Dataset Information

COMMD7 is correlated with a novel NF-?B positive feedback loop in hepatocellular carcinoma.

ABSTRACT: The correlation between nuclear factor-kappa B (NF-?B) and COMMD7 in hepatocellular carcinoma (HCC) development remained unclear. Here, our clinicopathological data showed that COMMD7 is overexpressed in HCC with a correlation to NF-?B. Using HepG2 and SMMC-7721 cells that aberrantly overexpressed COMMD7, we found that NF-?B directly binds with COMMD7 promoter and serves as an activator for COMMD7 transcription by luciferase reporter assay, chromatin immunoprecipitation (ChIP), and electrophoretic mobility shift assay (EMSA). In both HepG2 cells and SMMC-7721 cells, the silencing of COMMD7 significantly inhibited the cell proliferation, whereas NF-?B silencing inhibited the expression of COMMD7 and further inhibited cell proliferation. In addition, cell apoptosis was promoted by COMMD7 silencing, and further promoted by NF-?B silencing. Cell migration and invasion were also inhibited by COMMD7 silencing, and further inhibited by NF-?B silencing. Thus, COMMD7 is correlated with a novel NF-?B positive feedback loop in hepatocellular carcinoma. Developing strategies for the treatment of HCC should consider the correlation between NF-?B and COMMD7, so as to improve the specificity and sensitivity of therapy and to reduce toxicity.

SUBMITTER: Zheng L

PROVIDER: S-EPMC5078050 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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COMMD7 is correlated with a novel NF-κB positive feedback loop in hepatocellular carcinoma.

Zheng Lu L Deng Chang-Lin CL Wang Liang L Huang Xiao-Bing XB You Nan N Tang Yi-Chen YC Wu Ke K Liang Ping P Mi Na N Li Jing J

Oncotarget 20160501 22

The correlation between nuclear factor-kappa B (NF-κB) and COMMD7 in hepatocellular carcinoma (HCC) development remained unclear. Here, our clinicopathological data showed that COMMD7 is overexpressed in HCC with a correlation to NF-κB. Using HepG2 and SMMC-7721 cells that aberrantly overexpressed COMMD7, we found that NF-κB directly binds with COMMD7 promoter and serves as an activator for COMMD7 transcription by luciferase reporter assay, chromatin immunoprecipitation (ChIP), and electrophoret ...[more]

PMID: 27129158

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Project description:BackgroundHepatitis B Virus (HBV) contributes to liver carcinogenesis via various epigenetic mechanisms. The newly defined epigenetics, epitranscriptomics regulation, has been reported to involve in multiple cancers including Hepatocellular Carcinoma (HCC). Our previous study found that HBx, HBV encodes X protein, mediated H3K4me3 modification in WDR5-dependent manner to involve in HBV infection and contribute to oncogene expression. AlkB Homolog 5 (ALKBH5), one of epitranscriptomics enzymes, has been identified to be associated with various cancers. However, whether and how ALKBH5 is dysregulated in HBV-related HCC remains unclear yet. This study aims to investigate ALKBH5 function, clinical significance and mechanism in HBV related HCC (HBV-HCC) patients derived from Chinese people.MethodsThe expression pattern of ALKBH5 was evaluated by RT-qPCR, Western blot, data mining and immunohistochemistry in total of 373 HBV-HCC tissues and four HCC cell lines. Cell Counting Kit 8 (CCK8) assay, Transwell and nude mouse model were performed to assess ALKBH5 function by both small interference RNAs and lentiviral particles. The regulation mechanism of ALKBH5 was determined in HBx and WDR5 knockdown cells by CHIP-qPCR. The role of ALKBH5 in HBx mRNA N6-methyladenosine (m6A) modification was further evaluated by MeRIP-qPCR and Actinomycin D inhibitor experiment in HBV-driven cells and HBx overexpression cells.ResultALKBH5 increased in tumor tissues and predicts a poor prognosis of HBV-HCC. Mechanically, the highly expressed ALKBH5 is induced by HBx-mediated H3K4me3 modification of ALKBH5 gene promoter in a WDR5-dependent manner after HBV infection. The increased ALKBH5 protein catalyzes the m6A demethylation of HBx mRNA, thus stabilizing and favoring a higher HBx expression level. Furthermore, there are positive correlations between HBx and ALKBH5 in HBV-HCC tissues, and depletion of ALKBH5 significantly inhibits HBV-driven tumor cells' growth and migration in vitro and in vivo.ConclusionsHBx-ALKBH5 may form a positive-feedback loop to involve in the HBV-induced liver carcinogenesis, and targeting the loop at ALKBH5 may provide a potential way for HBV-HCC treatment.

Project description:BACKGROUND:Human T-cell leukemia virus type 1 (HTLV-1) infects primarily CD4+ T-lymphocytes and evoques severe diseases, predominantly Adult T-Cell Leukemia/ Lymphoma (ATL/L) and HTLV-1-associated Myelopathy/ Tropical Spastic Paraparesis (HAM/TSP). The viral transactivator of the pX region (Tax) is important for initiating malignant transformation, and deregulation of the major signaling pathway nuclear factor of kappa B (NF-?B) by Tax represents a hallmark of HTLV-1 driven cancer. RESULTS:Here we found that Tax mutants which are defective in NF-?B signaling showed diminished protein expression levels compared to Tax wildtype in T-cells, whereas Tax transcript levels were comparable. Strikingly, constant activation of NF-?B signaling by the constitutive active mutant of inhibitor of kappa B kinase (IKK2, IKK-?), IKK2-EE, rescued protein expression of the NF-?B defective Tax mutants M22 and K1-10R and even increased protein levels of Tax wildtype in various T-cell lines while Tax transcript levels were only slightly affected. Using several Tax expression constructs, an increase of Tax protein occurred independent of Tax transcripts and independent of the promoter used. Further, Tax and M22 protein expression were strongly enhanced by 12-O-Tetradecanoylphorbol-13-Acetate [TPA; Phorbol 12-myristate 13-acetate (PMA)]/ ionomycin, inducers of NF-?B and cytokine signaling, but not by tumor necrosis factor alpha (TNF-?). On the other hand, co-expression of Tax with a dominant negative inhibitor of ?B, I?B?-DN, or specific inhibition of IKK2 by the compound ACHP, led to a vast decrease in Tax protein levels to some extent independent of Tax transcripts in transiently transfected and Tax-transformed T-cells. Cycloheximide chase experiments revealed that co-expression of IKK2-EE prolongs the half-life of M22, and constant repression of NF-?B signaling by I?B?-DN strongly reduces protein stability of Tax wildtype suggesting that NF-?B activity is required for Tax protein stability. Finally, protein expression of Tax and M22 could be recovered by NH4Cl and PYR-41, inhibitors of the lysosome and the ubiquitin-activating enzyme E1, respectively. CONCLUSIONS:Together, these findings suggest that Tax's capability to induce NF-?B is critical for protein expression and stabilization of Tax itself. Overall, identification of this novel positive feedback loop between Tax and NF-?B in T-cells improves our understanding of Tax-driven transformation.

Dataset Information

COMMD7 is correlated with a novel NF-?B positive feedback loop in hepatocellular carcinoma.

Publications

COMMD7 is correlated with a novel NF-κB positive feedback loop in hepatocellular carcinoma.

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