Abstract
BackgroundColorectal 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.MethodsRT-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.ResultsmiR-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.ConclusionsTaken 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.
Highlights
Colorectal cancer (CRC) is one of the frequently occurred malignancies in the world
Results miR-96 targeted AMPKα2 and inhibited its expression in miR-96 has been reported to have the ability to accelerate the occurrence of CRC [16], but the specific mechanism by which miR-96 controls the occurrence of CRC remains unclear
CRC samples obtained from microarray GSE38389 from the GEO database. b: The expression of miR-96 in clinical CRC tissues and non-tumor tissues determined by Reverse transcription quantitative polymerase chain reaction (RT-qPCR) (n = 60 for patients in each group). c: The expression of miR-96 in CRC cells and HIEC cells determined by RT-qPCR. d: Map of differentially expressed genes in TCGA database
Summary
Colorectal cancer (CRC) is one of the frequently occurred malignancies in the world. Several onco-microRNAs (miRNAs or miRs), including miR-96, have been identified in the pathogenesis of CRC. We aimed to corroborate the oncogenic effect of miR-96 on CRC and to identify the specific mechanisms related to AMPKα2/FTO/m6A/MYC. Colorectal cancer (CRC) represents the third most frequently occurring cancers on a global scale [1]. MiR-96 has been widely implicated in the progression and metastatic potential of a plethora of cancers, including cervical [11], and ovarian [12] cancers. MiR-96 is witnessed to link to tumor invasion in addition to cancer cell migration and invasion in CRC [7, 13], little is well-understood regarding its downstream mechanisms related to the pathophysiological events of CRC
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