HOTTIP Predicts Poor Survival in Gastric Cancer Patients and Contributes to Cisplatin Resistance by Sponging miR-216a-5p
HOTTIP Predicts Poor Survival in Gastric Cancer Patients and Contributes to Cisplatin Resistance by Sponging miR-216a-5p
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DOI：
10.3389/fcell.2020.00348
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发表时间：
2020-05
影响因子：
5.5
通讯作者：
Rui Zhao;Xin Zhang;Yan-li Zhang;Ya-ping Zhang;Yong-mei Yang;Yue Sun;Xin Zheng;Ai-lin Qu
中科院分区：
文献类型：
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作者：
Rui Zhao;Xin Zhang;Yan-li Zhang;Ya-ping Zhang;Yong-mei Yang;Yue Sun;Xin Zheng;Ai-lin Qu
胃癌（GC）是一个重大的全球公共卫生负担，顺铂耐药是导致化疗失败的主要原因。以往的研究表明，HOXA转录在远端（HOTTIP）参与了胃癌的病理，并与总生存率低。然而，HOTTIP在GC化疗耐药性中的功能作用仍不清楚。本研究采用实时荧光定量PCR技术分析HOTTIP在胃癌细胞系和接受顺铂化疗的胃癌患者组织中的表达。HOTTIP介导的化疗耐药性的机制，使用细胞活力，凋亡和自噬测定进行了评估。HOTTIP、miR-216 a-5 p和Bcl-2之间的关系使用荧光素酶报告基因和蛋白质印迹分析来确定。HOTTIP在接受胃切除术和顺铂化疗的胃癌患者的组织中显著上调，尤其是在那些复发的肿瘤中。此外，HOTTIP增加顺铂耐药细胞系，SGC 7901/DDP，与亲本细胞，SGC 7901。功能分析表明，HOTTIP的表达促进顺铂耐药，并抑制胃癌细胞的凋亡和自噬。HOTTIP可能通过吸收miR-216 a-5 p来调控胃癌细胞的功能。miR-216 a-5 p过表达降低Bcl-2表达，增强Beclin 1表达和活性自噬。总之，我们的研究表明HOTTIP与GC患者的复发密切相关。HOTTIP表达通过调节miR-216 a-5 p/BCL-2/Beclin 1/自噬途径赋予顺铂耐药性，这为克服GC对化疗的耐药性提供了一种新的策略。
Gastric cancer (GC) is a significant public health burden worldwide, and cisplatin resistance is the leading cause for the failure of chemotherapy in this disease. Previous studies have revealed that HOXA transcript at the distal tip (HOTTIP) is involved in the pathology of GC and is associated with poor overall survival. However, the functional role of HOTTIP in GC chemoresistance remains unclear. In this study, quantitative real-time PCR was used to analyze HOTTIP expression in GC cell lines and in tissues of GC patients who received cisplatin-based chemotherapy. The mechanism of HOTTIP-mediated chemoresistance was assessed using cell viability, apoptosis, and autophagy assays. The relationships among HOTTIP, miR-216a-5p, and Bcl-2 were determined using luciferase reporter and western blot assays. HOTTIP was markedly upregulated in the tissues of GC patients who were treated with gastrectomy and cisplatin chemotherapy, especially in those with recurrent tumors. Further, HOTTIP was increased in the cisplatin-resistant cell line, SGC7901/DDP, compared to the parental cells, SGC7901. Functional assays demonstrated that HOTTIP expression promoted cisplatin resistance and inhibited apoptosis and autophagy in GC cells. Mechanistic investigations revealed that HOTTIP may regulate the functions of GC cells by sponging miR-216a-5p. MiR-216a-5p overexpression decreased Bcl-2 expression, enhanced Beclin1 expression, and active autophagy. Taken together, our study demonstrated that HOTTIP is closely associated with recurrence in GC patients. HOTTIP expression confers cisplatin resistance by regulating the miR-216a-5p/BCL-2/Beclin1/autophagy pathway, which provides a novel strategy to overcome resistance to chemotherapy in GC.