Sun Li, Liu Lili, Liu Xiangqiang, Wang Yafang, Li Mengbin, Yao Liping, Yang Jianjun, Ji Genlin, Guo Changcun, Pan Yanglin, Liang Shuhui, Wang Biaoluo, Ding Jie, Zhang Hongwei, Shi Yongquan
State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an 710032, P.R. China.
Department of Oncology, Tangdu Hospital, Fourth Military Medical University, Xi'an 710038, P.R. China.
Oncol Rep. 2014 Jul;32(1):105-14. doi: 10.3892/or.2014.3184. Epub 2014 May 15.
Adhesion of cancer cells to the extracellular matrix (ECM) causes a novel acquired chemotherapeutic drug‑resistant phenotype, referred to as cell adhesion-mediated drug resistance (CAM-DR). Our previous studies suggested that the adhesion molecule MGr1-Ag/37LRP may promote multidrug resistance in gastric cancer cells. Therefore, we investigated MGr1-Ag/37LRP binding-induced adhesion, and its role in CAM-DR. Initial studies revealed that, after adhesion to the ECM, the multidrug-resistant gastric cancer cell lines SGC7901/VCR and SGC7901/ADR showed significantly higher mean adhesive cell numbers than non‑resistant SGC7901 cells. We then investigated expression of MGr1-Ag/37LRP in gastric cancer cells adhering to laminin. Western blotting, RT-PCR and dual-luciferase reporter assays showed that laminin induced MGr1-Ag/37LRP expression and activity. In vitro and in vivo assays revealed that small interfering RNA against MGr1-Ag/37LRP significantly reduced CAM-DR in SGC7901/VCR cells. In vivo and in vitro analyses revealed that binding of MGr1-Ag/37LRP decreased intracellular drug accumulation by increasing P-glycoprotein and multidrug-associated protein expression, and inhibited drug-induced apoptosis by regulating Bcl-2 and Bax expression. These results indicate that MGr1-Ag/37LRP contributes to laminin-mediated CAM-DR in gastric cancer cells, and is a potentially effective target for reversing this phenomenon in gastric cancer.
癌细胞与细胞外基质（ECM）的黏附会导致一种新获得的化疗耐药表型，称为细胞黏附介导的耐药性（CAM-DR）。我们之前的研究表明，黏附分子MGr1-Ag/37LRP可能促进胃癌细胞的多药耐药性。因此，我们研究了MGr1-Ag/37LRP结合诱导的黏附及其在CAM-DR中的作用。初步研究表明，在黏附到ECM后，多药耐药的胃癌细胞系SGC7901/VCR和SGC7901/ADR的平均黏附细胞数显著高于非耐药的SGC7901细胞。然后，我们研究了黏附于层粘连蛋白的胃癌细胞中MGr1-Ag/37LRP的表达。蛋白质免疫印迹法、逆转录-聚合酶链反应和双荧光素酶报告基因检测表明，层粘连蛋白诱导了MGr1-Ag/37LRP的表达和活性。体外和体内实验表明，针对MGr1-Ag/37LRP的小干扰RNA显著降低了SGC7901/VCR细胞中的CAM-DR。体内和体外分析表明，MGr1-Ag/37LRP的结合通过增加P-糖蛋白和多药相关蛋白的表达降低了细胞内药物蓄积，并通过调节Bcl-2和Bax的表达抑制了药物诱导的细胞凋亡。这些结果表明，MGr1-Ag/37LRP促成了层粘连蛋白介导的胃癌细胞CAM-DR，并且是逆转胃癌中这种现象的潜在有效靶点。
