Expression profiling reveals dysregulation of cellular cytoskeletal genes in HBx–induced hepatocarcinogenesis

Genetic Laboratory of Development and Diseases, Institute of Biotechnology, Beijing, PR, China.
Cancer biology & therapy (Impact Factor: 3.07). 06/2007; 6(5):668-74. DOI: 10.4161/cbt.6.5.3955
Source: PubMed


The molecular mechanisms underlying hepatitis B virus encoded HBx protein-mediated tumorigenesis are not fully understood. In order to gain a better view of the effects of HBx on transcriptional regulation and hepatocarcinogenesis, the expression profiles of liver and tumor tissues from 6- and 18-month-old p21-HBx transgenic and control mice were monitored using oligo microarrays. Data analysis demonstrated that 42 genes were deregulated in both 6- and 18-month-old HBx transgenic mouse tissues. Gene ontology assisted analysis classified these genes into functionally related clusters that encode proteins related to metabolism, signal transduction, transcription regulation and stress responses. Among them, cytoskeletal genes, including microtubule genes tubulinbeta2 (Tubb2), tubulinbeta3 (Tubb3) and tubulinbeta6 (Tubb6), intermediate filament genes periplakin, keratin 8 (K8) and keratin 18 (K18) and actingamma1 (Actg1), were closely clustered and upregulated in liver tissues. These results were validated by semi-quantitative RT-PCR in both mouse and human HCC tissues. The upregulation of K8 and K18 was only detected in p21-HBx but not p21-HBsAg liver tissues, suggesting that the global change in the expression of cellular cytoskeletal genes was correlated with the expression of HBx transgene. These findings propose for the first time that systemic dysregulation of cellular cytoskeletal genes is involved in HBx-induced hepatocarcinogenesis.

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    • "Other protein targets for HBx are damaged DNA binding proteins, p53, proteasome subunits; these proteins interacts with the cyclic AMP-responsive element, ATF-2 and basal transcription factors [69]. It has been found that during HBx-induced-HCC many cellular cytoskeletal genes such as microtubule genes tubulinb 2, tubulinb 3, tubulinb 6, keratin 8 (K-8) and keratin 18 (K-18), acting1 (Actg1) and intermediate filament genes periplakin were dysregulated, As it has been documented that these genes were closely clustered and up regulated in liver tissues [70]. The metastasis-associated protein 1 (MTA1) gene is one of the important transcriptional target of HBx protein; It has been found that MTA1 activates hypoxia-inducible factor 1α and vascular endothelial growth factor which contributes to angiogenesis in hepatic cancer [71]. "
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    ABSTRACT: Hepatocellular carcinoma (HCC) is a deadly and emerging disease leading to death in Asian countries. High hepatitis B virus (HBV) load and chronic hepatitis B (CHB) infection increase the risk of developing HCC. HBV is a DNA virus that can integrate DNA into host genome thereby increase the yield of transactivator protein HBxAg that may deregulate many pathways involving in metabolism of cells. Several monogenic and polygenic risk factors are also involved in HCC development. This review summarizes the mechanism involved in HCC development and discusses some promising therapies to make HCC curative.
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    • "Immunoblotting were carried out mainly as described (44) using antibodies against Smad4 (provided by Dr Ye-Guang Chen), Smad2/3 (#3102, Cell Signal Technology, Inc.), eIF5 (sc-282, Santa Cruz Biotechnology, Inc.), MEF2 (sc-313, Santa Cruz Biotechnology), Myogenin (QC1653, Yuanpinghao Biotechnology, Beijing, China), caveolin3 (ab2912, Abcam plc, Cambridge, UK) and α-actin (BM0001, Boster Biological Technology, Wuhan, China). Immunostaining was carried out mainly as described (45). "
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