MiR-744 facilitates non-small cell lung cancer progression by direct transcriptional regulation and indirect MAPK pathway activation mediated upregulation of C-FOS

Abstract

Background: Metastasis is the leading cause of lung cancer associated death. Here, we focused on the function and molecular mechanism of miR-744 and its potential clinical application in lung carcinoma. Methods: The clinical cohort and data from TCGA were analyzed for the correlation of miR-744 and outcomes. Multiple NSCLC cell lines and a xenograft model were applied for the functional studies. Reporter assays were explored for transcriptional regulatory mechanism.Results: It was confirmed that the overexpression of miR-744 was significantly correlated with lymph node metastasis and poor prognosis in NSCLC. Both in vitro and in vivo studies revealed that miR-744 overexpression aggravated the growth, invasion and metastasis of NSCLC cells. MiR-744 enhanced the resistance of lung cancer cells to radiotherapy and paclitaxel. MiR-744 positively regulated C-FOS by directly binding to the promoter of C-FOS and -1195 to -1227 and -298 to -323 bp upstream of C-FOS gene were the direct and efficient miR-744 binding sites. MiR-744 could also indirectly upregulate c-FOS protein by activating MAPK pathway.Conclusion: Our findings uncover the function and a novel mechanism of miR-744 in mediating growth and metastasis of NSCLC cells. Our data suggests that miR-744 may serve as a possible therapeutic target for NSCLC.