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The role of a novel CAR-induced gene TUBA8 in hepatocellular carcinoma cell lines

ABSTRACT: The Tuba8 gene was identified as a CAR-regulated gene that was induced during phenobarbital (PB) promotion of liver tumor. TUBA8 was then over-expressed in heaptocarcinoma cells to determine the function of TUBA8.

ORGANISM(S): Mus musculus

PROVIDER: GSE29108 | GEO | 2011/11/29

SECONDARY ACCESSION(S): PRJNA140371

REPOSITORIES: GEO

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The role of a novel CAR-induced gene TUBA8 in hepatocellular carcinoma cell lines

Project description:The Tuba8 gene was identified as a CAR-regulated gene that was induced during phenobarbital (PB) promotion of liver tumor. TUBA8 was then over-expressed in heaptocarcinoma cells to determine the function of TUBA8. First, identify genes that are regulated by CAR and are induced during liver tumor development. Second, overexpressiong of an identified gene in transformed cells to detemine the biolgical function of the gene product. In this manuscript, the TUBA8 gene was examined.

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Role of a novel CAR-induced gene, TUBA8, in hepatocellular carcinoma cell lines.

Project description:Phenobarbital (PB), a nongenotoxic carcinogen, activates the nuclear constitutive active/androstane receptor (CAR), resulting in the transcriptional induction or repression of various hepatic genes. We previously demonstrated that liver tumors developed after chronic PB treatment only when CAR is present. To understand the molecular mechanism of tumor promotion, cDNA microarray analysis was performed. We identified tubulin alpha 8 (TUBA8) as one of the candidate genes that may be involved in liver tumor promotion. Tuba8 mRNA was induced with PB treatment in mouse livers before tumor development as well as in tumor tissues. Because the functions of TUBA8 are unknown in liver, we investigated the effects of TUBA8 gene expression on cell growth, proliferation, and cell migration. Sense or antisense cDNA for Tuba8 was stably transfected into Huh7 and HepG2 cells. Exogenous overexpression of Tuba8 inhibited cell growth and proliferation in Huh7 but not in HepG2 cells, while cell migration was increased in HepG2 cells but not Huh7 cells. These results indicate that TUBA8 can play a role in the regulation of cell growth, proliferation, and cell migration in a cell-specific manner in vitro, suggesting that TUBA8 may contribute to mouse liver tumorigenesis through these functions.

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Project description:Using a chimeric mouse humanized liver model, we provided evidence that human hepatocytes are refractory to the mitogenic effects of rodent constitutive androstane receptor (CAR) activators. To evaluate the functional reliability of this model, the present study examined mitogenic responses to phenobarbital (PB) in chimeric mice transplanted with rat hepatocytes, since rats are responsive to CAR activators. Treatment with 1000 ppm PB for 7 days significantly increased replicative DNA synthesis (RDS) in rat hepatocytes of the chimeric mice, demonstrating that the transplanted hepatocyte model is functionally reliable for cell proliferation analysis. Treatment of humanized CAR and pregnane X receptor (PXR) mice (hCAR/hPXR mice) with 1000 ppm PB for 7 days significantly increased hepatocyte RDS together with increases in several mitogenic genes. Global gene expression analysis was performed with liver samples from this and from previous studies focusing on PB-induced Wnt/β-catenin signaling, and showed that altered genes in hCAR/hPXR mice clustered most closely with liver tumor samples from a diethylnitrosamine/PB initiation/promotion study than with wild type mice. However, different gene clusters were observed for chimeric mice with human hepatocytes for Wnt/ß-catenin signaling when compared to those of hCAR/hPXR mice, wild type mice and liver tumor samples. The results of this study demonstrate clear differences in the effects of PB on hepatocyte RDS and global gene expression between human hepatocytes of chimeric mice and hCAR/hPXR mice, suggesting that the chimeric mouse model is relevant to humans for studies on the hepatic effects of rodent CAR activators, whereas the hCAR/hPXR mouse is not.

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