OncoTargets and Therapy (Dec 2019)
Exosome-Mediated Transfer of lncRNA HOTTIP Promotes Cisplatin Resistance in Gastric Cancer Cells by Regulating HMGA1/miR-218 Axis
Abstract
Jingyu Wang,1,* Baojun Lv,1,* Yonghui Su,1 Xiao Wang,1 Juyuan Bu,1 Lan Yao2 1Department of Gastrointestinal Surgery, The Fifth Affiliate Hospital of Sun Yat-Sen University, Zhuhai, People’s Republic of China; 2Department of Emergency Medicine, The Fifth Affiliate Hospital of Sun Yat-Sen University, Zhuhai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Juyuan BuDepartment of Gastrointestinal Surgery, The Fifth Affiliate Hospital of Sun Yat-Sen University, No. 52, Meihua East Road, Zhuhai, Guangdong 519000, People’s Republic of ChinaEmail [email protected] Lan YaoDepartment of Emergency Medicine, The Fifth Affiliate Hospital of Sun Yat-Sen University, No. 52, Meihua East Road, Zhuhai, Guangdong 519000, People’s Republic of ChinaEmail [email protected]: Chemoresistance has become a major obstacle for cancer therapy in clinic. Long noncoding RNAs (lncRNAs) have been reported to play critical roles in the development of chemoresistance in various tumors, including gastric cancer (GC). However, the role of HOXA transcript at the distal tip (HOTTIP) within extracellular vesicles (exosomes) in cisplatin-resistant GC cells remains largely unknown.Materials and methods: Cell proliferation, migration and invasion were detected using Cell Counting Kit-8 (CCK-8) and transwell assays, respectively. Western blot assay was employed to analyze the protein levels of E-cadherin, N-cadherin, Vimentin, CD63, CD83, GRP78, HMGA1, and high-mobility group A1 (HMGA1). The expression levels of HOTTIP, microRNA-218 (miR-218) and HMGA1were measured by quantitative real-time polymerase chain reaction (qRT-PCR). The interaction between miR-218 and HOTTIP or HMGA1 was predicted by bioinformatics software and confirmed by the dual-luciferase reporter and RNA immunoprecipitation (RIP) assays.Results: Cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) were promoted in cisplatin-resistant GC cells. HOTTIP level was upregulated in cisplatin-resistant GC cells and its downregulation enhanced cisplatin sensitivity. Moreover, extracellular HOTTIP could be incorporated into exosomes and transmitted to sensitive cells, thus disseminating cisplatin resistance. Additionally, exosomal HOTTIP promoted cisplatin resistance via activating HMGA1 in GC cells. Interestingly, HMGA1 was a target of miR-218 and miR-218 could directly bind to HOTTIP. Clinically, high expression of exosomal HOTTIP in serum was associated with poor response to cisplatin treatment in GC patients.Conclusion: Exosomal HOTTIP contributed to cisplatin resistance in GC cells by regulating miR-218/HMGA1 axis, providing a novel avenue for the treatment of GC.Keywords: gastric cancer, cisplatin resistance, HOTTIP, exosomes, HMGA1, miR-218
