TIMP-2 stimulates cell proliferation through c-Src activation, which influences a worse prognosis for pathological stage I lung adenocarcinoma

Abstract

Tissue inhibitors of metalloproteinases (TIMPs) have been known to be involved in tumorigenesis in both matrix metalloproteinase (MMP)-dependent and MMP-independent manner. This manuscript highlights key findings from our recent research describing the mechanism by which TIMP-2 stimulates lung adenocarcinoma cell proliferation. Our study showed for the first time that TIMP-2 induces lung adenocarcinoma cell proliferation through c-Src kinase activation, independent of MMP inhibition. c-Src kinase activity, induced by TIMP-2, concomitantly in­­­creased FAK, phosphoinositide 3-kinase (PI3-kinase)/AKT, and ERK1/2 activation. Furthermore, we showed from multiple cohorts that high TIMP-2 expression in lung adenocarcinomas is associated with a worse prognosis, especially for stage I lung adenocarcinoma. Through integrated analysis of The Cancer Genome Atlas data, Reverse Phase Protein Assay data showed that Src phosphorylation at Y418 significantly increased when TIMP-2 was highly expressed. TIMP-2 expression was significantly associated with the alteration of driving genes and activation of the PI3-kinase/AKT pathway. Taken together, our results suggest that TIMP-2 may play a key role in tumorigenesis of lung adenocarcinoma.