Secreted LOXL2 is a novel therapeutic target that promotes gastric cancer metastasis via the Src/FAK pathway.
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.
Peng
Liang
L
State Key Laboratory of Molecular Oncology, Cancer Institute (Hospital), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China.
Ran
Yu-Liang
YL
Hu
Hai
H
Yu
Long
L
Liu
Qian
Q
Zhou
Zhuan
Z
Sun
Yue-Min
YM
Sun
Li-Chao
LC
Pan
Jian
J
Sun
Li-Xin
LX
Zhao
Ping
P
Yang
Zhi-Hua
ZH
D000594:Amino Acid Oxidoreductases / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology / Q000627:therapeutic use; D000818:Animals; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D017931:DNA Primers; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D055029:Inverted Repeat Sequences / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis / Q000473:pathology; D013274:Stomach Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D014162:Transfection; D019061:src-Family Kinases / Q000378:metabolism
D017931:DNA Primers; D000594:Amino Acid Oxidoreductases; C119091:LOXL2 protein, human; D051416:Focal Adhesion Protein-Tyrosine Kinases; D019061:src-Family Kinases