Abstract
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.
Highlights
Gastric cancer (GC) is a leading cause of cancer-related deaths worldwide, accounting for over 720,000 deaths annually (Torre et al, 2015)
We found that ectopic expression of HOXA transcript at the distal tip (HOTTIP) did not affect cisplatin resistance, apoptosis, or autophagy ability in SGC7901 compared to cells transfected with the empty vector after blocking miR-216a-5p (Supplementary Figures S2A–D)
Cisplatin is an effective and standard chemotherapeutic drug used in GC (Einhorn and Donohue, 1977), and resistance to cisplatin is closely associated with poor prognosis
Summary
Gastric cancer (GC) is a leading cause of cancer-related deaths worldwide, accounting for over 720,000 deaths annually (Torre et al, 2015). It is important to study the chemoresistance mechanism in GC, which may help to improve the efficacy of chemotherapy in GC. HOTTIP (HOXA transcript at the distal tip) is a tumor-related long noncoding RNA (lncRNA) located at the chromosomal locus 7p15.2 (Wang et al, 2011). Our previous study showed that HOTTIP was markedly upregulated in the serum of GC patients and positively associated with tumor invasion depth, advanced TNM stage, and poor overall survival (Zhao et al, 2018). Chang et al (2016) reported that HOTTIP was an oncogene in GC progression and downregulation of HOTTIP inhibits cell growth and impairs cell invasion and migration by reducing the expression of HOXA13. The biological function and molecular mechanism of HOTTIP in chemoresistance in GC remain unclear
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