microRNA-96 promotes occurrence and progression of colorectal cancer via regulation of the AMPKα2-FTO-m6A/MYC axis
Authors: Ziyue Li
Jugao Chen
Jierong Chen
Yunmiao Guo
Caifeng Yue
Laisheng Li
Journal: Journal of Experimental & Clinical Cancer Research (2020)
Discipline: CLINICAL MEDICINE
Keywords: AMPKα2; Colorectal cancer; FTO; MYC; m6A modification
Affiliations: Department of Laboratory Medicine, Central People's Hospital of Zhanjiang, Guangdong Medical University Zhanjiang Central Hospital, 236 Yuanzhu Road, 524045, Zhanjiang, P. R. China., Division of Laboratory Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, 510080, Guangzhou, P. R. China., Guangzhou Women and Children's Medical Center, Guangzhou Medical University, 510623, Guangzhou, P. R. China., Department of Laboratory Medicine, The First Affiliated Hospital of Sun Yat-Sen University, 510080, Guangzhou, P. R. China., Department of Oncology, Shenzhen People's Hospital, Second Clinical Medical College of Jinan University, First Affiliated Hospital of Southern University of Science and Technology, No. 3046, Shennan East Road, Luohu District, 518020, Shenzhen, Guangdong Province, P. R. China. ., Clinical Research Institute of Zhanjiang, Central People's Hospital of Zhanjiang, Guangdong Medical University Zhanjiang Central Hospital, 236 Yuanzhu Road, 524045, Zhanjiang, Guangdong Province, P. R. China. .

Abstract:  Background: Colorectal cancer (CRC) is one of the frequently occurred malignancies in the world. To date, several onco-microRNAs (miRNAs or miRs), including miR-96, have been identified in the pathogenesis of CRC. In the present study, we aimed to corroborate the oncogenic effect of miR-96 on CRC and to identify the specific mechanisms related to AMPKα2/FTO/m6A/MYC. Methods: RT-qPCR and Western blot analysis were performed to examine the expression pattern of miR-96, AMPKα2, FTO and MYC in the clinical CRC tissues and cells. The relationship between miR-96 and AMPKα2 was then predicted using in silico analysis and identified by dual-luciferase reporter assay. Gain- or loss-of-function approaches were manipulated to evaluate the modulatory effects of miR-96, AMPKα2, FTO and MYC on cell growth, cycle progression and apoptosis. The mechanism of FTO-mediated m6A modification of MYC was analyzed via Me-RIP and PAR-CLIP analysis. The mediatory effects of miR-96 antagomir on cancerogenesis were validated in vivo. Results: miR-96, FTO and MYC were upregulated, while AMPKα2 was downregulated in CRC tissues and cells. miR-96 could down-regulate AMPKα2, which led to increased expression of FTO and subsequent upregulated expression of MYC via blocking its m6A modification. This mechanism was involved in the pro-proliferative and anti-apoptotic roles of miR-96 in CRC cells. Besides, down-regulation of miR-96 exerted inhibitory effect on tumor growth in vivo. Conclusions: Taken together, miR-96 antagomir could potentially retard the cancerogenesis in CRC via AMPKα2-dependent inhibition of FTO and blocking FTO-mediated m6A modification of MYC, highlighting novel mechanisms associated with colorectal cancerogenesis. 

Retracted: No

PubPeer comments:
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