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

被引:110
作者
Dong, Qian-ze [1 ]
Wang, Yang [1 ]
Tang, Zhong-ping [1 ]
Fu, Lin [1 ]
Li, Qing-chang [1 ]
Wang, En-di [3 ]
Wang, En-Hua [1 ,2 ]
机构
[1] China Med Univ, Dept Pathol, Affiliated Hosp 1, Shenyang 110001, Liaoning, Peoples R China
[2] China Med Univ, Coll Basic Med Sci, Shenyang 110001, Liaoning, Peoples R China
[3] Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA
基金
中国国家自然科学基金;
关键词
GROWTH-FACTOR RECEPTOR; MATRIX-METALLOPROTEINASE EXPRESSION; SIGNALING PATHWAYS; BREAST-CARCINOMA; AP-1; ACTIVATION; MATRIX-METALLOPROTEINASE-9; METASTASIS; MUTATIONS; THERAPY; KINASE;
D O I
10.1016/j.ajpath.2012.11.019
中图分类号
R36 [病理学];
学科分类号
100104 ;
摘要
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. (Am J Pathol 2013, 182: 954-964; http://dx.doi.org/10.1016/j.ajpath.2012.11.019)
引用
收藏
页码:954 / 964
页数:11
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