CircHIPK3 Promotes Oxaliplatin-Resistance of Colorectal Cancer Through Autophagy by Sponging miR-637

Abstract

Background: Resistance to oxaliplatin-based chemotherapy is a major cause of recurrence in colorectal cancer (CRC) patients. There is increasing evidence that circHIPK3 is involved in the development and progression of tumors. However, little is known about the potential role of circHIPK3 in CRC chemotherapy, and its molecular mechanisms in the chemoresistance also remain unclear. Methods: Quantitative real-time PCR was used to detect circHIPK3 expression in tissues of 2 cohorts CRC patients received oxaliplatin-based chemotherapy. The chemoresistance effects of circHIPK3 were assessed by cell viability, apoptosis and autophagy assays. The relationships among circHIPK3, miR-637, and Stat3 were confirmed by biotinylated RNA pull-down, luciferase reporter and western blot assays. Findings: In the pilot study, increased circHIPK3 expression was observed in CRC chemoresistance patients. Functional assays showed that circHIPK3 promoted oxaliplatin resistance dependent on the inhibition of autophagy. Mechanistically, circHIPK3 sponged miR-637 to promote Stat3 expression, thereby activating the downstream Bcl-2/Beclin-1 signaling pathway. Clinical cohort study showed circHIPK3 was upregulated in recurrence CRC tissues and correlated with tumor size, regional lymph nodes metastasis, distant metastasis, and survival. Interpretation: circHIPK3 functions as a chemoresistance gene in CRC cells by targeting the miR-637/Stat3/Bcl-2/Beclin-1 axis and may provide a prognostic predictor for CRC patients received oxaliplatin-based chemotherapy. Funding Statement: National Natural Science Foundation of China(81301506), Shandong Medical and Health Technology Development Project (2018WSB20002), Shandong Key Research and Development Program (2016GSF201122), Natural Science Foundation of Shandong Province (ZR2017MH044), Jinan Science and Technology Development Plan (201805084, 201805003). Declaration of Interests: There are no relevant conflicts of interest. Ethics Approval Statement: This study was approved by the Ethics Committee of Shandong Provincial Third Hospital and Qilu Hospital of Shandong University, and written informed consent was obtained from each patient.