title: Transforming growth factor-beta signaling promotes hepatocarcinogenesis induced by p53 loss.
abstract: Hepatocellular carcinoma (HCC) results from the accumulation of deregulated tumor suppressor genes and/or oncogenes in hepatocytes. Inactivation of TP53 and inhibition of transforming growth factor-beta (TGF-β) signaling are among the most common molecular events in human liver cancers. Thus, we assessed whether inactivation of TGF-β signaling, by deletion of the TGF-β receptor, type II (Tgfbr2), cooperates with Trp53 loss to drive HCC formation. Albumin-cre transgenic mice were crossed with floxed Trp53 and/or floxed Tgfbr2 mice to generate mice lacking p53 and/or Tgfbr2 in the liver. Deletion of Trp53 alone (Trp53(KO) ) resulted in liver tumors in approximately 41% of mice by 10 months of age, whereas inactivation of Tgfbr2 alone (Tgfbr2(KO) ) did not induce liver tumors. Surprisingly, deletion of Tgfbr2 in the setting of p53 loss (Trp53(KO) ;Tgfbr2(KO) ) decreased the frequency of mice with liver tumors to around 17% and delayed the age of tumor onset. Interestingly, Trp53(KO) and Trp53(KO) ;Tgfbr2(KO) mice develop both HCC and cholangiocarcinomas, suggesting that loss of p53, independent of TGF-β, may affect liver tumor formation through effects on a common liver stem cell population. Assessment of potential mechanisms through which TGF-β signaling may promote liver tumor formation in the setting of p53 loss revealed a subset of Trp53(KO) tumors that express increased levels of alpha-fetoprotein. Furthermore, tumors from Trp53(KO) mice express increased TGF-β1 levels compared with tumors from Trp53(KO) ;Tgfbr2(KO) mice. Increased phosphorylated Smad3 and ERK1/2 expression was also detected in the tumors from Trp53(KO) mice and correlated with increased expression of the TGF-β responsive genes, Pai1 and Ctgf.
  
  
  CONCLUSIONS
  TGF-β signaling paradoxically promotes the formation of liver tumors that arise in the setting of p53 inactivation.
authors: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA.
authors: Shelli M
authors: SM
authors: Morris
authors: Ji Yeon
authors: JY
authors: Baek
authors: Amanda
authors: A
authors: Koszarek
authors: Samornmas
authors: S
authors: Kanngurn
authors: Sue E
authors: SE
authors: Knoblaugh
authors: William M
authors: WM
authors: Grady
mesh_terms: D000818:Animals; D001650:Bile Duct Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001653:Bile Ducts, Intrahepatic; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018281:Cholangiocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D008114:Liver Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010766:Phosphorylation / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018000:Receptors, Peptide / Q000235:genetics / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; D018000:Receptors, Peptide; D018125:Receptors, Transforming Growth Factor beta; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D053773:Transforming Growth Factor beta1; D016159:Tumor Suppressor Protein p53; C489008:alpha-fetoprotein receptor, mouse; D017346:Protein Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II