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Positive feedback loop of AKR1B10P1/miR-138/SOX4 promotes cell growth in hepatocellular carcinoma cells

ABSTRACT: Potential functions of pseudogenes on tumorigenesis and development of human malignancies have been gradually revealed recently. However, the specific regulation and intracellular events associated with pseudogenes have not been illustrated clearly in hepatocellular carcinoma (HCC). AKR1B10P1 is an isoform pseudogene of oncogenic AKR1B10, and is barely transcribed in normal hepatocytes. In this study, anomalous transcript of AKR1B10P1 was detected in both HCC tissues and cell lines, and is positively correlated with its parental genes. High level of AKR1B10P1 transcript is correlated with dismal clinicopathologic features, including large tumor dimension, high level of serum Alpha-fetoprotein (AFP), advanced TNM stages, tumor microsatellite formation and venous invasion. Loss-of and gain-of function assays demonstrated the exact impact of AKR1B10P1 on promoting HCC cell proliferation. Furthermore, transcription factor SOX4 was discovered facilitating the activation of AKR1B10P1 transcription, and was validated as a down-stream target degraded by tumor-suppressing miR-138. Meanwhile, we discovered the existence of a positive feedback from AKR1B10P1, by which miR-138 interacts with AKR1B10P1 via a competing endogenous RNA (ceRNA) way. Thus, we suggest a positive feedback loop of AKR1B10P1/miR-138/SOX4, promoting HCC cell proliferation. In summary, the AKR1B10P1/miR-138/SOX4 loop in HCC cells provides us potential and probable targets contributing to HCC prevention and therapeutic treatment.

SUBMITTER: Wang N

PROVIDER: S-EPMC7540089 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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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.

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Positive feedback loop of AKR1B10P1/miR-138/SOX4 promotes cell growth in hepatocellular carcinoma cells

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