Unknown,Transcriptomics,Genomics,Proteomics

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Astrocyte elevated gene-1 (AEG-1) and c-Myc cooperate to promote hepatocarcinogenesis

ABSTRACT: Double transgenic mice with hepatocyte-specific expression of AEG-1 and c-Myc show aggressive HCC compared to single transgenics. Gene expression was analyzed to understand the molecular mechanism by which AEG-1 and c-Myc cooperate to promote hepatocarcinogenesis. Livers were collected from naïve adult mice (3 mice/group). Total RNA was extrancted and subjected to RNA-Seq.

ORGANISM(S): Mus musculus

SUBMITTER: Hung-I Chen

PROVIDER: E-GEOD-61875 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Astrocyte elevated gene-1 and c-Myc cooperate to promote hepatocarcinogenesis in mice.

Srivastava Jyoti J Siddiq Ayesha A Gredler Rachel R Shen Xue-Ning XN Rajasekaran Devaraja D Robertson Chadia L CL Subler Mark A MA Windle Jolene J JJ Dumur Catherine I CI Mukhopadhyay Nitai D ND Garcia Dawn D Lai Zhao Z Chen Yidong Y Balaji Uthra U Fisher Paul B PB Sarkar Devanand D

Hepatology (Baltimore, Md.) 20150123 3

<h4>Unlabelled</h4>Astrocyte elevated gene-1 (AEG-1) and c-Myc are overexpressed in human hepatocellular carcinoma (HCC) functioning as oncogenes. AEG-1 is transcriptionally regulated by c-Myc, and AEG-1 itself induces c-Myc by activating the Wnt/β-catenin-signaling pathway. We now document the cooperation of AEG-1 and c-Myc in promoting hepatocarcinogenesis by analyzing hepatocyte-specific transgenic mice expressing either AEG-1 (albumin [Alb]/AEG-1), c-Myc (Alb/c-Myc), or both (Alb/AEG-1/c-Myc ...[more]

PMID: 25065684

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Project description:Astrocyte elevated gene-1 (AEG-1) and c-Myc are overexpressed in human hepatocellular carcinoma (HCC) functioning as oncogenes. AEG-1 is transcriptionally regulated by c-Myc, and AEG-1 itself induces c-Myc by activating the Wnt/?-catenin-signaling pathway. We now document the cooperation of AEG-1 and c-Myc in promoting hepatocarcinogenesis by analyzing hepatocyte-specific transgenic mice expressing either AEG-1 (albumin [Alb]/AEG-1), c-Myc (Alb/c-Myc), or both (Alb/AEG-1/c-Myc). Wild-type and Alb/AEG-1 mice did not develop spontaneous HCC. Alb/c-Myc mice developed spontaneous HCC without distant metastasis, whereas Alb/AEG-1/c-Myc mice developed highly aggressive HCC with frank metastasis to the lungs. Induction of carcinogenesis by N-nitrosodiethylamine significantly accelerated the kinetics of tumor formation in all groups. However, in Alb/AEG-1/c-Myc, the effect was markedly pronounced with lung metastasis. In vitro analysis showed that Alb/AEG-1/c-Myc hepatocytes acquired increased proliferation and transformative potential with sustained activation of prosurvival and epithelial-mesenchymal transition-signaling pathways. RNA-sequencing analysis identified a unique gene signature in livers of Alb/AEG-1/c-Myc mice that was not observed when either AEG-1 or c-Myc was overexpressed. Specifically, Alb/AEG-1/c-Myc mice overexpressed maternally imprinted noncoding RNAs (ncRNAs), such as Rian, Meg-3, and Mirg, which are implicated in hepatocarcinogenesis. Knocking down these ncRNAs significantly inhibited proliferation and invasion by Alb/AEG-1/c-Myc hepatocytes.Our studies reveal a novel cooperative oncogenic effect of AEG-1 and c-Myc that might explain the mechanism of aggressive HCC. Alb/AEG-1/c-Myc mice provide a useful model to understand the molecular mechanism of cooperation between these two oncogenes and other molecules involved in hepatocarcinogenesis. This model might also be of use for evaluating novel therapeutic strategies targeting HCC.

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.

Dataset Information

Astrocyte elevated gene-1 (AEG-1) and c-Myc cooperate to promote hepatocarcinogenesis

Publications

Astrocyte elevated gene-1 and c-Myc cooperate to promote hepatocarcinogenesis in mice.

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