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 α2β1 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 μg/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 up-regulating 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.

中文翻译：

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阻断 ITGA2 可诱导胃癌细胞凋亡并抑制细胞迁移。

背景技术胃癌目前是全世界癌症相关死亡的第四大原因。胃癌通常在晚期被诊断出来，治疗结果通常很差。因此，迫切需要确定这种癌症的新治疗靶点。整合素α2（ITGA2）亚基与β1亚基形成异源二聚体，是细胞外基质的跨膜受体，是参与肿瘤细胞增殖、存活和迁移的重要分子。整合素 α2β1 在多种癌细胞中过度表达，但在大多数正常器官和静息内皮细胞中表达量较低或不存在。结果 在本报告中，我们使用来自 TCGA 数据集的生物信息学工具评估了 ITGA2 作为潜在的治疗靶点，该数据集由 375 个胃癌组织和 32 个胃正常组织组成。根据癌细胞系百科全书（CCLE）数据库的信息，选择ITGA2高表达的AGS细胞系和低表达的SUN-1细胞系进行进一步研究。有趣的是，抗 ITGA2 抗体（3 μg/ml）抑制了大约 50% 的 AGS 细胞存活（过表达的 ITGA2），但对 SNU-1 细胞没有影响（ITGA2 阴性）。抗体介导的癌症抑制程度与 ITGA2 的表达水平呈正相关。我们进一步表明，抗 ITGA2 抗体通过上调 RhoA-p38 MAPK 信号传导以促进 Bim、Apaf-1 和 Caspase-9 的表达来诱导细胞凋亡，而 Ras 和 Bax/Bcl-2 的表达不受影响. 而且，用较低剂量的特异性抗体阻断 ITGA2 也抑制了胃癌细胞的细胞迁移。特异性抗体阻断 ITGA2 可下调 N-WASP、PAK 和 LIMK 的表达，从而阻碍胃癌细胞的肌动蛋白组织和细胞迁移。结论 在此，我们发现与正常组织相比，ITGA2 的 mRNA 表达水平显着增加。此外，研究结果表明，抗体靶向整合素α2亚基不仅可以抑制细胞迁移，还可以诱导胃癌细胞凋亡。有趣的是，ITGA2 的较高表达水平导致抗 ITGA2 抗体治疗期间对细胞凋亡进展的显着影响，这表明 ITGA2 表达水平与其功能直接相关。