Li Rong-kun, Zhao Wen-yi, Fang Fang, Zhuang Chun, Zhang Xiao-xin, Yang Xiao-mei, Jiang Shu-heng, Kong Fan-zhi, Tu Lin, Zhang Wen-ming, Yang Sheng-li, Cao Hui, Zhang Zhi-gang
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, 800 Dongchuan Road, Shanghai, 200240, China.
J Cancer Res Clin Oncol. 2015 Feb;141(2):269-81. doi: 10.1007/s00432-014-1823-z. Epub 2014 Sep 14.
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.
赖氨酰氧化酶样4（LOXL4）在多种人类恶性肿瘤中被发现上调，但其在胃癌（GC）中的临床意义和功能作用仍不清楚。
通过定量实时聚合酶链反应、蛋白质印迹法和免疫组织化学分析评估肿瘤组织和人胃癌细胞系中赖氨酰氧化酶样4（LOXL4）的表达水平。通过使用组织芯片分析379例胃癌患者的组织样本推断其临床意义。通过基因过表达、RNA干扰和重组蛋白分析LOXL4在体外细胞增殖、迁移和侵袭中的作用。通过蛋白质印迹法检测LOXL4对粘着斑激酶/ Src激酶（FAK / Src）途径调节的影响。
与配对的非肿瘤组织相比，赖氨酰氧化酶样4（LOXL4）在胃癌组织中上调，并且这种过表达与肿瘤大小、肿瘤浸润深度、淋巴结转移、肿瘤-淋巴结-转移（TNM）分期和较差的总生存率显著相关。LOXL4的过表达对体外胃癌细胞增殖、迁移和侵袭具有促进作用，与此一致，LOXL4敲低对胃癌细胞增殖、迁移和侵袭具有抑制作用。此外，重组人LOXL4蛋白也促进胃癌细胞增殖和迁移。随后的机制研究表明，LOXL4可以激活FAK / Src途径以增强细胞与细胞外基质的粘附。
综上所述，我们的数据表明，LOXL4表达上调在胃癌进展中是常见事件，有助于肿瘤细胞增殖和转移，并且LOXL4可能是胃癌潜在的独立预后标志物和治疗靶点。
