CircRNA_101505 sensitizes hepatocellular carcinoma cells to cisplatin by sponging miR-103 and promotes oxidored-nitro domain-containing protein 1 expression

Abstract

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors and a leading cause of cancer-related deaths worldwide. Emerging studies have shown that circular RNAs (circRNAs) are differentially expressed in HCC and play an important role in HCC pathogenesis and metastasis. However, the mechanism of circRNA in the chemoresistance of HCC remains unclear. In this study, we aimed to investigate the role of circRNA in cisplatin resistance of HCC. We identified a novel circRNA circRNA_101505 that was decreased in cisplatin-resistant HCC tissues and cell lines, and associated with a poor survival outcome. Gain-of-function investigations showed that overexpression of circRNA_101505 suppressed cancer cell growth in vivo and in vitro, and enhanced cisplatin toxicity in HCC cells. Mechanistic studies found that circRNA_101505 could sensitize HCC cells to cisplatin by sponging miR-103, and thereby promoting oxidored-nitro domain-containing protein 1 (NOR1) expression. In conclusion, the significant inhibitory effects indicate circRNA_101505 to be a potential therapeutic target for HCC treatment. Our findings provide significant evidence to further elucidate the therapeutic use of circRNA in HCC.

Functions and mechanisms of circular RNAs in cancer radiotherapy and chemotherapy resistance

“…The effective cir-cRNAs can be loosely divided into two groups depending on their functions in cancer: suppressors (inhibitors of resistance) and promoters (enhancers of resistance) [6,[28][29][30]. For instance, circRHOT1 is upregulated in hepatocellular carcinoma (HCC), while circRNA_101505 is downregulated in cisplatin-resistant HCC tissues, and both are related to the survival of HCC patients [23,31].…”

“…CircRNA_101505 confers HCC cells with resistance to cisplatin by regulating miR-103 [31]. MiR-103 is downregulated in lung cancer cells, and upregulation of miR-103 enhances the sensitivity of NSCLC cells to gefitinib [156].…”

“…Hepatocellular carcinoma Circ_0003418 and circRNA_ 101505 are decreased in HCC tissues, while circ-SMARCA5 is reduced in intrahepatic cholangiocarcinoma (ICC) [31,160,161]. Silencing circ_0003418 promotes cisplatin resistance, probably though miR-7-and miR-383mediated effects on the Wnt/β-catenin pathway, but this mechanism still needs further investigation [161].…”

“…Silencing circ_0003418 promotes cisplatin resistance, probably though miR-7-and miR-383mediated effects on the Wnt/β-catenin pathway, but this mechanism still needs further investigation [161]. Cir-cRNA_101505 is especially lower in cisplatin-resistant HCC cells than in sensitive cells [31]. HCC or ICC patients with a lower level of circRNA_101505 or circ-SMARCA5 have a shorter overall survival period than patients with higher levels of these circRNAs [31,160].…”

“…Cir-cRNA_101505 is especially lower in cisplatin-resistant HCC cells than in sensitive cells [31]. HCC or ICC patients with a lower level of circRNA_101505 or circ-SMARCA5 have a shorter overall survival period than patients with higher levels of these circRNAs [31,160]. Overexpression of circRNA_101505 increases its ability to sponge miR-103 and subsequently elevates the expression of the tumor suppressor oxidored-nitro domaincontaining protein 1 (NOR1), which sensitizes HCC cells to cisplatin-induced apoptosis [31].…”