Identification of miRNA-491-5p and GIT1 as the modulators and biomarkers for oral squamous cell carcinoma (OSCC) invasion and metastasis
Abstract:
MicroRNAs are molecules that could play an abstruse role in cancer progression and metastasis. This study is to identify relevant micro-RNAs associated with invasive phenotype of oral cancer. We have established isogenic highly invasive oral squamous cell carcinoma (OSCC) lines from their respective low invasive parental lines via in vitro and in vivo selection protocols. Using microRNA microarray analysis, we found that miR-491-5p level was significantly decreased in the selected invasive lines compared with their parental lines. Overexpression of miR-491-5p in those highly invasive cells suppressed their migration/invasion and metastatic ability, which could be inversed by anti-miR-491-5p. The scaffold protein G protein-coupled receptor kinase-interacting protein 1 (GIT1) is a direct target of miR-491-5p by 3'UTR reporter assays. The miR-491-5p-mediated inhibition of migration/invasion and lung metastasis could be rescued by overexpression of GIT1. Depletion of GIT1 inhibited migration/invasion and lung metastasis of OSCC cells in a tail vein xenograft model. Overexpression of miR-491-5p or depletion of GIT1 reduced focal adhesions and concurrently reduced steady state levels of paxillin, phospho-paxillin, phospho-FAK, EGF/EGFR-mediated ERK1/2 activation as well as decreased MMP2/9 levels and activity. Elevated GIT1 was detected in OSCC tumors compared to their paired normal tissues and was significantly correlated with lymph node metastasis. Expression levels of miR-491-5p and GIT1 displayed an inverse relationship in OSCC. Low expression of miR-491-5p and high expression of GIT1 correlated with high grade of OSCC. Our study identified miR-491-5p and GIT1 as potential prognosis markers for OSCC.
