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MiR-30a and miR-379 modulate retinoic acid pathway by targeting DNA methyltransferase 3B in oral cancer.

ABSTRACT: BACKGROUND:Epigenetic silencing of retinoic acid (RA) signaling-related genes have been linked with the pathogenesis and clinical outcome in oral squamous cell carcinoma (OSCC) carcinogenesis. However, the precise mechanisms underlying the abnormal silencing of RA signaling-related genes in OSCC have not been well investigated. METHODS:Using combined analysis of genome-wide gene expression and methylation profile from 40 matched normal-tumor pairs of OSCC specimens, we found a set of retinoid signaling related genes are frequently hypermethylated and downregulated in OSCC patient samples, including alcohol dehydrogenase, iron containing 1 (ADHFE1) and aldehyde dehydrogenase 1 family, member A2 (ALDH1A2), which are the important rate-limiting enzymes in synthesis of RA. The expression of ADHFE1 and ALDH1A2 in OSCC patients was determine by quantitative real-time PCR (qRT-PCR) and immunohistochemistry. The binding sites of miR-30a and miR-379 with DNA methyltransferase 3B (DNMT3B) were predicted using a series of bioinformatic tools, and validated using dual luciferase assay and Western blot analyses. The functions of miR-30a, miR-379, and DNMT3B were accessed by growth and colony formation analyses using gain- and loss-of-function approaches. Chromatin immunoprecipitation (ChIP) was performed to explore the molecular mechanisms by arecoline and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) treatment. RESULTS:We demonstrated that deregulated miR-30a and miR-379 could represent a mechanism for the silencing of ADHFE1 and ALDH1A2 in OSCC through targeting DNMT3B. Ectopic expression of miR-30a and miR-379 could induce re-expression of methylation-silenced ADHFE1 and ALDH1A2, and lead to growth inhibition in oral cancer cells. Furthermore, the dysregulation of the miRNAs and DNMT-3B may result from exposure to tobacco smoking and betel quid chewing. CONCLUSIONS:Our results demonstrate that tobacco smoking and betel quid chewing could repress miR-30a and miR-379, which upregulate the DNMT3B expression, in turn, lead to the hypermethylation of ADHFE1 and ALDH1A genes, consequently, promote the oncogenic activity. These findings highlight the potential use of retinoids in combination with epigenetic modifiers for the prevention or treatment of oral cancer.

SUBMITTER: Shiah SG

PROVIDER: S-EPMC7114797 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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MiR-30a and miR-379 modulate retinoic acid pathway by targeting DNA methyltransferase 3B in oral cancer.

Shiah Shine-Gwo SG Hsiao Jenn-Ren JR Chang Hsiao-Ju HJ Hsu Yuan-Ming YM Wu Guan-Hsun GH Peng Hsuan-Yu HY Chou Sung-Tau ST Kuo Ching-Chuan CC Chang Jang-Yang JY

Journal of biomedical science 20200402 1

<h4>Background</h4>Epigenetic silencing of retinoic acid (RA) signaling-related genes have been linked with the pathogenesis and clinical outcome in oral squamous cell carcinoma (OSCC) carcinogenesis. However, the precise mechanisms underlying the abnormal silencing of RA signaling-related genes in OSCC have not been well investigated.<h4>Methods</h4>Using combined analysis of genome-wide gene expression and methylation profile from 40 matched normal-tumor pairs of OSCC specimens, we found a set ...[more]

PMID: 32238162

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Project description:BACKGROUND:Toll-like receptor 4 (TLR4) is well known for activating the innate immune system; however, it is also highly expressed in adaptive immune cells, such as CD4+ T-helper 17 (Th17) cells, which play a key role in multiple sclerosis (MS) pathology. However, the function and governing mechanism of TLR4 in Th17 remain unclear. METHODS:The changes of TLR4 in CD4+ T cells from MS patients and experimental autoimmune encephalomyelitis (EAE) mice were tested. TLR4-deficient (TLR4-/-) naïve T cells were induced in vitro and transferred into Rag1-/- mice to measure Th17 differentiation and EAE pathology. DNA sequence analyses combining with deletion fragments and mutation analyses, chromatin immunoprecipitation (ChIP), and electrophoretic mobility shift assay (EMSA) were used to explore the mechanism of TLR4 signaling pathway in regulating Th17 differentiation. RESULTS:The levels of TLR4 were increased in CD4+ Th17 cells both from MS patients and EAE mice, as well as during Th17 differentiation in vitro. TLR4-/- CD4+ naïve T cells inhibited their differentiation into Th17, and transfer of TLR4-/- CD4+ naïve T cells into Rag1-/- mice was defective in promoting EAE, characterized by less demyelination and Th17 infiltration in the spinal cord. TLR4 signal enhanced Th17 differentiation by activating RelA, downregulating the expression of miR-30a, a negative regulator of Th17 differentiation. Inhibition of RelA activity increased miR-30a level, but decreased Th17 differentiation rate. Furthermore, RelA directly regulated the expression of miR-30a via specific binding to a conserved element of miR-30a gene. CONCLUSIONS:TLR4-/- CD4+ naïve T cells are inadequate in differentiating to Th17 cells both in vitro and in vivo. TLR4-RelA-miR-30a signal pathway regulates Th17 differentiation via direct binding of RelA to the regulatory element of miR-30a gene. Our results indicate modulating TLR4-RelA-miR-30a signal in Th17 may be a therapeutic target for Th17-mediated neurodegeneration in neuroinflammatory diseases.

Dataset Information

MiR-30a and miR-379 modulate retinoic acid pathway by targeting DNA methyltransferase 3B in oral cancer.

Publications

MiR-30a and miR-379 modulate retinoic acid pathway by targeting DNA methyltransferase 3B in oral cancer.

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