Dataset Information

Aflatoxin B1 negatively regulates Wnt/?-catenin signaling pathway through activating miR-33a.

ABSTRACT: MicroRNAs are known to play an important role in modulating gene expression in various diseases including cancers and cardiovascular disorders, but only a few of them are associated with the pathology of aflatoxin B1 (AFB1), a potent mycotoxin. Here, we discovered a novel regulatory network between AFB1, miR-33a and ?-catenin in human carcinoma cells. The level of miR-33a was up-regulated in hepatocellular carcinoma (HCC) cells treated with AFB1, while in the same cells causing the decrease in ?-catenin expression when treated at their IC50 values. miR-33a, specifically miR-33a-5p, was demonstrated to down-regulate the expression of ?-catenin, affect the ?-catenin pathway, and inhibit cell growth. Also, by employing a luciferase assay, we found that miR-33a down-regulated ?-catenin by directly binding to the 3'-UTR of ?-catenin. These results suggested that AFB1 might down-regulate ?-catenin by up-regulating miR-33a. This understanding opens new lines of thought in the potential role of miR-33a in the clinical therapy of cancer.

SUBMITTER: Fang Y

PROVIDER: S-EPMC3754916 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Aflatoxin B1 negatively regulates Wnt/β-catenin signaling pathway through activating miR-33a.

Fang Yi Y Feng Youjun Y Wu Tongjin T Srinivas Swaminath S Yang Weiqiang W Fan Jue J Yang Chi C Wang Shihua S

PloS one 20130827 8

MicroRNAs are known to play an important role in modulating gene expression in various diseases including cancers and cardiovascular disorders, but only a few of them are associated with the pathology of aflatoxin B1 (AFB1), a potent mycotoxin. Here, we discovered a novel regulatory network between AFB1, miR-33a and β-catenin in human carcinoma cells. The level of miR-33a was up-regulated in hepatocellular carcinoma (HCC) cells treated with AFB1, while in the same cells causing the decrease in β ...[more]

PMID: 24015284

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Project description:Triggering Receptor Expressed on Myeloid cells 2 (TREM2), which is expressed on myeloid cells including microglia in the CNS, has recently been identified as a risk factor for Alzheimer's disease (AD). TREM2 transmits intracellular signals through its transmembrane binding partner DNAX-activating protein 12 (DAP12). Homozygous mutations inactivating TREM2 or DAP12 lead to Nasu-Hakola disease; however, how AD risk-conferring variants increase AD risk is not clear. To elucidate the signaling pathways underlying reduced TREM2 expression or loss of function in microglia, we respectively knocked down and knocked out the expression of TREM2 in in vitro and in vivo models. We found that TREM2 deficiency reduced the viability and proliferation of primary microglia, reduced microgliosis in Trem2-/- mouse brains, induced cell cycle arrest at the G1/S checkpoint, and decreased the stability of β-catenin, a key component of the canonical Wnt signaling pathway responsible for maintaining many biological processes, including cell survival. TREM2 stabilized β-catenin by inhibiting its degradation via the Akt/GSK3β signaling pathway. More importantly, treatment with Wnt3a, LiCl, or TDZD-8, which activates the β-catenin-mediated Wnt signaling pathway, rescued microglia survival and microgliosis in Trem2-/- microglia and/or in Trem2-/- mouse brain. Together, our studies demonstrate a critical role of TREM2-mediated Wnt/β-catenin pathway in microglial viability and suggest that modulating this pathway therapeutically may help to combat the impaired microglial survival and microgliosis associated with AD.SIGNIFICANCE STATEMENT Mutations in the TREM2 (Triggering Receptor Expressed on Myeloid cells 2) gene are associated with increased risk for Alzheimer's disease (AD) with effective sizes comparable to that of the apolipoprotein E (APOE) ε4 allele, making it imperative to understand the molecular pathway(s) underlying TREM2 function in microglia. Our findings shed new light on the relationship between TREM2/DNAX-activating protein 12 (DAP12) signaling and Wnt/β-catenin signaling and provide clues as to how reduced TREM2 function might impair microglial survival in AD pathogenesis. We demonstrate that TREM2 promotes microglial survival by activating the Wnt/β-catenin signaling pathway and that it is possible to restore Wnt/β-catenin signaling when TREM2 activity is disrupted or reduced. Therefore, we demonstrate the potential for manipulating the TREM2/β-catenin signaling pathway for the treatment of AD.

Dataset Information

Aflatoxin B1 negatively regulates Wnt/?-catenin signaling pathway through activating miR-33a.

Publications

Aflatoxin B1 negatively regulates Wnt/β-catenin signaling pathway through activating miR-33a.

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