Derlin-1 Is Overexpressed in Non-Small Cell Lung Cancer and Promotes Cancer Cell Invasion via EGFR-ERK–Mediated Up-Regulation of MMP-2 and MMP-9

• Published in: The American journal of pathology Vol. 182; no. 3; pp. 954 - 964
• Main Authors: Dong, Qian-ze, Wang, Yang, Tang, Zhong-ping, Fu, Lin, Li, Qing-chang, Wang, En-di, Wang, En-Hua
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-03-2013
• Subjects: Aged; Carcinoma, Non-Small-Cell Lung - enzymology; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - pathology; Cell Line, Tumor; Cell Proliferation; Down-Regulation - genetics; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases - metabolism; Female; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Lung Neoplasms - enzymology; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Male; MAP Kinase Signaling System - genetics; Matrix Metalloproteinase 2 - genetics; Matrix Metalloproteinase 2 - metabolism; Matrix Metalloproteinase 9 - genetics; Matrix Metalloproteinase 9 - metabolism; Membrane Proteins - genetics; Membrane Proteins - metabolism; Middle Aged; Multivariate Analysis; Neoplasm Invasiveness; Pathology; Proportional Hazards Models; Protein Binding - genetics; Receptor, Epidermal Growth Factor - metabolism; Up-Regulation - genetics
• ISSN: 0002-9440; 1525-2191
• DOI: 10.1016/j.ajpath.2012.11.019

Previous studies indicated a role of Derlin-1 in human cancers; however, its expression pattern in non-small cell lung cancer (NSCLC) and the molecular mechanism of Derlin-1 on cancer progression have not been characterized. In the present study, Derlin-1 expression was examined in lung cancer cell lines and human tissues. Derlin-1 overexpression correlated with pTNM stage, lymph node metastasis, and poor overall survival. siRNA knockdown of Derlin-1 impaired anchorage-dependent and anchorage-independent cell growth and invasion in A549 and H1299 cell lines, and its overexpression promoted proliferation and invasion in HBE and LTE cell lines. Derlin-1 depletion decreased matrix metalloproteinase (MMP)-2/9 at both protein and mRNA levels, with decreased MAP kinase/extracellular signal–regulated kinase (ERK)/ERK phosphorylation. Derlin-1 overexpression up-regulated MMP-2/9 expression and ERK phosphorylation, which could be reversed by MAP kinase/ERK kinase inhibitor, PD98059. The effect of Derlin-1 on MMP-2/9 up-regulation was abolished in ERK1/2 siRNA-treated cells. Further analysis showed that Derlin-1 overexpression induced EGFR phosphorylation. EGFR inhibitor blocked Derlin-1–mediated up-regulation of EGFR and ERK phosphorylation. MMP-2/9 and p -ERK up-regulation by Derlin-1 was partly blocked in EGFR-depleted cells with siRNA treatment. Immunoprecipitation confirmed the association between Derlin-1 and EGFR. In summary, our results showed that Derlin-1 is overexpressed in NSCLC and promotes invasion by EGFR-ERK–mediated up-regulation of MMP-2 and MMP-9. Derlin-1 may serve as a therapeutic target for NSCLC.