Secreted LOXL2 is a novel therapeutic target that promotes gastric cancer metastasis via the Src/FAK pathway

Abstract

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.

LOXL2 Is Highly Expressed in Cancer-Associated Fibroblasts and Associates to Poor Colon Cancer Survival

“…BGN and TGM2 are associated to the ECM. Recently, LOXL2 has been shown to be critical in metastatic niche formation in hepatocellular carcinoma (33) and a marker of poor prognosis in breast, gastric cancer, and squamous cell carcinomas (34)(35)(36), mostly associated to metastasis. In colon cancer, LOXL2 was associated to less differentiated tumors (37), but no effect on prognosis was reported.…”

Post-translational Modifications of Recombinant Human Lysyl Oxidase-like 2 (rhLOXL2) Secreted from Drosophila S2 Cells*

“…Recently, the extracellular matrix (ECM) stiffening caused by hLOX and hLOXL2 has been linked to activation of the focal adhesion kinase (FAK)/Src signaling pathway and up-regulation of tissue inhibitor of metalloproteinase-1 (TIMP-1) and matrix metalloproteinase-9 (MMP-9), thereby increasing degradation/remodeling of the ECM and enabling subsequent metastatic dissemination (1,4,5). hLOXL2 is generally considered to play an equivalent role to hLOX in the ECM.…”

Lysine-Specific Histone Demethylases Contribute to Cellular Differentiation and Carcinogenesis

“…Different human cancers show an LOXL2 up-regulation [178,179] that correlates with tumor grade, poor prognosis, and decreased survival [168]. In fact, a possible role for LOXL2 in pre-metastatic niche formation has been suggested [180].…”