Lack of microRNA‐101 causes E‐cadherin functional deregulation through EZH2 up‐regulation in intestinal gastric cancer

Abstract

E-cadherin expression disruption is commonly observed in metastatic epithelial cancers and is a crucial step in gastric cancer (GC) initiation and progression. As aberrant expression of microRNAs often perturb the normal expression/function of pivotal cancer-related genes, we characterized and dissected a pathway that causes E-cadherin dysfunction via loss of microRNA-101 and up-regulation of EZH2 expression in GC. MicroRNA microarray expression profiling and array-CGH were used to reinforce miR-101 involvement in GC. By using quantitative real-time PCR and quantitative SNaPshot genomic PCR, we confirmed that miR-101 was significantly down-regulated in GC (p < 0.0089) in comparison with normal gastric mucosas and, at least in 65% of the GC cases analysed, this down-regulation was caused by deletions and/or microdeletions at miR-101 genomic loci. Moreover, around 40% of cases showing miR-101 down-regulation displayed concomitant EZH2 over-expression (at the RNA and protein levels), which, in turn, was associated with loss/aberrant expression of E-cadherin. Interestingly, this occurred preferentially in intestinal-type GCs, retaining allele(s) untargeted by classical CDH1-inactivating mechanisms. We also demonstrated that miR-101 gain of function or direct inhibition of EZH2 in Kato III GC cells led to a strong depletion of endogenous EZH2 and consequent rescue of E-cadherin membranous localization, mimicking results obtained in clinical GC samples. In conclusion, we show that deletions and/or microdeletions at both miR-101 genomic loci cause mature miR-101 down-regulation, subsequent EZH2 over-expression and E-cadherin dysfunction, specifically in intestinal-type GC.

miR-101 Promotes Breast Cancer Cell Apoptosis by Targeting Janus Kinase 2

“…In addition, a lower expression of miR-101 is associated with poorer prognosis. A functional analysis has demonstrated that reduced expression of miR-101 promotes cancer proliferation and suppresses apoptosis by directly targeting EZH2 [22,23,24]. Another study showed that overexpression of miR-101 in gastric cancer cell lines inhibits cell proliferation and induces apoptosis in vitro, and inhibits tumor growth in vivo [25].…”

miR-564 is downregulated in gastric carcinoma and targets E2F3

“…miRNAs can be measured through high-throughput microarray analysis. In GC, aberrant miRNA expression profiles have been associated with GC progression, prognosis and pathogenesis (16,17) by perturbing the function of target genes (18)(19)(20)(21). For example, miR-148a is significantly downregulated in GC cell lines and tissue (22)(23)(24).…”

Dynamic microRNA-101a and Fosab expression controls zebrafish heart regeneration

“…It remains vital to define the contributions of other conserved miRNAs in the context of both injury-induced CM proliferation and scar tissue removal. miR-101a is among a suite of highly conserved miRNAs with documented roles in cellular proliferation in the context of cancer, degenerative diseases and, more recently, in myocardial infarction injury to the adult mammalian heart (Carvalho et al, 2012;Pan et al, 2012;Varambally et al, 2008;Wang et al, 2010). Injuryinduced decreases in miR-101a expression stimulated cardiac fibrosis through enhanced fibroblast proliferation but showed no effects on CM proliferation (Pan et al, 2012).…”