21]. Finally, it is suggested that miRNA can aid as potential therapeutic target by either blocking or mimicking the miRNA activity, however, further research need to be carried out [22,23].…”