Limits...
Von Hippel-Lindau status influences phenotype of liver cancers arising from PTEN loss.

Sendor AB, Hacker KE, Chen S, Corona AL, Sen O, Chiang DY, Snavely A, Rogers AB, Montgomery SA, Rathmell WK, McRee AJ - Gastrointest Cancer (2015)

Bottom Line: The factors that influence the penetrance of these conditions are unclear.Pten deletion alone led to large hepatic tumors with widespread hepatosteatosis.Co-deletion of Vhl and Pten results 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.

View Article: PubMed Central - PubMed

Affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.

ABSTRACT

Background: PTEN loss 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 of Pten and Vhl in a murine model.

Methods: We used a CreER-linked Keratin 18 mouse model to conditionally delete Pten, Vhl or 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: Both Pten deletion genotypes developed liver tumors, but with differing phenotypes. Pten deletion alone led to large hepatic tumors with widespread hepatosteatosis. Co-deletion of Pten and Vhl with 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.

Conclusion: Pten deletion in Keratin 18 expressing cells leads to aggressive tumor formation and widespread steatosis in mouse livers. Co-deletion of Vhl and Pten results 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.

No MeSH data available.


Related in: MedlinePlus

Genes related to hypoxia and fatty liver are differentially expressed between mouse genotypes.Notes: (A) Selected HIF target genes are upregulated in Pten−/−;Vhl−/− mouse tumors compared to Pten−/− mouse tumors. Significantly upregulated genes include: VEGFA, SLC2A1, PGK1, and HK1. Vhl is downregulated in Pten−/−;Vhl−/− due to the induced deletion. (B) Genes known to be downregulated in human fatty liver disease show reduced or unchanged expression in the Pten−/− mouse tumors compared to the Pten−/−;Vhl−/− tumors. (C) Genes known to be upregulated in human fatty liver show increased or unchanged expression in the Pten−/− mouse tumors compared to the Pten−/−; Vhl−/− tumors. *P<0.05; **P<0.01. Error bars indicate standard deviation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2 - License 3
getmorefigures.php?uid=PMC4383253&req=5

Figure 2: Genes related to hypoxia and fatty liver are differentially expressed between mouse genotypes.Notes: (A) Selected HIF target genes are upregulated in Pten−/−;Vhl−/− mouse tumors compared to Pten−/− mouse tumors. Significantly upregulated genes include: VEGFA, SLC2A1, PGK1, and HK1. Vhl is downregulated in Pten−/−;Vhl−/− due to the induced deletion. (B) Genes known to be downregulated in human fatty liver disease show reduced or unchanged expression in the Pten−/− mouse tumors compared to the Pten−/−;Vhl−/− tumors. (C) Genes known to be upregulated in human fatty liver show increased or unchanged expression in the Pten−/− mouse tumors compared to the Pten−/−; Vhl−/− tumors. *P<0.05; **P<0.01. Error bars indicate standard deviation.

Mentions: To verify the expected relative expression changes corresponding with Vhl deletion, we examined the tumors of Pten−/− and Pten−/−;Vhl−/− mice by microarray expression profiling. Direct assessment of HIFα protein was not possible due to high levels of nonspecific interactions in multiple antibodies tested. We observed an expected decrease in Vhl gene expression in the Pten−/−;Vhl−/− samples, compared to the single deletion mutant, Pten−/− (Figure 2A). A corresponding increase in expression of a panel of canonical HIF target genes was also observed in those tumors harboring a Vhl deletion (Figure 2A).


Von Hippel-Lindau status influences phenotype of liver cancers arising from PTEN loss.

Sendor AB, Hacker KE, Chen S, Corona AL, Sen O, Chiang DY, Snavely A, Rogers AB, Montgomery SA, Rathmell WK, McRee AJ - Gastrointest Cancer (2015)

Genes related to hypoxia and fatty liver are differentially expressed between mouse genotypes.Notes: (A) Selected HIF target genes are upregulated in Pten−/−;Vhl−/− mouse tumors compared to Pten−/− mouse tumors. Significantly upregulated genes include: VEGFA, SLC2A1, PGK1, and HK1. Vhl is downregulated in Pten−/−;Vhl−/− due to the induced deletion. (B) Genes known to be downregulated in human fatty liver disease show reduced or unchanged expression in the Pten−/− mouse tumors compared to the Pten−/−;Vhl−/− tumors. (C) Genes known to be upregulated in human fatty liver show increased or unchanged expression in the Pten−/− mouse tumors compared to the Pten−/−; Vhl−/− tumors. *P<0.05; **P<0.01. Error bars indicate standard deviation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2 - License 3
Show All Figures
getmorefigures.php?uid=PMC4383253&req=5

Figure 2: Genes related to hypoxia and fatty liver are differentially expressed between mouse genotypes.Notes: (A) Selected HIF target genes are upregulated in Pten−/−;Vhl−/− mouse tumors compared to Pten−/− mouse tumors. Significantly upregulated genes include: VEGFA, SLC2A1, PGK1, and HK1. Vhl is downregulated in Pten−/−;Vhl−/− due to the induced deletion. (B) Genes known to be downregulated in human fatty liver disease show reduced or unchanged expression in the Pten−/− mouse tumors compared to the Pten−/−;Vhl−/− tumors. (C) Genes known to be upregulated in human fatty liver show increased or unchanged expression in the Pten−/− mouse tumors compared to the Pten−/−; Vhl−/− tumors. *P<0.05; **P<0.01. Error bars indicate standard deviation.
Mentions: To verify the expected relative expression changes corresponding with Vhl deletion, we examined the tumors of Pten−/− and Pten−/−;Vhl−/− mice by microarray expression profiling. Direct assessment of HIFα protein was not possible due to high levels of nonspecific interactions in multiple antibodies tested. We observed an expected decrease in Vhl gene expression in the Pten−/−;Vhl−/− samples, compared to the single deletion mutant, Pten−/− (Figure 2A). A corresponding increase in expression of a panel of canonical HIF target genes was also observed in those tumors harboring a Vhl deletion (Figure 2A).

Bottom Line: The factors that influence the penetrance of these conditions are unclear.Pten deletion alone led to large hepatic tumors with widespread hepatosteatosis.Co-deletion of Vhl and Pten results 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.

View Article: PubMed Central - PubMed

Affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.

ABSTRACT

Background: PTEN loss 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 of Pten and Vhl in a murine model.

Methods: We used a CreER-linked Keratin 18 mouse model to conditionally delete Pten, Vhl or 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: Both Pten deletion genotypes developed liver tumors, but with differing phenotypes. Pten deletion alone led to large hepatic tumors with widespread hepatosteatosis. Co-deletion of Pten and Vhl with 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.

Conclusion: Pten deletion in Keratin 18 expressing cells leads to aggressive tumor formation and widespread steatosis in mouse livers. Co-deletion of Vhl and Pten results 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.

No MeSH data available.


Related in: MedlinePlus