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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 specific to the hypoxia response show variable expression between human HCC and CC.Notes: (A) Expression of two genes specific to the HIF pathway (HK and SLC2A1) were significantly elevated in CC relative to HCC. (B) CC HIF pathway expression was identified as either CC HIF UP or CC HIF DOWN following median centering. The CC tumors were then clustered by HIF target gene expression. (C) Using the CC HIF UP or CC HIF DOWN designation, genes involved in fatty liver disease were able to cluster CC cases using expression datasets. **P<0.01.Abbreviations: HCC, hepatocellular carcinoma; CC, cholangiocarcinoma.
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Figure 4: Genes specific to the hypoxia response show variable expression between human HCC and CC.Notes: (A) Expression of two genes specific to the HIF pathway (HK and SLC2A1) were significantly elevated in CC relative to HCC. (B) CC HIF pathway expression was identified as either CC HIF UP or CC HIF DOWN following median centering. The CC tumors were then clustered by HIF target gene expression. (C) Using the CC HIF UP or CC HIF DOWN designation, genes involved in fatty liver disease were able to cluster CC cases using expression datasets. **P<0.01.Abbreviations: HCC, hepatocellular carcinoma; CC, cholangiocarcinoma.

Mentions: In a similar analysis, we examined the expression of common HIF target genes in human HCC and CC tumors. VHL has not been implicated as a disease gene in either human HCC or CC, however, multiple mechanisms can alter hypoxia signaling. Using the same panel of canonical HIF target genes examined in the Pten−/− and Pten−/−;Vhl−/− mice, we also observed a significant increase in the expression of hypoxia target genes hexokinase and SLC2A1 in the human CC dataset as compared with HCC (Figure 4A). The expression level of VHL is unchanged, as expected, suggesting that any activation of hypoxia response signaling likely occurs via physiologic hypoxia signaling.


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 specific to the hypoxia response show variable expression between human HCC and CC.Notes: (A) Expression of two genes specific to the HIF pathway (HK and SLC2A1) were significantly elevated in CC relative to HCC. (B) CC HIF pathway expression was identified as either CC HIF UP or CC HIF DOWN following median centering. The CC tumors were then clustered by HIF target gene expression. (C) Using the CC HIF UP or CC HIF DOWN designation, genes involved in fatty liver disease were able to cluster CC cases using expression datasets. **P<0.01.Abbreviations: HCC, hepatocellular carcinoma; CC, cholangiocarcinoma.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Genes specific to the hypoxia response show variable expression between human HCC and CC.Notes: (A) Expression of two genes specific to the HIF pathway (HK and SLC2A1) were significantly elevated in CC relative to HCC. (B) CC HIF pathway expression was identified as either CC HIF UP or CC HIF DOWN following median centering. The CC tumors were then clustered by HIF target gene expression. (C) Using the CC HIF UP or CC HIF DOWN designation, genes involved in fatty liver disease were able to cluster CC cases using expression datasets. **P<0.01.Abbreviations: HCC, hepatocellular carcinoma; CC, cholangiocarcinoma.
Mentions: In a similar analysis, we examined the expression of common HIF target genes in human HCC and CC tumors. VHL has not been implicated as a disease gene in either human HCC or CC, however, multiple mechanisms can alter hypoxia signaling. Using the same panel of canonical HIF target genes examined in the Pten−/− and Pten−/−;Vhl−/− mice, we also observed a significant increase in the expression of hypoxia target genes hexokinase and SLC2A1 in the human CC dataset as compared with HCC (Figure 4A). The expression level of VHL is unchanged, as expected, suggesting that any activation of hypoxia response signaling likely occurs via physiologic hypoxia signaling.

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