Molecular Mechanisms in Clear Cell Renal Cell Carcinoma: Role of miRNAs and Hypermethylated miRNA Genes in Crucial Oncogenic Pathways and Processes

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.

miR-124 and miR-203 synergistically inactivate EMT pathway via coregulation of ZEB2 in clear cell renal cell carcinoma (ccRCC)

“…Recent evidence pointed out a specific tumorsuppressive or oncogenic effect of miR-124 and miR-203, that both miRNAs can mediate tumorigenic processes, e.g. proliferation, migration, apoptosis and metastasis [31].…”

Sarcomatoid renal cell carcinoma: biology, natural history and management

“…In addition to genomic alterations, EMT can be related to epigenetic regulatory mechanisms such as methylation of gene promoters, histone modifications or microRNA-induced expression changes 83 – 86 . Studies on epigenetic regulatory mechanisms specific to sRCCs are not yet available, although these mechanisms have been reported in RCCs 83 , 84 , 87 . In a 2010 study that used clinical tumour samples and xenograft models to assess genomics and promoter methylation in the establishment of RCC metastasis 83 , variations in methylation contributed to the expression of pro-metastatic mesenchymal genes in non-metastatic RCC cells.…”

Gene Expression and Co-expression Networks Are Strongly Altered Through Stages in Clear Cell Renal Carcinoma

“…Regarding epigenetic modifications, comprehensive revisions have reported an increasing number of them (see Jung et al, 2009 ; Redova et al, 2011 ; Li et al, 2015 ). For instance, for ccRC, miR-99a, miR-106a, miR-125b, miR-144, miR-203, miR-378, or mir-28-5p have shown a dual behavior, oncogenic and oncosuppressive (Wang et al, 2016 ; Braga et al, 2019 ). Genes such as the aforementioned VHL, or RASSF1A, CDH1, and APAF1 have been found to be susceptible to hypermethylation (Dmitriev et al, 2014 ; Braga et al, 2015 ).…”