title: Von Hippel-Lindau status influences phenotype of liver cancers arising from PTEN loss.
abstract: BACKGROUND
  PTENloss contributes to the development of liver diseases including hepatic steatosis and both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). The factors that influence the penetrance of these conditions are unclear. We explored the influence of sustained hypoxia signaling through co-deletion ofPtenandVhlin a murine model.
  
  
  METHODS
  We used a CreER-linked Keratin 18 mouse model to conditionally deletePten,Vhlor both in somatic cells of adult mice, evaluating the resultant tumors by histology and gene expression microarray. Existing sets of gene expression data for human HCC and CC were examined for pathways related to those observed in the murine tumors, and a cohort of human CC samples was evaluated for relationships between HIF-1α expression and clinical outcomes.
  
  
  RESULTS
  BothPtendeletion genotypes developed liver tumors, but with differing phenotypes.Ptendeletion alone led to large hepatic tumors with widespread hepatosteatosis. Co-deletion ofPtenandVhlwith the Keratin 18 promoter resulted in reduced steatosis and a reduced tumor burden that was characterized by a trabecular architecture similar to CC. Genes associated with hepatic steatosis were coordinately expressed in the human HCC dataset, while genes involved in hypoxia response were upregulated in tumors from the human CC dataset. HIF-1α expression and overall survival were examined in an independent cohort of human CC tumors with no statistical differences uncovered.
  
  
  CONCLUSIONS
  Ptendeletion in Keratin 18 expressing cells leads to aggressive tumor formation and widespread steatosis in mouse livers. Co-deletion ofVhlandPtenresults in lower tumor burden with gene expression profiling suggesting a switch from a profile of lipid deposition to an expression profile more consistent with upregulation of the hypoxia response pathway. A relationship between tumor hypoxia signaling and altered hepatic steatotic response suggests that competing influences may alter tumor phenotypes.
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Adam B
authors.initials: AB
authors.lastname: Sendor
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Hacker
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Shufen
authors.initials: S
authors.lastname: Chen
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Armando L
authors.initials: AL
authors.lastname: Corona
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Oishee
authors.initials: O
authors.lastname: Sen
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Derek Y
authors.initials: DY
authors.lastname: Chiang
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Snavely
authors.affiliation: Section of Pathology, Department of Biomedical Sciences, Cummings School of Veterinary Medicine, Tufts University, Boston, MA, USA.
authors.forename: Arlin B
authors.initials: AB
authors.lastname: Rogers
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Montgomery
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: W Kimryn
authors.initials: WK
authors.lastname: Rathmell
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Autumn J
authors.initials: AJ
authors.lastname: McRee
keywords: Von Hippel-Lindau (VHL); cholangiocarcinoma (CC); hepatocellular-cholangiocarcinoma (HCC); phosphatase and tension homologue deleted on chromosome 10 (PTEN)
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