Oncogene-specific gene expression signatures at preneoplastic stage in mice define distinct mechanisms of hepatocarcinogenesis

Coulouarn, Cédric; Gómez–Quiroz, Luis E.; Lee, Ju Seog; Kaposi-Novák, Pál; Conner, Elizabeth A.; Goldina, Tatyana A.; Онищенко, Г. Е.; Factor, Valentina M.; Thorgeirsson, Snorri S.

doi:10.1002/hep.21293

Cited by 53 publications

(53 citation statements)

References 50 publications

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“…Both Mdr2-KO and E2F1-transgenic mice are characterized by progressive steatosis. In E2F1-transgenic mice, the transcription factor Srebp1 (Srebf1) was recently identified as a candidate responsible for induction of lipogenic enzymes (42). However, most analyzed liver tumors of Mdr2-KO mice did not show a consistent pattern of up-regulation of Srebp1 target genes, as was the case in tumors of E2F1-transgenic mice.…”

Section: Discussionmentioning

confidence: 99%

Molecular Mechanisms of Liver Carcinogenesis in the Mdr2-Knockout Mice

Katzenellenbogen¹,

Mizrahi²,

Pappo

et al. 2007

Molecular Cancer Research

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Mouse models of hepatocellular carcinoma (HCC) simulate specific subgroups of human HCC. We investigated hepatocarcinogenesis in Mdr2-knockout (Mdr2-KO) mice, a model of inflammationassociated HCC, using gene expression profiling and immunohistochemical analyses. Gene expression profiling showed that although Mdr2-KO mice differ from other published murine HCC models, they share several important deregulated pathways and many coordinately differentially expressed genes with human HCC data sets. Analysis of genome positions of differentially expressed genes in liver tumors revealed a prolonged region of down-regulated genes on murine chromosome 8 in three of the six analyzed tumor samples. This region is syntenic to human chromosomal regions that are frequently deleted in human HCC and harbor multiple tumor suppressor genes. Real-time reverse transcription-PCR analysis of 16 tumor samples confirmed down-regulation of several tumor suppressors in most tumors. We show that in the aged Mdr2-KO mice, cyclin D1 nuclear level is increased in dysplastic hepatocytes that do not form nodules; however, it is decreased in most dysplastic nodules and in liver tumors. We found that this decrease is mostly at the protein, rather than the mRNA, level.These findings raise the question on the role of cyclin D1 at early stages of hepatocarcinogenesis in the Mdr2-KO HCC model. Furthermore, we show that most liver tumors in Mdr2-KO mice were characterized by the absence of B-catenin activation.In conclusion, the Mdr2-KO mouse may serve as a model for B-catenin -negative subgroup of human HCCs characterized by low nuclear cyclin D1 levels in tumor cells and by down-regulation of multiple tumor suppressor genes.

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Section: Discussionmentioning

confidence: 99%

Molecular Mechanisms of Liver Carcinogenesis in the Mdr2-Knockout Mice

Katzenellenbogen¹,

Mizrahi²,

Pappo

et al. 2007

Molecular Cancer Research

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“…It has been previously shown that c-myc can regulate cellular metabolism by transcriptional up-regulation of target genes involved in glucose uptake and lactate production such as Lactate Dehydrogenase A (LDH-A) [24,25]. Since a recent study suggested that accumulation of lactate in liver has pro-fibrotic properties [26], we evaluated whether the increased collagen deposition in alb-myc tg mice was related to c-myc-dependent deregulation of the hepatic metabolism.…”

Section: Overexpression Of C-myc In Hepatocytes Is Associated With Almentioning

confidence: 98%

Overexpression of c-myc in hepatocytes promotes activation of hepatic stellate cells and facilitates the onset of liver fibrosis

Nevzorova

Cubero

et al. 2013

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…The deregulating mutations impact either on the c-myc gene itself or on upstream regulatory sequences, and point mutations or gene amplification of c-myc was reported in human HCC (Feitelson, 2006). Moreover, several studies revealed that the mouse models with overexpression of c-myc developed liver cancers (Murakami et al, 1993;Coulouarn et al, 2006). Thus, it is tempting to speculate that increased AID expression might be responsible for the enhanced susceptibility of the hepatocytes to somatic gene alterations in tumor-related genes including c-myc, which might facilitate HCC development.…”

Section: Expression Of Aid In Human Hepatocytes Via Nf-jb Y Endo Et Almentioning

confidence: 99%

Expression of activation-induced cytidine deaminase in human hepatocytes via NF-κB signaling

et al. 2007

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Activation-induced cytidine deaminase (AID) is involved in somatic DNA alterations of the immunoglobulin gene for amplification of immune diversity. The fact that constitutive expression of AID in mice causes tumors in various organs, including lymphoid tissues and lungs, suggests the important role of the aberrant editing activity of AID on various tumor-related genes for carcinogenesis. AID expression, however, is restricted to activated B cells under physiological conditions. We demonstrate here that ectopic AID expression is induced in response to tumor necrosis factor-a stimulation in cultured human hepatocytes. The proinflammatory cytokine-mediated expression of AID is achieved by IjB kinase-dependent nuclear factor (NF)-jB signaling pathways. Hepatitis C virus, one of the leading causes of hepatocellular carcinoma (HCC), enhanced AID expression via NF-jB activation through expression of viral core protein. The aberrant expression of AID in hepatoma-derived cells resulted in accumulation of genetic alterations in the c-myc and pim1 genes, suggesting that inappropriate expression of AID acts as a DNA mutator that enhances the genetic susceptibility to mutagenesis in human hepatocytes. Our current findings indicate that the inappropriate expression of AID is induced by proinflammatory cytokine stimulation and may provide the link between hepatic inflammation and the development of HCC.

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Oncogene-specific gene expression signatures at preneoplastic stage in mice define distinct mechanisms of hepatocarcinogenesis

Cited by 53 publications

References 50 publications

Molecular Mechanisms of Liver Carcinogenesis in the Mdr2-Knockout Mice

Molecular Mechanisms of Liver Carcinogenesis in the Mdr2-Knockout Mice

Overexpression of c-myc in hepatocytes promotes activation of hepatic stellate cells and facilitates the onset of liver fibrosis

Expression of activation-induced cytidine deaminase in human hepatocytes via NF-κB signaling

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