microRNA-96 promotes occurrence and progression of colorectal cancer via regulation of the AMPKα2-FTO-m6A/MYC axis.
J Exp Clin Cancer Res
; 39(1): 240, 2020 Nov 12.
Article
en En
| MEDLINE
| ID: mdl-33183350
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Neoplasias Colorrectales
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Proteínas Proto-Oncogénicas c-myc
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MicroARNs
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Proteínas Quinasas Activadas por AMP
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Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato
Límite:
Aged
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Animals
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Humans
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Middle aged
Idioma:
En
Revista:
J Exp Clin Cancer Res
Año:
2020
Tipo del documento:
Article
Pais de publicación:
Reino Unido