title: 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.
abstract: 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.
authors.affiliation: Department of Pathology, the First Affiliated Hospital and College of Basic Medical Sciences of China Medical University, Shenyang, Liaoning, China.
authors.forename: Qian-ze
authors.initials: QZ
authors.lastname: Dong
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.forename: Zhong-ping
authors.initials: ZP
authors.lastname: Tang
authors.forename: Lin
authors.initials: L
authors.lastname: Fu
authors.forename: Qing-chang
authors.initials: QC
authors.lastname: Li
authors.forename: En-di
authors.initials: ED
authors.lastname: Wang
authors.forename: En-Hua
authors.initials: EH
authors.lastname: Wang
mesh_terms: D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015536:Down-Regulation / Q000235:genetics; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D020935:MAP Kinase Signaling System / Q000235:genetics; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D015999:Multivariate Analysis; D009361:Neoplasm Invasiveness; D016016:Proportional Hazards Models; D011485:Protein Binding / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
chemical_list: C487709:DERL1 protein, human; D008565:Membrane Proteins; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9