HOTTIP Predicts Poor Survival in Gastric Cancer Patients and Contributes to Cisplatin Resistance by Sponging miR-216a-5p

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.

Prognostic Autophagy-Related Genes of Gastric Cancer Patients on Chemotherapy

“…The process of autophagy in particular in GC is ancient, regulating cellular mechanisms and homeostasis [21] .Several researches have demonstrated that this process is related to some proteomics and chemotherapeutic resistance in GC victims [22,23] . Studies have found that the autophagy of gastric cancer cells with enhanced chemotherapy-drug resistanceisenhanced, and inhibition of autophagy can eliminate chemotherapy-resistance [24,25] .Considering the importance of autophagy in chemotherapy resistance of GC, we can further explore the prognostic value of autophagy in the treatment of GC. In this study, we combined TCGA and GEO databases to accomplish our work.…”

Prognostic Autophagy-Related Genes of Gastric Cancer Patients on Chemotherapy

“…Several researches demonstrated this process is related to some proteomics and chemotherapeutic resistance in GC victims [22,23] . Studies have found that gastric cancer cells with enhanced resistance to chemotherapy have enhanced autophagy, and inhibition of autophagy can eliminate chemotherapy-resistance [24,25] . Considering the importance of autophagy in chemotherapy resistance of GC, we can further explore the prognostic value of autophagy in the treatment of GC.…”

The Role of Autophagy in Gastric Cancer Chemoresistance: Friend or Foe?

“…LncRNAs have been found to regulate autophagy and drug resistance ( Figure 5B) by acting as a competing endogenous RNA (ceRNA) or directly binding to proteins to modulate their expression and functions (as summarized in Table 2). It has been found that the expression levels of HOTTIP (HOXA distal transcript antisense RNA), MALAT1 (metastasis associated lung adenocarcinoma transcript 1), and HULC (hepatocellular carcinoma up-regulated long non-coding RNA) are elevated in chemotherapy-resistant gastric cancer cell lines and tumor tissues (YiRen et al, 2017;Xin et al, 2019;Zhao et al, 2020). Zhao et al (2020) have indicated that HOTTIP may function as a ceRNA of miR-216a-5p, increasing the expression level of BCL-2 and decreasing the expression level of Beclin-1.…”

“…It has been found that the expression levels of HOTTIP (HOXA distal transcript antisense RNA), MALAT1 (metastasis associated lung adenocarcinoma transcript 1), and HULC (hepatocellular carcinoma up-regulated long non-coding RNA) are elevated in chemotherapy-resistant gastric cancer cell lines and tumor tissues ( YiRen et al, 2017 ; Xin et al, 2019 ; Zhao et al, 2020 ). Zhao et al (2020) have indicated that HOTTIP may function as a ceRNA of miR-216a-5p, increasing the expression level of BCL-2 and decreasing the expression level of Beclin-1. Further studies have shown that HOTTIP overexpression inhibits autophagy and induces DDP resistance in gastric cancer while the silencing of HOTTIP increases the sensitivity of gastric cancer cells to DDP ( Zhao et al, 2020 ).…”

“… Zhao et al (2020) have indicated that HOTTIP may function as a ceRNA of miR-216a-5p, increasing the expression level of BCL-2 and decreasing the expression level of Beclin-1. Further studies have shown that HOTTIP overexpression inhibits autophagy and induces DDP resistance in gastric cancer while the silencing of HOTTIP increases the sensitivity of gastric cancer cells to DDP ( Zhao et al, 2020 ). YiRen et al (2017) have reported that MALAT1 acts as a ceRNA against miR-23b-3p and attenuates the inhibitory effects of miR-23b-3p on ATG12, leading to autophagy induction and VCR resistance in gastric cancer cells.…”