Integrin α5 promotes migration and cisplatin resistance in esophageal squamous cell carcinoma cells
Integrin α5 promotes migration and cisplatin resistance in esophageal squamous cell carcinoma cells
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整合素α5促进食管鳞状细胞癌细胞的迁移和顺铂耐药
DOI：
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发表时间：
2019
影响因子：
5.3
通讯作者：
Hongcan Shi
中科院分区：
文献类型：
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作者：
Sicong Hou;Weiguo Jin;Weiming Xiao;Bin Deng;Dacheng Wu;Jiehua Zhi;Keyan Wu;Xiaowei Cao;Shuai Chen;Yanbing Ding;Hongcan Shi
顺铂是治疗食管鳞癌的一线化疗药物。然而，顺铂耐药和转移的发生仍然是临床治疗的挑战。为了研究顺铂耐药的机制，我们从Eca 109和TE-1亲本细胞（Par）中建立了顺铂耐药细胞系（Res），并观察到与Par细胞相比，Res细胞中纤维连接蛋白（FN）介导的细胞迁移和铺展能力显著增强。此外，我们还发现整合素α5在Res细胞中的表达显著上调，抑制α5可导致更多的凋亡，并使Res细胞在体外和体内对顺铂重新敏感。在一种机制上，我们确定BARD 1的表达在Res细胞中显著增加，并且BARD 1的沉默逆转了α5对顺铂耐药性的影响。此外，我们发现Res细胞中α5/FAK/PI 3 K/AKT信号轴被激活，这介导了BARD 1表达的增加，以及顺铂抗性和细胞存活。因此，我们的研究结果表明，α5通过促进FAK/PI 3 K/AKT/BARD 1信号通路防止细胞凋亡和增强DNA损伤修复能力而成为顺铂耐药所必需的。总之，我们的研究提供了ESCC细胞中α5介导的顺铂耐药的合理机制，强调抑制α5可能是改善顺铂化疗疗效的潜在靶点。
Cisplatin, as one of the front-line chemotherapeutic drugs, is employed for the treatment of esophageal squamous cell carcinoma (ESCC). However, the occurrence of cisplatin resistance and metastasis remain as challenges in clinical therapy. To investigate the mechanism involved in cisplatin resistance, in this study, we established cisplatin resistant cell lines (Res) from Eca109 and TE-1 parental cells (Par), and we observed that fibronectin (FN)-mediated cell migration and spreading abilities are significantly increased in Res cells when compared to Par cells. Furthermore, we found that the integrin α5 expression is remarkably upregulated in Res cells, and inhibition of α5 results in more apoptosis and endows the Res cells resensitize to cisplatin in vitro and in vivo. In a mechanistic manner, we identified the expression of BARD1 is significantly increased in Res cells, and silencing of BARD1 reverse the effects of α5 on cisplatin resistance. Moreover, we found that the α5/FAK/PI3K/AKT signal axis is activated in Res cells, which mediates the increased expression of BARD1, as well as the cisplatin resistance and cell survival. Thus, our results demonstrate that α5 is required for cisplatin resistance through the promotion of FAK/PI3K/AKT/BARD1 signaling to prevent cells from apoptosis and enhance the DNA damage repair ability. Taken together, our study provides plausible mechanisms of α5-mediated cisplatin resistance in ESCC cells, highlighting that inhibition of α5 may be a potential target for improving efficacy in cisplatin-based chemotherapy.