Exosome-Mediated Transfer of lncRNA HOTTIP Promotes Cisplatin Resistance in Gastric Cancer Cells by Regulating HMGAI/miR-218 Axis

Background: 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 (miR218) and HMGA1 were 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 miR218 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.