Regulation of Integrin Subunit Alpha 2 by miR-135b-5p Modulates Chemoresistance in Gastric Cancer
Regulation of Integrin Subunit Alpha 2 by miR-135b-5p Modulates Chemoresistance in Gastric Cancer
复制标题
miR-135b-5p 对整合素亚基 Alpha 2 的调节可调节胃癌的化疗耐药性
DOI：
10.3389/fonc.2020.00308
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发表时间：
2020-03-13
影响因子：
4.7
通讯作者：
Zhao, Xiaodi
中科院分区：
文献类型：
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作者：
Wang, Qi;Cao, Tianyu;Zhao, Xiaodi
在过去的几十年里，化疗大大改善了胃癌（GC）患者的预后。然而，化疗耐药性的发展已成为治疗失败的主要原因。尽管许多分子参与了胃癌化疗耐药，但其病理机制仍不清楚。在这里，我们发现整合素α 2亚基（ITGA 2）在化疗耐药的GC细胞中上调，并且ITGA 2水平的增加与接受化疗的GC患者的不良预后相关。ITGA 2过表达导致胃癌细胞化疗耐药性升高和药物诱导的凋亡抑制。ITGA 2基因敲低导致体外和体内化疗耐药GC细胞的化疗敏感性恢复和凋亡增加。NanoString分析揭示了ITGA 2沉默后GC细胞中失调途径表达的独特特征。ITGA 2基因敲低后，MAPK/ERK通路和上皮-间质转化（EMT）表达下调。miR-135 b-5 p被鉴定为ITGA 2的直接上游调节因子。miR-135 b-5 p过表达可降低胃癌细胞的化疗耐药性并诱导凋亡，并通过抑制MAPK信号传导和EMT减弱ITGA 2诱导的化疗耐药性和抗凋亡作用。总之，本研究强调了ITGA 2在GC中的作用和机制，并提出新的miR-135 b-5 p/ITGA 2轴是化疗耐药性的表观遗传原因，具有诊断和治疗意义。
Chemotherapy has substantially improved gastric cancer (GC) patient outcomes in the past decades. However, the development of chemotherapy resistance has become the major cause of treatment failure. Although numerous molecules have been implicated in GC chemoresistance, its pathological mechanisms are still unclear. Here, we found that integrin subunit alpha 2 (ITGA2) is upregulated in chemoresistant GC cells and that increased ITGA2 levels correlated with the poor prognosis of GC patients who received chemotherapy. ITGA2 overexpression led to elevated chemotherapy resistance and drug-induced apoptosis inhibition in GC cells. ITGA2 knockdown resulted in restored chemosensitivity and increased apoptosis in chemoresistant GC cells both in vitro and in vivo. NanoString analysis revealed a unique signature of deregulated pathway expression in GC cells after ITGA2 silencing. The MAPK/ERK pathway and epithelial-mesenchymal transition (EMT) were found to be downregulated after ITGA2 knockdown. miR-135b-5p was identified as a direct upstream regulator of ITGA2. miR-135b-5p overexpression reduced chemoresistance and induced apoptosis in GC cells and attenuated ITGA2-induced chemoresistance and antiapoptotic effects by inhibiting MAPK signaling and EMT. In conclusion, this study underscored the role and mechanism of ITGA2 in GC and suggested the novel miR-135b-5p/ITGA2 axis as an epigenetic cause of chemoresistance with diagnostic and therapeutic implications.