HOTTIP Predicts Poor Survival in Gastric Cancer Patients and Contributes to Cisplatin Resistance by Sponging miR-216a

Background: Gastric cancer (GC) is a huge burden worldwide and cisplatin resistance is the major obstruction in the effective chemotherapy of this disease. Previous studies have revealed that HOTTIP was involved in the pathology of GC and related to the poor overall survival of patients. However, the functional role of HOTTIP in GC chemoresistance remains obscure. Methods: Quantitative real-time PCR was used to detect HOTTIP expression in tissues of GC patients received cisplatin-based chemotherapy and GC cells. The chemoresistance effects of HOTTIP were assessed by cell viability, apoptosis and autophagy assays. The relationships among HOTTIP, miR-216a and Bcl-2 were confirmed by luciferase reporter and western blot assay. Findings: HOTTIP was remarkably upregulated in tissues of GC patients who were treated with gastrectomy and cisplatin chemotherapy, especially those with recurrent tumor. Meanwhile, HOTTIP was increased in the cisplatin-resistant cell, SGC7901/DDP, than in its parental cell, SGC7901. Functional assays demonstrated that HOTTIP expression could promote cisplatin-resistance and inhibit apoptosis and autophagy in GC cells. Mechanistic investigations revealed that HOTTIP might regulate functions of GC cells by sponging miR-216a. MiR-216a overexpression could decrease Bcl-2 expression, enhance Beclin1 expression and active autophagy. Interpretation: HOTTIP is closely associated with the recurrence of GC patients. And HOTTIP expression confers the cisplatin resistance via regulating miR-216a/BCL-2/Beclin1/autophagy pathways, which provides a novel strategy to overcome the resistance to chemotherapy in GC. Funding: The study was sponsored by Shandong Key Research and Development Program (2016GSF201122), Natural Science Foundation of Shandong Province (ZR2017MH044), Jinan Science and Technology Development Plan (201805084, 201805003), Shandong Medical and Health Technology Development Project (2018WSB20002). Declaration of Interest: The authors declare that they have no potential conflicts of interest. Ethical Approval: All patients provided their written informed consents and the Ethic committee of the Qilu Hospital of Shandong University approved this study.