Epithelial mesenchymal transition (EMT) plays a pivotal role in cancer progression and metastasis. Matrix metalloproteinases (MMPs) have a major role in remodeling the extracellular matrix (ECM) and are implicated in the invasion and metastasis of various malignancies. MMP12 is involved in many pathological processes including cancer, but has not been fully understood yet. To investigate the role of MMP12 in lung cancer cells, we examined the effect of overexpression or knockdown of MMP12 in A549 cells and measured the protein expression level of EMT markers. MMP12 overexpression induced considerable EMT phenotypic changes compared to the control group, both in vitro and in vivo. The mRNA levels of EMT markers, snail2/slug, snail1, zeb1, TGFβ-1, and fibronectin, increased significantly upon MMP12 overexpression. We observed that changes in the expression level of ECM components such as, collagen, lamin, and proteoglycans led to MMP12 overexpression-induced EMT. These alterations promoted the aggressiveness of the A549 cells, evident from changes in functional properties of the cell, such as proliferation, migration, invasion, and adhesion capacity. On the contrary, MMP12 suppression abrogated malignancy of A549 cells. MMP12 knockdown in A549 cells led to decreased mRNA expression of EMT marker proteins associated with adherence, invasion, and migration. Our results suggest that MMP12 is a key regulator of EMT in non-small cell lung cancer (NSCLC). MMP12 overexpression in A549 cells results in changes in the expression of EMT markers and ECM composition. Interestingly, the dynamic changes in the ECM components by MMP12 overexpression cause EMT reprogramming and induce malignant functional properties. Thus, we suggest that the control of MMP12 expression can be a potential target for new therapeutic strategies of NSCLC.

Citation Format: Na-Kyung Han, Yoon-Jin Lee, Hae-June Lee. MMP12 promotes EMT-mediated tumor aggressiveness in lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 166.