MicroRNA-361-3p suppresses tumor cell proliferation and metastasis by directly targeting SH2B1 in NSCLC

Abstract

BackgroundLung cancer is the most common malignancies worldwide. However, the detailed molecular mechanisms underlying lung cancer progression are still not completely clear. MicroRNAs are small noncoding RNAs which occupy a crucial role of cancer metastasis. Accumulating evidence suggests that miR-361 plays important roles in human carcinogenesis. However, its precise biological role remains largely elusive, especially in lung cancer. This study examined the role of miR-361-3p in non-small cell lung cancer (NSCLC).MethodsReal-time quantitative PCR (qRT-PCR) was used to analyze the expression of miR-361-3p in NSCLC tissue and in compared adjacent non-cancerous tissues. The effect of miR-361-3p on proliferation was evaluated by CCK8 and colony formation assays. The effect of miR-361-3p on migration and invasion was evaluated by transwell assays. Western blotting and immunohistochemical staining were applied to analyze the expression of target proteins and downstream molecule, and the luciferase reporter assay to assess the target genes of miR-361-3p in non-small cell lung cancer cells.ResultsmiR-361-3p was significantly decreased in NSCLC tissue and cell lines, and its expression levels were highly correlated with lymph node metastasis (P < 0.01) and TNM stages (P < 0.05). Down-regulation of miR-361-3p promoted cell growth, proliferation, colony formation, invasion and migration in vitro, and promoted proliferation and metastasis in vivo (P < 0.01); whereas up-regulation of miR-361-3p had the contrary effects. The luciferase reporter assay showed that SH2B1 was a direct target gene of miR-361-3p. Enforced expression of miR-361-3p inhibited the expression of SH2B1 significantly and the restoration of SH2B1 expression reversed the inhibitory effects of miR-361-3p on NSCLC cell proliferation and metastasis.ConclusionsmiR-361-3p functions as a novel tumor suppressor in NSCLC and the anti-oncogenic activity may involve its inhibition of the target gene SH2B1. These findings suggest the possibility for miR-361-3p as a therapeutic target in NSCLC.

Circulating SH2B1 is associated with an increased risk of gastric cancer

“…It has been demonstrated that SH2B1 acts as an oncogene in lung cancer, esophageal cancer and neuroblastoma (9)(10)(11)(12). However, its functions in GC remain unknown.…”

“…All three members share a common domain structure that includes a dimerization domain, a pleckstrin homology domain, several proline-rich regions and a SH2 domain near the C-terminus (7). Previous studies have demonstrated that SH2B1 contributes to the malignant progression of tumors, including colon, ovary and non-small cell lung tumors (8)(9)(10)(11)(12). However, the effect of SH2B1 expression on GC has not yet been reported.…”

Downregulation of miR‐3127‐5p promotes epithelial‐mesenchymal transition via FZD4 regulation of Wnt/β‐catenin signaling in non‐small‐cell lung cancer

“…MicroRNAs (miRNAs) are small non‐coding RNAs that function by binding to the 3′‐untranslated regions (UTRs) of target mRNAs. Recent studies have demonstrated the involvement of miRNAs, such as miR‐29, miR‐143, miR‐191, and miR‐361, in regulating EMT, and tumor metastasis in NSCLC . Many miRNAs are dysregulated in cancer metastasis, and there are likely additional miRNAs involved in this process, which have not yet been identified.…”

“…Recent studies have demonstrated the involvement of miRNAs, such as miR-29, miR-143, miR-191, and miR-361, in regulating EMT, and tumor metastasis in NSCLC. [17][18][19][20] Many miRNAs are dysregulated in cancer metastasis, and there are likely additional miRNAs involved in this process, which have not yet been identified. We previously demonstrated that miR-3127-5p, which functions as a tumor suppressor, is downregulated in NSCLC, and associated with clinical stage and tumor recurrence.…”

SH2B1 promotes epithelial‐mesenchymal transition through the IRS1/β‐catenin signaling axis in lung adenocarcinoma

“…9 Both in central nervous system and in peripheral tissues, SH2B1 is widely expressed and systemic changes in SH2B1 expression, dominantly deletion mutation, could have profound effects to result in energy imbalance, obesity, severe leptin resistance, and type 2 diabetes in mice and humans. 17 Clinical importance for the field of SH2B1 research is not only focused on endocrine disease, 18,19 but also concerned with some solid tumors, including lung cancer, 20,21 esophageal cancer, 22 and thyroid carcinomas, 23 which detected somatic gain-of-function mutations. In addition, emerging several lines of basic research in cultured cells show that the function of SH2B1 is involved in actin cytoskeletal reorganization, 24,25 focal adhesion assembly and disassembly, 26 filopodium formation, 27,28 and mitogenic response, 29 suggesting that SH2B1 could regulate cells motility, 24,30 proliferation and differentiation 17,29 by enhancing Rac, 30 RET, 23 mTOR, 31 and STATs 29 signals, which are generally established mediators in tumorigenesis and EMT program in tumors.…”