MicroRNA regulatory pathway analysis identifies miR-142-5p as a negative regulator of TGF-β pathway via targeting SMAD3

Abstract

MicroRNAs (miRNAs) are non-coding RNAs with functions of posttranscriptional regulation. The abnormally expressed miRNAs have been shown to be crucial contributors and may serve as biomarkers in many diseases. However, determining the biological function of miRNAs is an ongoing challenge. By combining miRNA targets prediction, miRNA and mRNA expression profiles in TCGA cancers, and pathway data, we performed a miRNA-pathway regulation inference by Fisher's exact test for enrichment analysis. Then we constructed a database to show the cancer related miRNA-pathway regulatory network (http://bioinfo.life.hust.edu.cn/miR_path). As one of the miRNAs targeting many cancer related pathways, miR-142-5p potentially regulates the maximum number of genes in TGF-β signaling pathway. We experimentally confirmed that miR-142-5p directly targeted and suppressed SMAD3, a key component in TGF-β signaling. Ectopic overexpression of miR-142-5p significantly promoted tumor cell proliferation and inhibited apoptosis, while silencing of miR-142-5p inhibited the tumor cell proliferation and promoted apoptosis in vitro. These findings indicate that miR-142-5p plays as a negative regulator in TGF-β pathway by targeting SMAD3 and suppresses TGF-β-induced growth inhibition in cancer cells. Our study proved the feasibility of miRNA regulatory pathway analysis and shed light on combining bioinformatics with experiments in the research of complex diseases.

MiR-142-5p Suppresses Tumorigenesis by Targeting PIK3CA in Non-Small Cell Lung Cancer

“…Previously, miR-142 displays a functional role in various cellular fuctions and disease, including cancer, virus infection, inflammation, and immune tolerance [29]. It has been reported that miR-142-5p suppresses TGF-β-induced growth inhibition by targeting SMAD3in cancer cells [30]; miR-375 and miR-142-5p regulate several oncogenic genes of TP53, MAPK and Wnt signal pathways in gastric cancer [31]; miR-142-5p inhibits cell growth and induce apoptosis by regulating FOXO in HCC [32]; miR-142-5p, targeting CLDN1, plays an important role in Hashimoto’s thyroiditis (HT) pathogenesis [33]; downregulated miR-142-5p significantly reduced cell migration and invasion in HCC [34]. In the current study, we found miR-142-5p was down-regulated in NSCLC cells.…”

MicroRNA‐142 is a multifaceted regulator in organogenesis, homeostasis, and disease

“…In particular, miR‐142‐5p targets Smad3 thereby suppressing TGFß‐induced growth inhibition in cancer cells. Overexpression of miR‐142‐5p leads to increased tumor cell proliferation and decreased apoptosis, while silencing of miR‐142‐5p leads to the opposite effects (Ma et al, ). Similarly miR‐142‐3p can repress TGFß‐induced growth inhibition by targeting the Tgf ß r1 receptor in nonsmall cell lung carcinoma cell lines (Lei et al, ).…”

Downregulation of miR-142-5p promotes tumor metastasis through directly regulating CYR61 expression in gastric cancer

“…Liu et al pointed that miR-142-5p promoted proliferation and colony formation, but inhibited apoptosis in colorectal cancer (CRC) [9]. Ma et al reported that miR-142-5p promoted cell proliferation by attenuating TGF-β mediated inhibitory effects via targeting SMAD3 [10]. Saito et al revealed that miR-142-5p suppressed the pro-apoptotic gene TP53INP1 as its target and facilitated the pathogenesis of gastric mucosa-associated lymphoid tissue (MALT) lymphoma [11].…”