title: Notch1 differentially regulates oncogenesis by wildtype p53 overexpression and p53 mutation in grade III hepatocellular carcinoma.
abstract: The tumor suppressor p53 is a key prognostic factor in hepatocellular carcinoma (HCC), yet only 35% of grade III tumors exhibit mutation of p53. Several other pathways have been implicated in HCC and, among these, the role of the Notch1/Snail pathway remains unclear. Therefore, we investigated the expression of p53, Notch1, and Snail proteins in HCC with regard to both clinical grade and p53 mutational status. Immunoblotting for p53 revealed that, whereas in many tumors increased p53 was a result of p53 mutation, wildtype p53 (p53WT) expression was also frequently elevated in HCCs. Coordinated evaluation of p53, Notch1, and Snail expression suggests that grade III HCC can be subdivided based on the expression of these three proteins. We found that Notch1 expression in HCC tissues and cell lines is differentially affected by p53WT and mutant p53 (p53Mut). Notch1 expression was correlated with p53 expression in cells expressing p53WT, but was not elevated in p53Mut-expressing cells. Virally mediated expression or silencing of p53WT or p53Mut confirmed that p53WT overexpression causes Notch1 up-regulation in HCC. Surprisingly, the consequence of Notch1 overexpression for the proliferative and invasive capacity of HCC cells depends on both the p53 mutational status and activation of the Snail pathway.
  
  
  CONCLUSIONS
  In the presence of p53WT, Snail/Notch1 activation increased the invasiveness of HCC cells. In contrast, in the absence of p53WT, Notch1 decreased the invasiveness of HCC. Taken together, these findings shed new light on the complex role of the Notch1/Snail axis in HCC and provide a framework for further classifying HCC based on the expression and mutational status of p53 and the expression of Notch1 and Snail.
authors.affiliation: Department of Biological Sciences, Seoul National University, Seoul, Korea.
authors.forename: Seung-Oe
authors.initials: SO
authors.lastname: Lim
authors.forename: Young Min
authors.initials: YM
authors.lastname: Park
authors.forename: Hyeon Seop
authors.initials: HS
authors.lastname: Kim
authors.forename: Xiaoyuan
authors.initials: X
authors.lastname: Quan
authors.forename: Jeong Eun
authors.initials: JE
authors.lastname: Yoo
authors.forename: Young Nyun
authors.initials: YN
authors.lastname: Park
authors.forename: Gi Hong
authors.initials: GH
authors.lastname: Choi
authors.forename: Guhung
authors.initials: G
authors.lastname: Jung
mesh_terms: D000328:Adult; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000145:classification / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D051881:Receptor, Notch1 / Q000502:physiology*; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000096:biosynthesis; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53