The Mechanism Study Of MiR-182 Inhibiting The Invasion And Metastasis Of Lung Cancer

The microRNA miR-182,belonging to the miR-183 family,is one of the most frequently studied cancer-related oncogenic miRNAs that is dysregulated in various cancer tissues,and it plays a crucial role in tumorigenesis and tumor progression.Studies revealed that miR-182 might function as an oncogenic or tumor suppressor miRNA in different tissues.However,the role of miR-182 in the development of lung cancer remains largely unknown.miR-182 expression in tumor samples from 58 patients,normal lung tissue samples,and lung cancer cell lines were evaluated by qRTPCR.Survival curves were analyzed using the Kaplan-Meier method and compared with a log-rank test.Our study demonstrated that miR-182 is frequently downregulated in metastatic NSCLC cells compared with primary tumor tissues.Over-expression of miR-182 significantly inhibited the migration and invasion of lung cancer cells and promoted the expression of the epithelial marker(E-cadherin)in addition to reducing the levels of Snail in lung cancer cells.Further studies demonstrated that miR-182 negatively regulated Met via direct binding to the Met 3?-untranslated region(3?-UTR).Furthermore,we found that miR-182 suppressed the phosphorylation of AKT and the nuclear accumulation of Snail,a transcription factor that promotes the epidermal to mesenchymal transition(EMT).Moreover,miR-182 could repress cell migration,invasion,and EMT of lung cancer cells induced by hepatocyte growth factor(HGF).miR-182 might suppress the EMT and metastasis via inactivation of Met/AKT/Snail in non-small cell lung cancer(NSCLC)cells,which implicates miR-182 may be useful as a new therapeutic target in NSCLC.Invadopodia,which are cancer-specific protrusive structures,play a crucial role in the metastatic cascade through degradation of the basement membrane and surrounding stroma,but the exact mechanism of regulation is not yet fully understood.In this study,we show that cortactin(CTTN),an important component of invadopodia,is upregulated in lung cancer tissues and is a marker of poorer prognosis in human NSCLC.Phorbol 12,13-dibutyrate and hepatocyte growth factor(HGF)can induce CTTN expression and motility,as well as invadopodia formation in non-small cell lung cancer(NSCLC).MicroRNA-182(miR-182)suppresses metastasis and invadopodia formation by targeting CTTN in NSCLC.qRT-PCR results showed that CTTN expression was inversely correlated with expression of miR-182.miR-182/CTTN suppresses invadopodia formation of lung cancer cells via suppression of the Cdc42/NWASP pathway.Furthermore,miR-182 negatively regulates invadopodia function and suppresses extracellular matrix degradation in lung cancer cells by inhibiting CTTN.In conclusion,our results demonstrated that miR-182 targets CTTN in NSCLC and suppresses lung cancer invadopodia formation and thus suppresses lung cancer metastasis,suggesting a therapeutic application of miR-182 in NSCLC.