1. circHIPK3 promotes oxaliplatin-resistance in colorectal cancer through autophagy by sponging miR-637
- Author
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Xin Zheng, Yanlei Wang, Chen Li, Xin Zhang, Yongmei Yang, Xinfeng Liu, Rui Zhao, Yanli Zhang, and Yi Zhang
- Subjects
0301 basic medicine ,Male ,Research paper ,Colorectal cancer ,medicine.medical_treatment ,OXA, oxaliplatin ,Pilot Projects ,STAT3 ,Mice ,0302 clinical medicine ,ceRNA, competing endogenous RNA ,Medicine ,CircRNAs, circular rnas ,3' Untranslated Regions ,biology ,Intracellular Signaling Peptides and Proteins ,General Medicine ,Middle Aged ,Prognosis ,Gene Expression Regulation, Neoplastic ,Oxaliplatin ,5FU, 5-fluorouracil ,030220 oncology & carcinogenesis ,CRC, colorectal cancer ,RNA Interference ,Colorectal Neoplasms ,Chemoresistance ,medicine.drug ,Signal Transduction ,Adult ,circHIPK3 ,miR-637 ,Cell Survival ,ROC, Receiver operating characteristic ,Protein Serine-Threonine Kinases ,General Biochemistry, Genetics and Molecular Biology ,OS, overall survival ,AUC, area under the ROC curve ,03 medical and health sciences ,Cell Line, Tumor ,Autophagy ,Animals ,Humans ,Viability assay ,Gene Silencing ,Aged ,Cell Proliferation ,Chemotherapy ,Dose-Response Relationship, Drug ,business.industry ,Competing endogenous RNA ,medicine.disease ,Xenograft Model Antitumor Assays ,digestive system diseases ,DFS, disease free survival ,Disease Models, Animal ,MicroRNAs ,030104 developmental biology ,RT-qPCR, reverse transcription quantitative real-time PCR ,ROC Curve ,Apoptosis ,Drug Resistance, Neoplasm ,Cancer research ,biology.protein ,RECIST, response evaluation criteria in solid tumours ,business ,Biomarkers - Abstract
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 ).
- Published
- 2019