Role of microRNAs as Clinical Cancer Biomarkers for Ovarian Cancer: A Short Overview

Abstract

Ovarian cancer has the highest mortality rate among gynecological cancers. Early clinical signs are missing and there is an urgent need to establish early diagnosis biomarkers. MicroRNAs are promising biomarkers in this respect. In this paper, we review the most recent advances regarding the alterations of microRNAs in ovarian cancer. We have briefly described the contribution of miRNAs in the mechanisms of ovarian cancer invasion, metastasis, and chemotherapy sensitivity. We have also summarized the alterations underwent by microRNAs in solid ovarian tumors, in animal models for ovarian cancer, and in various ovarian cancer cell lines as compared to previous reviews that were only focused the circulating microRNAs as biomarkers. In this context, we consider that the biomarker screening should not be limited to circulating microRNAs per se, but rather to the simultaneous detection of the same microRNA alteration in solid tumors, in order to understand the differences between the detection of nucleic acids in early vs. late stages of cancer. Moreover, in vitro and in vivo models should also validate these microRNAs, which could be very helpful as preclinical testing platforms for pharmacological and/or molecular genetic approaches targeting microRNAs. The enormous quantity of data produced by preclinical and clinical studies regarding the role of microRNAs that act synergistically in tumorigenesis mechanisms that are associated with ovarian cancer subtypes, should be gathered, integrated, and compared by adequate methods, including molecular clustering. In this respect, molecular clustering analysis should contribute to the discovery of best biomarkers-based microRNAs assays that will enable rapid, efficient, and cost-effective detection of ovarian cancer in early stages. In conclusion, identifying the appropriate microRNAs as clinical biomarkers in ovarian cancer might improve the life quality of patients.

Keywords: biomarker; early diagnosis; microRNA; molecular clustering analysis; ovarian cancer.

Figure 1

miRNA biogenesis involves five steps: 1. Transcription. Most miRNAs genes are transcribed by RNA polymerase II. However, a few miRNAs genes use RNA polymerase III. The initial long primary transcript is named primary microRNA (pri-miRNA) and is a hairpin containing transcript with imperfect double-stranded regions. 2. First Cleavage. The Microprocessor complex formed by DROSHA nuclease and RNA-binding protein DGCR8 removes the 5′ and 3′ ends of the pri-miRNA. The result is a pre-microRNA (pre-miRNA), a short hairpin of about 60 to 70 nt. 3. Nuclear export. pre-miRNA is translocated through nuclear pore into the cytoplasm, and after that, it is bound up and form a complex with Exportin-5, Ran, and GTP. 4. Second cleavage. In the cytoplasm, the pre-miRNA interacts with RNA-Induced Silencing Complex (RISC) loading complex (DICER1, plus an Argonaute protein and either TARBP2 or PRKRA) and is cleaved by DICER1 to a double-stranded miRNA (21 to 23 nucleotides) with a two-nucleotide 3′ overhang of 2-3 nt. 5. Incorporation into RNA-RISC and strand selection. The double-stranded miRNA is passed to the Argonaute protein where the passenger strand, will be removed and degraded, while the guide strand (the less Table 5′ end), will be selected. RISC can now regulate the gene expression of the mRNA transcript.

Figure 2

OncomiRNAs shown promise in cancer studies due to their stability and specificity to cells and tumors. Observe their association with gene targeting, tumor formation, cancer patient survival, and tumor stage and grade. OncomiRNAs associations raise the possibility of anticancer therapeutics by using miRNA inhibitors.