MicroRNA-146a inhibits epithelial mesenchymal transition in non-small cell lung cancer by targeting insulin receptor substrate 2

Abstract

Abstract. During cancer progression, some tumor cells show changes in their plasticity by morphological and phenotypical conversions, as an expression of mesenchymal markers and loss of epithelial markers, collectively referred to as epithelialmesenchymal transition (EMT). EMT has been increasingly recognized as a critical phenomenon in lung cancer progression. The goal of this study was to identify microRNAs involved in lung cancer progression. A microarray and qRT-PCR were performed to investigate the miRNA expression profiles in mesenchymal-like lung cancer cells. The role of miR-146a in lung cancer progression was measured by invasion and migration assays in vitro. Bioinformatics and luciferase report assays were used to identify the target of miR-146a. The expression of miR-146a was reduced in mesenchymal-like lung cancer cell lines. The overexpression of miR-146a induced a marked reduction of the mesenchymal marker and increase the epithelial marker in lung cancer cell lines. Moreover, the overexpression of miR-146a suppressed lung cancer cell migration and invasion. Co-treatment with miR-146a and gefitinib treatment showed a significant reduction of invasion in the resistant lung cancer cells induced by EMT. The expression of miR-146a was downregulated in advanced lung cancer tissues. Insulin receptor substrate 2 (IRS2), an adaptor protein that modulates normal growth, metabolism, survival, and differentiation, was identified as a target of miR-146a. miR-146a regulated the expression of IRS2 at the mRNA and protein levels. These data demonstrate for the first time that miR-146a suppresses lung cancer progression by repressing IRS2 expression. This provides new insight into the post-transcriptional regulation of lung cancer progression by miRNAs, a potential approach for the treatment of lung cancer.

The crosstalk between lncRNA and microRNA in cancer metastasis: orchestrating the epithelial-mesenchymal plasticity

“…Decreased expressions of them suppress E-cadherin and initiate EMT by targeting transcription factors ZEB1 and ZEB2. Conversely, ectopic expressions of these miRNAs in mesenchymal cells induce MET through downregulating ZEB1/2 levels, and thus increasing E-cadherin and decreasing N-cadherin [39-41]. Given the fact that miR-200 family members inhibit expression of ZEB by binding to highly conserved target sites in their 3’UTRs and ZEB factors in turn repress the genes of miR-200 family members by binding to highly conserved recognition sequences in their promoters, Emerging data have demonstrated that there is a double-negative feedback loop between them.…”

MiR-146a rs2910164 polymorphism and head and neck carcinoma risk: a meta-analysis based on 10 case-control studies

“…For instance, in a study on breast cancer, activated miR-146a may attenuate epidermal growth factor receptor expression, thus influencing the disease progression, and clinical prognosis [26]. In addition, miR-146a can inhibit epithelial mesenchymal transition and thus suppress lung cancer progression [27]. Therefore, inhibition of miR-146a expression may have an association with cancer risk.…”

Integrated microRNA and gene expression profiling reveals the crucial miRNAs in curcumin anti‐lung cancer cell invasion

“…miR‐483‐5p is upregulated in human lung adenocarcinoma, which is correlated with the progression of lung cancer . Recently, several miRNAs, such as miR‐135a, miR‐146a, and miR‐200, have been shown to be involved in the EMT of lung cancer . Furthermore, studies have shown that miR‐29a and miR‐200 inhibit proliferation and invasion in lung cancer cells in vitro, and this function might be mediated through the post‐transcriptional regulation of several proteins or abrogate the capacity of cells to undergo EMT .…”

“…13 Recently, several miRNAs, such as miR-135a, miR-146a, and miR-200, have been shown to be involved in the EMT of lung cancer. [14][15][16] Furthermore, studies have shown that miR-29a and miR-200 inhibit proliferation and invasion in lung cancer cells in vitro, and this function might be mediated through the post-transcriptional regulation of several proteins or abrogate the capacity of cells to undergo EMT. 17,18 These results show the important roles of miRNAs in anti-lung cancer metastasis.…”