Abstract
Clear cell renal cell carcinoma (ccRCC) is the third most common urological cancer, and it has the highest mortality rate. The increasing drug resistance of metastatic ccRCC has resulted in the search for new biomarkers. Epigenetic regulatory mechanisms, such as genome-wide DNA methylation and inhibition of protein translation by interaction of microRNA (miRNA) with its target messenger RNA (mRNA), are deeply involved in the pathogenesis of human cancers, including ccRCC, and may be used in its diagnosis and prognosis. Here, we review oncogenic and oncosuppressive miRNAs, their putative target genes, and the crucial pathways they are involved in. The contradictory behavior of a number of miRNAs, such as suppressive and anti-metastatic miRNAs with oncogenic potential (for example, miR-99a, miR-106a, miR-125b, miR-144, miR-203, miR-378), is examined. miRNAs that contribute mostly to important pathways and processes in ccRCC, for instance, PI3K/AKT/mTOR, Wnt-β, histone modification, and chromatin remodeling, are discussed in detail. We also separately consider their participation in crucial oncogenic processes, such as hypoxia and angiogenesis, metastasis, and epithelial-mesenchymal transition (EMT). The review also considers the interactions of long non-coding RNAs (lncRNAs) and miRNAs of significance in ccRCC. Recent advances in the understanding of the role of hypermethylated miRNA genes in ccRCC and their usefulness as biomarkers are reviewed based on our own data and those available in the literature. Finally, new data and perspectives concerning the clinical applications of miRNAs in the diagnosis, prognosis, and treatment of ccRCC are discussed.
Highlights
Renal cell carcinoma (RCC) is diagnosed in approximately 90% of patients with kidney cancer
Reduced expressions of miR-149-5p and miR-149-3p are correlated in Clear cell renal cell carcinoma (ccRCC) with increased tumor aggressiveness and miRNAs in Crucial Pathways in Renal Carcinoma metastases (Okato et al, 2017). The authors attributed this to the fact that the target of both miRNAs is forkhead box protein M1 (FOXM1), a transcriptional activator that regulates the expression of cyclins, such as cyclin B1 and cyclin D1
MiR-124-3p interacts with the long non-coding RNAs (lncRNAs) HOX transcript antisense intergenic RNA (HOTAIR), miR-137 with lncRNA Small Nucleolar RNA Host Gene 1 (SNHG1), miR-182-5p with lncRNA MALAT1, and miR-203 with the HOTAIR and SNHG14 lncRNAs. These data reinforce the role of lncRNAs in the regulatory functions of miRNA, apparently by acting primarily as competing endogenous RNA (ceRNA) to reduce the content of specific miRNAs depending on other factors
Summary
The increasing drug resistance of metastatic ccRCC has resulted in the search for new biomarkers. Epigenetic regulatory mechanisms, such as genome-wide DNA methylation and inhibition of protein translation by interaction of microRNA (miRNA) with its target messenger RNA (mRNA), are deeply involved in the pathogenesis of human cancers, including ccRCC, and may be used in its diagnosis and prognosis. We review oncogenic and oncosuppressive miRNAs, their putative target genes, and the crucial pathways they are involved in. Recent advances in the understanding of the role of hypermethylated miRNA genes in ccRCC and their usefulness as biomarkers are reviewed based on our own data and those available in the literature.
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