Laminin 332 γ2 (LAMC2) enhances metastatic potential in lung adenocarcinoma

Abstract

Metastasis is the main cause of mortality in patients with non-small cell lung cancer (NSCLC), but the genetic predisposition of NSCLC to the progression of metastatic tumor remains unexplained. Using genome-wide transcriptional analysis in an experimental metastasis model, here we identified a causal gene signature, LAMC2, which cooperates with the diverse signaling pathways to enhance human NSCLC metastasis in vivo. We verified our gene discovery by qPCR and, using 3 independent microarray datasets constituting 453 samples, found a correlation between high expression of LAMC2 and high risk of recurrence or death in patients with lung adenocarcinoma, but not squamous cell carcinoma. Immunohistochemistry of stage I NSCLC (n=250) confirmed microarray data and showed localization of LAMC2 predominantly at the boundary of tumor and stroma, suggestive of potential role of LAMC2 on spread of tumor. Consistent with metastasis-enhancing function of LAMC2, ectopic expression of LAMC2 increased migration and invasion in a wide spectrum of lung adenocarcinoma cell lines whereas these metastatic abilities were ablated with shRNA-mediated knockdown of LAMC2 in both in vitro and in vivo. Unexpectedly, we found that ectopic expression or suppression of LAMC2 affected epithelial-mesenchymal transition (EMT) programming, involving ZEB1 and/or SNAIL. LAMC2-mediated migration and invasion occurred in the setting of activated EMT pathway. We conclude that LAMC2 enhances metastatic potential in lung ADC in the context of EMT and suggests thereby that LAMC2 could be a potential prognostic marker and therapeutic target of lung adenocarcinoma metastasis.