標題: Blockade of ITGA2 Induces Apoptosis and Inhibits Cell Migration in Gastric Cancer
作者: Chuang, Yu-Chang
Wu, Hsin-Yi
Lin, Yu-Ling
Tzou, Shey-Cherng
Chuang, Cheng-Hsun
Jian, Ting-Yan
Chen, Pin-Rong
Chang, Yuan-Ching
Lin, Chi-Hsin
Huang, Tse-Hung
Wang, Chao-Ching
Chan, Yi-Lin
Liao, Kuang-Wen
生物科技學院
生物科技學系
分子醫學與生物工程研究所
生物資訊研究中心
College of Biological Science and Technology
Department of Biological Science and Technology
Institute of Molecular Medicine and Bioengineering
Center for Bioinformatics Research
關鍵字: Integrin alpha-2;ITGA2;Gastric cancer;Cell migration;Proliferation;Apoptosis;Therapeutic target
公開日期: 1-May-2018
摘要: Background: Gastric cancer is currently the fourth leading cause of cancer-related death worldwide. Gastric cancer is often diagnosed at advanced stages and the outcome of the treatment is often poor. Therefore, identifying new therapeutic targets for this cancer is urgently needed. Integrin alpha 2 (ITGA2) subunit and the beta 1 subunit form a heterodimer for a transmembrane receptor for extracellular matrix, is an important molecule involved in tumor cell proliferation, survival and migration. Integrin alpha 2 beta 1 is over-expressed on a variety of cancer cells, but is low or absent in most normal organs and resting endothelial cells. Results: In this report, we assessed the ITGA2 as the potential therapeutic target with the bioinformatics tools from the TCGA dataset in which composed of 375 gastric cancer tissues and 32 gastric normal tissues. According to the information from the Cancer Cell Line Encyclopedia (CCLE) database, the AGS cell line with ITGA2 high expression and the SUN-1 cell line with low expression were chosen for the further investigation. Interestingly, the anti-ITGA2 antibody (at 3 mu g/ml) inhibited approximately 50% survival of the AGS cells (over-expressed ITGA2), but had no effect in SNU-1 cells (ITGA2 negative). The extents of antibody-mediated cancer inhibition positively correlated with the expression levels of the ITGA2. We further showed that the anti-ITGA2 antibody induced apoptosis by upregulating the RhoA-p38 MAPK signaling to promote the expressions of Bim, Apaf-1 and Caspase-9, whereas the expressions of Ras and Bax/Bcl-2 were not affected. Moreover, blocking ITGA2 by the specific antibody at lower doses also inhibited cell migration of gastric cancer cells. Blockade of ITGA2 by a specific antibody down-regulated the expression of N-WASP, PAK and LIMK to impede actin organization and cell migration of gastric cancer cells. Conclusions: Here, we showed that the mRNA expression levels of ITGA2 comparing to normal tissues significantly increased. In addition, the results revealed that targeting integrin alpha 2 subunit by antibodies did not only inhibit cell migration, but also induce apoptosis effect on gastric cancer cells. Interestingly, higher expression level of ITGA2 led to significant effects on apoptosis progression during anti-ITGA2 antibody treatment, which indicated that ITGA2 expression levels directly correlate with their functionality. Our findings suggest that ITGA2 is a potential therapeutic target for gastric cancer.
URI: http://dx.doi.org/10.1186/s12575-018-0073-x
http://hdl.handle.net/11536/144928
ISSN: 1480-9222
DOI: 10.1186/s12575-018-0073-x
期刊: BIOLOGICAL PROCEDURES ONLINE
Volume: 10
Appears in Collections:Articles