Journal
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
Volume 39, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s13046-020-01731-7
Keywords
Colorectal cancer; microRNA-96; m6A modification; AMPKα 2; FTO; MYC
Categories
Funding
- National Natural Science Foundation of China [81602416, 81602691]
- Guangzhou Science and Technology Projects [201803010094]
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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 AMPK alpha 2/FTO/m6A/MYC. Methods RT-qPCR and Western blot analysis were performed to examine the expression pattern of miR-96, AMPK alpha 2, FTO and MYC in the clinical CRC tissues and cells. The relationship between miR-96 and AMPK alpha 2 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, AMPK alpha 2, 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 AMPK alpha 2 was downregulated in CRC tissues and cells. miR-96 could down-regulate AMPK alpha 2, 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 AMPK alpha 2-dependent inhibition of FTO and blocking FTO-mediated m6A modification of MYC, highlighting novel mechanisms associated with colorectal cancerogenesis.
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