circHIPK3 promotes oxaliplatin-resistance in colorectal cancer through autophagy by sponging miR-637Research in context

Background: Resistance to oxaliplatin-based chemotherapy is a major cause of recurrence in colorectal cancer (CRC) patients. There is increasing evidence indicating that circHIPK3 is involved in the development and progression of tumours. However, little is known about the potential role of circHIPK3 in CRC chemotherapy and its molecular mechanisms in chemoresistance also remain unclear. Methods: Quantitative real-time PCR was performed to detect circHIPK3 expression in tissues of 2 cohorts of CRC patients who received oxaliplatin-based chemotherapy. The chemoresistant effects of circHIPK3 were assessed by cell viability, apoptosis, and autophagy assays. The relationship between circHIPK3, miR-637, and STAT3 mRNA was confirmed by biotinylated RNA pull-down, luciferase reporter, and western blot assays. Findings: In the pilot study, increased circHIPK3 expression was observed in chemoresistant CRC patients. Functional assays showed that circHIPK3 promoted oxaliplatin resistance, which was dependent on inhibition of autophagy. Mechanistically, circHIPK3 sponged miR-637 to promote STAT3 expression, thereby activating the downstream Bcl-2/beclin1 signalling pathway. A clinical cohort study showed that circHIPK3 was upregulated in tissues from recurrent CRC patients and correlated with tumour size, regional lymph node metastasis, distant metastasis, and survival. Interpretation: circHIPK3 functions as a chemoresistant gene in CRC cells by targeting the miR-637/STAT3/Bcl-2/beclin1 axis and might be a prognostic predictor for CRC patients who receive oxaliplatin-based chemotherapy. Funding: 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), and Jinan Science and Technology Development Plan(201805084, 201805003). Keywords: Colorectal cancer, Chemoresistance, circHIPK3, Autophagy, miR-637, STAT3