Carcinogenesis Advance Access originally published online on July 22, 2009
Carcinogenesis 2009 30(10):1660-1669; doi:10.1093/carcin/bgp178
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Secreted LOXL2 is a novel therapeutic target that promotes gastric cancer metastasis via the Src/FAK pathway
State Key Laboratory of Molecular Oncology
1 Department of Abdominal Surgical Oncology, Cancer Institute (Hospital), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, People's Republic of China
* To whom correspondence should be addressed. Tel: +86 10 87788769; Fax: +86 10 67783169; Email: yang_zhihua_prof{at}yahoo.com.cn
Correspondence may also be addressed to Ping Zhao. Tel: +86 10 87788207; Fax: +86 10 67787079; Email: dr.zhaoping{at}263.net
The purpose of this study was to investigate invasion- and metastasis-related genes in gastric cancer. To this end, we used the transwell system to select a highly invasive subcell line from minimally invasive parent cells and compared gene expression in paired cell lines with high- and low-invasive potentials. Lysyl oxidase-like 2 (LOXL2) was overexpressed in the highly invasive subcell line. Immunohistochemical analysis revealed that LOXL2 expression was markedly increased in carcinoma relative to normal epithelia, and this overexpression in primary tumor was significantly associated with depth of tumor invasion, lymph node metastasis and poorer overall survival. Moreover, LOXL2 expression was further increased in lymph node metastases compared with primary cancer tissues. RNA interference-mediated knockdown and ectopic expression of LOXL2 showed that LOXL2 promoted tumor cell invasion in vitro and increased gastric carcinoma metastasis in vivo. Subsequent mechanistic studies showed that LOXL2 could activate both the Snail/E-cadherin and Src kinase/Focal adhesion kinase (Src/FAK) pathways. However, secreted LOXL2 induced gastric tumor cell invasion and metastasis exclusively via the Src/FAK pathway. Expression correlation analysis in gastric carcinoma tissues also revealed that LOXL2 promoted invasion via the Src/FAK pathway but not the Snail/E-cadherin pathway. We then evaluated secreted LOXL2 as a target for gastric carcinoma treatment and found that an antibody against LOXL2 significantly inhibited tumor growth and metastasis. Overall, our data revealed that LOXL2 overexpression, a frequent event in gastric carcinoma progression, contributes to tumor cell invasion and metastasis, and LOXL2 may be a therapeutic target for preventing and treating metastases.
Abbreviations: H2O2, hydrogen peroxide; LOX, lysyl oxidase; LOXL2, lysyl oxidase-like 2; PBS, phosphate-buffered saline; rhLOXL2, recombinant human lysyl oxidase-like 2; RNAi, RNA interference; shEGFP, enhanced green fluorescent protein RNA interference; Src/FAK, Src kinase/Focal adhesion kinase
These authors contributed equally to this work. Received February 7, 2009; revised June 26, 2009; accepted July 17, 2009.