HBx-mediated miR-21 upregulation represses tumor-suppressor function of PDCD4 in hepatocellular carcinoma

Abstract

The hepatitis B virus (HBV) X protein (HBx) has a key role in the molecular pathogenesis of HBV-related hepatocellular carcinoma (HCC). However, the mechanism of HBx-mediated hepatocarcinogenesis remains to be elucidated. In this study, we aimed to better understand the effects of HBx on gene-expression profiles that participate in hepatocarcinogenesis and the mechanism by which HBx regulates these genes. Differentially expressed genes between L02-HBx and L02-Vector control cells were identified by microarray and validated using quantitative real-time PCR. HBx upregulates 456 genes and downregulates 843 genes, including programmed cell death 4 (PDCD4). PDCD4 was downregulated in clinical HCC specimens and the downregulation of PDCD4 in HCC is correlated with HBx. Furthermore, overexpression experiments in HCC cells proved that PDCD4 has strong tumor-suppressive effects both in vitro and in vivo, and may induce cell apoptosis to suppress the development of HCC. HBx induces expression of DNA methyltransferases (DNMTs), but failed to change the methylation status of the PDCD4 promoter. HBx downregulates PDCD4 expression at least partially through miR-21. Taken together, this study reported for the first time that HBx downregulates PDCD4 and upregulates miR-21 expression. The overexpression of PDCD4 could suppress tumorigenicity. The deregulation of PDCD4 by HBx through miR-21 represents a potential novel mechanism of the downregulation of PDCD4 in HBV-related HCC and provides new insights into HCC development.

Downregulation of MicroRNA-145 Caused by Hepatitis B Virus X Protein Promotes Expression of CUL5 and Contributes to Pathogenesis of Hepatitis B Virus-Associated Hepatocellular Carcinoma

“…miRNAs are believed to be an essential regulator in a wide range of human biological processes such as proliferation, apoptosis, cell cycle, and metastasis [28]. miRNAs may function as oncogene-or tumor-suppressive genes depending on the target genes.…”

The Role of the Clinical and Molecular Assays in Prostate Cancer Detection

“…MiR-21 (17q23), as an oncogene, is the most frequently in the development of many types of human cancers and in prostate cancer and patient follow-up [50][51][52]. Some studies reported that invasive tumors have over expression of miR-21 by targeting PTEN, TPM1, and PDCD4 genes in prostate cancer specimens [53,54]. The expression levels of miR-21, miR-125b, and miR-141 were highly expressed in prostate cancer as oncogenesis [55,56].…”

New horizon for radical cure of chronic hepatitis B virus infection

“…Moreover, HBx transgenic mice often de velop liver cancer [24,25] , and HBx protein has been found to accumulate in hepatocytes, affecting the expression of genes associated with signal transduction, cell cycle control, transcription, and immune response [23,26] . Expression of genes on the Xchromosome is regulated epigenetically, including by DNA and histone methyltransferases [27,28] , and by microRNAs [29,30] .…”