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MiR-374a suppresses lung adenocarcinoma cell proliferation and invasion by targeting TGFA gene expression.

ABSTRACT: Aberrant expression of miR-374a has been reported in several types of human cancers, including lung cancer. However, the functional significance and molecular mechanisms underlying the role of miR-374a in lung cancer remain largely unknown. We found that the expression of miR-374a was significantly downregulated in lung adenocarcinoma tissues compared to adjacent normal lung tissues in samples included in The Cancer Genome Atlas. Functional studies revealed that overexpression of miR-374a led to inhibition of lung adenocarcinoma cell proliferation, migration and invasion and that miR-374a negatively regulated transforming growth factor-alpha (TGFA) gene expression by directly targeting the 3'-UTR of TGFA mRNA. Treating lung adenocarcinoma cells with TGF-α neutralizing antibody resulted in suppression of cell proliferation and invasion, which mimicked the action of miR-374a. Additionally, TGFA gene expression was significantly higher in tumor tissues compared to adjacent normal tissue and high TGFA gene expression strongly correlated with poor survival in patients with lung adenocarcinoma. Taken together, our studies suggest that miR-374a suppresses lung adenocarcinoma cell proliferation and invasion via targeting TGFA gene expression. Our findings may provide novel treatment strategies for lung adenocarcinoma patients.

SUBMITTER: Wu H

PROVIDER: S-EPMC4876989 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background:CircLARP4 is reported to act as a tumor suppressor in some cancers. However, the detailed roles and molecular basis of circLARP4 in non-small cell lung cancer (NSCLC) tumorigenesis are still unclear. The aim of the study is to explore the potential roles and molecular basis of circLARP4 in NSCLC tumorigenesis. Materials and Methods:qRT-PCR was taken to detect circLARP4 and miR-135b expressions. MTT assay, ?transwell invasion assay and flow cytometry analysis were applied to evaluate cell proliferation, invasion and apoptosis, respectively. Glycolysis was assessed by measuring hexokinase2 (HK2) expression, glucose consumption and lactate production. Association between circLARP4 and miR-135a was examined by luciferase reporter and RIP assays. The changes of the phosphatase and tension homolog (PTEN)/protein kinase B (AKT)/hypoxia-inducible factor-1? (HIF-1?) pathway were evaluated by Western blot. The nude mouse xenograft models were applied to verify the regulation of circLARP4 in vivo. Results:CircLARP4 was decreased in NSCLC tissues and cells. CircLARP4 overexpression blocked cell proliferation and invasion, and facilitated apoptosis in NSCLC cells. Meanwhile, circLARP4 overexpression suppressed glycolysis in NSCLC cells, as evidenced by the reduced HK2, glucose consumption and lactate production levels. Further analyses proved a downregulation of miR-135b by circLARP4 in a ceRNA-dependent manner in NSCLC cells. CircLARP4-mediated tumor? suppression on NSCLC progression was partially overturned by overexpressing miR-135b. Moreover, we confirmed that circLARP4 had antitumor effect on xen?ograft tumors and downregulated miR-135b. Furthermore, circLARP4 overexpression inhibited the PTEN/AKT/HIF-1? pathway in NSCLC cells and xenograft tumors by downregulating miR-135b. Conclusion:Our findings suggested that ?circLARP4 suppressed NSCLC progression by sponging miR-135b through inactivation of the PTEN/AKT/HIF-1? pathway, which broadens our understanding concerning the roles of circLARP4 in NSCLC tumorigenesis.

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MiR-374a suppresses lung adenocarcinoma cell proliferation and invasion by targeting TGFA gene expression.

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