Unknown,Transcriptomics,Genomics,Proteomics

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Expression data of WHV/c-myc transgenic mice at preneoplastic and neoplastic stages

ABSTRACT: The WHV/c-myc transgenic mouse is an animal model of hepatocarcinogenesis that can exquisitely mimic the cancer staging in human Hepatocellular carcinoma (HCC), in which the c-myc oncogene is activated by adjacent woodchuck hepatitis virus (WHV) DNA sequences. Compared to other models of c-myc transgenic mice, WHV/c-myc mice stably develop HCC with a relatively short latent period of 8 to 12 months, with a high (near 100%) tumor incidence. The aim of this study was to discover new HCC biomarkers and analyze expression patterns of selected candidate biomarkers prior to liver tumor onset by employing WHV/c-myc transgenic mice. Using Affymetrix Mouse Genome 430 2.0 Expression Arrays, we studied hepatic gene expression profiles of WHV/c-myc transgenic mice at 5 months and 11 months, age-matched wild-type C57/BL6 mice were used as controls. At 5 months, the livers of transgenic mice exhibited mild to moderate hepatocyte dysplasia, this time point represents the preneoplastic stage. At 11 months, the tumors were visualized in WHV/c-myc transgenic mice and consisted mainly of well-differentiated, trabecular-type HCCs, and this time point was considered as neoplastic stage.

ORGANISM(S): Mus musculus

SUBMITTER: wang feng

PROVIDER: E-GEOD-39401 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:A complete understanding of molecular mechanisms that underlie cancer onset and progression could provide a basis to improve early diagnosis and more effective treatment. However, this is still a challenge in human, partly due to the difficulty of analyzing the early stages of the disease. In this context, genetically engineered mice represent a valuable alternative to model human carcinogenesis. Here, we studied cancer development in c-Myc/Tgfa transgenic mice that developed liver tumors which closely reproduce a subset of human hepatocellular carcinoma (HCC) with a poor prognosis. By using a functional genomics approach from early to late stages of HCC development, we demonstrated that hepatocarcinogenesis in c-Myc/Tgfa mice resulted from a progressive accumulation of transcriptional alterations due to an active hepatocyte proliferation in a chronic oxidative stress environment generated by a general metabolic disorder. One striking observation was the deregulation of numerous immune-related genes starting from an early stage of the disease. Particularly, we showed that activating ligands for natural killer (NK) cells were specifically induced in dysplastic hepatocytes which simultaneously lost the expression of MHC-I molecules. Besides this early mechanism of NK-mediated immune surveillance, we further reported a drastic decrease in hepatic NK cell population which may indeed contribute to the emergence and clonal expansion of progenitors for liver tumors. In conclusion, our study provided a detailed and comprehensive characterization of hepatocarcinogenesis in c-Myc/Tgfa transgenic mice and emphasized the critical role of the innate immune surveillance disruption at the early stages of liver cancer. In the present study, we reported a detailed and comprehensive dynamic characterization of the cellular and molecular alterations involved in tumor onset and progression in the liver of c-Myc/Tgfa double-transgenic mice (B6CBAxCD1 background). Liver samples from male animals were collected at various time-points ranging from 3 weeks to 9 months for c-Myc/Tgfa double-transgenic mice, or 18 months for c-Myc and Tgfa single-transgenic mice. Tissue samples were divided into two parts; one was fixed in 10% formalin for histological evaluation and the other was used for RNA analysis. Total RNAs were isolated from livers with moderate or severe hepatocyte dysplasia (at 3 weeks and 3 months, respectively), as well as from HCC and surrounding non-tumor livers (5-15 mice per group). Total RNAs were also isolated from the livers of B6CBAxCD1 wild-type mice at 3 weeks and 3 months. RNAs isolated from the normal livers of B6CBA WT mice (3 months old, n=10) were pooled and used as a common technical reference for all microarray experiments.

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Expression data of WHV/c-myc transgenic mice at preneoplastic and neoplastic stages

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