title: Astrocyte elevated gene-1 and c-Myc cooperate to promote hepatocarcinogenesis in mice.
abstract: 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). 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.
  
  
  CONCLUSIONS
  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.
authors: Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA.
authors: Jyoti
authors: J
authors: Srivastava
authors: Ayesha
authors: A
authors: Siddiq
authors: Rachel
authors: R
authors: Gredler
authors: Xue-Ning
authors: XN
authors: Shen
authors: Devaraja
authors: D
authors: Rajasekaran
authors: Chadia L
authors: CL
authors: Robertson
authors: Mark A
authors: MA
authors: Subler
authors: Jolene J
authors: JJ
authors: Windle
authors: Catherine I
authors: CI
authors: Dumur
authors: Nitai D
authors: ND
authors: Mukhopadhyay
authors: Dawn
authors: D
authors: Garcia
authors: Zhao
authors: Z
authors: Lai
authors: Yidong
authors: Y
authors: Chen
authors: Uthra
authors: U
authors: Balaji
authors: Paul B
authors: PB
authors: Fisher
authors: Devanand
authors: D
authors: Sarkar
mesh_terms: D000418:Albumins / Q000032:analysis; D000818:Animals; D063646:Carcinogenesis; D002478:Cells, Cultured; D058750:Epithelial-Mesenchymal Transition; D008114:Liver Neoplasms, Experimental / Q000209:etiology* / Q000473:pathology; D008175:Lung Neoplasms / Q000556:secondary; D008565:Membrane Proteins / Q000032:analysis / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D016271:Proto-Oncogene Proteins c-myc / Q000032:analysis / Q000502:physiology*; D016601:RNA-Binding Proteins
chemical_list: D000418:Albumins; D008565:Membrane Proteins; C483038:Mtdh protein, mouse; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D016601:RNA-Binding Proteins