Huafeng Jia, Deqing Zhang, Yong Ding, Yulian Zhang, Ailing Hu
Department of Gastroenterology, Hongze District People's Hospital, Huai'an, 223100 Jiangsu China.
2Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu China.
Cancer Cell Int. 2018 Apr 2;18:50. doi: 10.1186/s12935-018-0548-5. eCollection 2018.
Gastric cancer presents a major health burden worldwide. Therefore, many molecular targeting agents have been evaluated for treatment of gastric cancer. Gefitinib has shown anticancer activity against gastric cancer which work through inhibiting epidermal growth factor receptor (EGFR). However, the effect of gefitinib is limited due to its resistance. Therefore, understanding the mechanisms of gefitinib resistance is desperately needed to formulate novel strategies against gastric cancer. Here, we analyzed resistance mechanism from the crosstalk between EGFR and integrin β4.
Integrin β4-expression vector or siRNA were used to analyze the functional effects of integrin β4 on chemoresistance of gastric cancer cells to gefitinib. EGFR and integrin β4 expression, proliferation and apoptosis of gastric cancer cells were assayed by indirect immunofluorescence, western blot, MTT and flow cytometry respectively. EGFR and integrin β4 expression were also assayed on patient samples.
It was found that the integrin β4 expression was increased in gefitinib-resistant gastric cell line. The upregulated integrin β4 expression was identified to promote gefitinib resistance and proliferation, and inhibit apoptosis, while downregulation of integrin β4 was to inhibit gefitinib resistance and proliferation, and induce apoptosis. Moreover, the overexpression of integrin β4 in SGC7901 cells resulted in the down-regulation of p-EGFR protein levels while down-regulation of integrin β4, significantly resulted in overexpression of p-EGFR. The results of western blot from patients also showed there was obvious negative correlation between p-EGFR and integrin β4 in gastric cancer patients.
Considering the above results, it is concluded that the interaction of EGFR and integrin β4 may change the sensitivity of gefitinib treatment.
胃癌在全球范围内构成了重大的健康负担。因此，许多分子靶向药物已被评估用于治疗胃癌。吉非替尼已显示出对胃癌的抗癌活性，其作用机制是抑制表皮生长因子受体（EGFR）。然而，由于其耐药性，吉非替尼的疗效有限。因此，迫切需要了解吉非替尼耐药的机制，以制定针对胃癌的新策略。在此，我们从EGFR与整合素β4的相互作用中分析了耐药机制。
使用整合素β4表达载体或小干扰RNA（siRNA）分析整合素β4对胃癌细胞对吉非替尼化疗耐药性的功能影响。分别通过间接免疫荧光、蛋白质免疫印迹法（western blot）、MTT法和流式细胞术检测胃癌细胞中EGFR和整合素β4的表达、增殖及凋亡情况。还对患者样本检测了EGFR和整合素β4的表达。
发现在吉非替尼耐药的胃癌细胞系中整合素β4表达增加。整合素β4表达上调被证实可促进吉非替尼耐药性和细胞增殖，并抑制细胞凋亡，而整合素β4表达下调则抑制吉非替尼耐药性和细胞增殖，并诱导细胞凋亡。此外，SGC7901细胞中整合素β4的过表达导致p-EGFR蛋白水平下调，而整合素β4表达下调则显著导致p-EGFR过表达。患者的蛋白质免疫印迹结果也显示，胃癌患者中p-EGFR与整合素β4之间存在明显的负相关。
综合上述结果，得出结论：EGFR与整合素β4的相互作用可能会改变吉非替尼治疗的敏感性。
