Matrix metalloproteinase-19 promotes metastatic behavior in vitro and is associated with increased mortality in non-small cell lung cancer

• Published in: American journal of respiratory and critical care medicine 2014-10, Vol.190 (7), p.780-790
• Main Authors: Yu, Guoying, Herazo-Maya, Jose D, Nukui, Tomoko, Romkes, Marjorie, Parwani, Anil, Juan-Guardela, Brenda M, Robertson, Jennifer, Gauldie, Jack, Siegfried, Jill M, Kaminski, Naftali, Kass, Daniel J
• Format: Article
• Language: English
• Subjects: Apoptosis - genetics; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - mortality; Carcinoma, Non-Small-Cell Lung - pathology; Carcinoma, Non-Small-Cell Lung - secondary; Cell Death; Cell Line, Tumor; Down-Regulation - genetics; Epithelial-Mesenchymal Transition - genetics; Female; Gene Expression Regulation, Neoplastic - genetics; Humans; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - mortality; Lung Neoplasms - pathology; Male; Matrix Metalloproteinases, Secreted - genetics; MicroRNAs - genetics; Neoplasm Invasiveness - genetics; Original; Survival Rate
• ISSN: 1073-449X; 1535-4970
• DOI: 10.1164/rccm.201310-1903OC

Lung cancer is the leading cause of cancer death in both men and women in the United States and worldwide. Matrix metalloproteinases (MMPs) have been implicated in the development and progression of lung cancer, but their role in the molecular pathogenesis of lung cancer remains unclear. We have found that MMP19, a relatively novel member of the MMP family, is overexpressed in lung tumors when compared with control subjects. To test the hypothesis that MMP19 plays a significant role in the development and progression of non-small cell lung cancer (NSCLC). We have analyzed lung cancer gene expression data, immunostained lung tumors for MMP19, and performed in vitro assays to test the effects of MMP19 in NSCLC cells. We found that MMP19 gene and protein expression is increased in lung cancer tumors compared with adjacent and histologically normal lung tissues. In three independent datasets, increased MMP19 gene expression conferred a poorer prognosis in NSCLC. In vitro, we found that overexpression of MMP19 promotes epithelial-mesenchymal transition, migration, and invasiveness in multiple NSCLC cell lines. Overexpression of MMP19 with a mutation at the catalytic site did not impair epithelial-mesenchymal transition or expression of prometastasis genes. We also found that miR-30 isoforms, a microRNA family predicted to target MMP19, is markedly down-regulated in human lung cancer and regulates MMP19 expression. Taken together, these findings suggest that MMP19 is associated with the development and progression of NSCLC and may be a potential biomarker of disease severity and outcome.