Lysyl oxidase-like 4 (LOXL4) promotes proliferation and metastasis of gastric cancer via FAK/Src pathway

• DOI: 10.1007/s00432-014-1823-z
• Publication Date: 2014-09-13T02:20:38Z
• Authors: Rong-kun Li; Wen-yi Zhao; Fang Fang; Chun Zhuang; Xiao-xin Zhang; Xiao-mei Yang; Shu-heng Jiang; Fan-zhi Kong; Lin Tu; Wen-Ming Zhang; Sheng-li Yang; Hui Cao; Zhi-gang Zhang
• Keywords: Male; 0303 health sciences; Blotting, Western; Apoptosis; Adenocarcinoma; Middle Aged; Prognosis; 3. Good health; Gene Expression Regulation, Neoplastic; Immunoenzyme Techniques; Protein-Lysine 6-Oxidase; 03 medical and health sciences; Cell Movement; Focal Adhesion Kinase 1; Lymphatic Metastasis; Cell Adhesion; Humans; Female; Neoplasm Invasiveness; Amino Acid Oxidoreductases; RNA, Messenger; Cell Proliferation; Neoplasm Staging

Lysyl oxidase-like 4 (LOXL4) has been found up-regulated in a variety of human malignancies, but its clinical significance and functional roles in gastric cancer (GC) remain unknown.Lysyl oxidase-like 4 (LOXL4) expression level in tumor tissues and human GC cell lines was evaluated by quantitative real-time polymerase chain reaction, Western blotting and immunohistochemical analyses. Its clinical significance was inferred from the analysis of 379 tissue samples of patients with GC using tissue microarray. The roles of LOXL4 in cell proliferation, migration and invasion in vitro were analyzed by gene over-expression, RNA interference and recombinant protein. Effects of LOXL4 on regulation of focal adhesion kinase/Src kinase (FAK/Src) pathway were examined by Western blotting.Lysyl oxidase-like 4 (LOXL4) was up-regulated in GC tissues relative to paired non-tumor tissues, and this over-expression was significantly associated with tumor size, depth of tumor invasion, lymph node metastasis, tumor-node-metastasis (TNM) stages and poorer overall survival. Over-expression of LOXL4 has promotive effects on GC cell proliferation, migration and invasion in vitro, consistent with this, LOXL4 knockdown has inhibitive effects on GC cell proliferation, migration and invasion. Furthermore, recombinant human LOXL4 protein also promoted GC cell proliferation and migration. Subsequent mechanistic studies showed that LOXL4 could activate FAK/Src pathway to enhance cell-extracellular matrix adhesion.Taken together, our data reveal that up-regulation of LOXL4 expression is a frequent event in GC progression, contributes to tumor cell proliferation and metastasis, and LOXL4 may be a potential independent prognostic marker and therapeutic target for GC.