Yuhuan Li

BACKGROUND: Aberrant activation of the Wnt/β-catenin signaling pathway is frequently observed in colorectal cancer (CRC). β-catenin is the major Wnt signaling pathway effector and inactivation of adenomatous polyposis coli (APC) results in nuclear accumulation of β-catenin. It has been suggested that inactivation of APC plays an important role in activation of the Wnt/β-catenin pathway and in the progression of colorectal tumorigenesis. However, the mechanism through which APC mediates colorectal tumorigenesis is not understood. Increasing evidence suggests that the dysregulation of microRNAs (miRNAs) is involved in colorectal tumorigenesis. Although miR-494 has been reported as being an upregulated miRNA, the interplay between miR-494 and APC-mediated colorectal tumorigenesis progression remains unclear. METHODS: The expression of miR-494 in tissues from patients diagnosed with CRC was analyzed using a microarray and real-time PCR. The effects of miR-494 on cell proliferation and tumorigenesis in CRC cells were analyzed by flow cytometry, colony formation assays, BrdU incorporation assays, and CCK8 assays. The correlation between miR-494 expression and APC expression, as well as the mechanisms by which miR-494 regulates APC in CRC were also addressed. RESULTS: miR-494 was significantly upregulated in CRC tissues, and this increase was negatively associated with APC expression. APC was confirmed to be a direct target of miR-494 in CRC. Furthermore, overexpression of miR-494 induced Wnt/β-catenin signaling by targeting APC, thus promoting CRC cell growth. CONCLUSIONS: This study provides novel insights into the role of miR-494 in controlling CRC cell proliferation and tumorigenesis, and identifies miR-494 as a potential prognostic marker and therapeutic target.

Abstract N 6-methyladenosine (m6A) is one of the most abundant modifications on mRNAs and plays important roles in various biological processes. The formation of m6A is catalyzed by a methyltransferase complex (MTC) containing a key factor methyltransferase-like 3 (Mettl3). However, the functions of Mettl3 and m6A modification in hepatic lipid and glucose metabolism remain unclear. Here, we showed that both Mettl3 expression and m6A level increased in the livers of mice with high fat diet (HFD)-induced metabolic disorders. Overexpression of Mettl3 aggravated HFD-induced liver metabolic disorders and insulin resistance. In contrast, hepatocyte-specific knockout of Mettl3 significantly alleviated HFD-induced metabolic disorders by slowing weight gain, reducing lipid accumulation, and improving insulin sensitivity. Mechanistically, Mettl3 depletion-mediated m6A loss caused extended RNA half-lives of metabolism-related genes, which consequently protected mice against HFD-induced metabolic syndrome. Our findings reveal a critical role of Mettl3-mediated m6A in HFD-induced metabolic disorders and hepatogenous diabetes.