Liver cancers are a major cause of cancer-related deaths. Large-scale genetic analyses have associated liver cancer with dysregulation of numerous molecular pathways, but disruptions in insulin signaling pathways appear to have a particularly important contribution to liver tumor formation. Obesity is a major risk factor for developing liver cancer, and the nuclear receptor PPARγ critically controls fat uptake and storage in the liver by regulating the transcription of metabolism-associated genes. However, whether PPARγ also plays a role in promoting the growth of liver tumors is not clear.
This week in the JCI , research led by Ganna Panasyuk at INSERM examined the link between PPARγ and liver tumor formation. The findings identify a metabolic pathway with pro-tumor effects that can be suppressed by selectively blocking PPARγ. Researchers initially observed that increases in PPARγ expression and activity in human liver tumors were associated with loss-of-function of the transcription factor hepatocyte nuclear factor 1α (HNF1α). In a mouse model, they determined that loss of HNF1α led to abnormal increases in PPARγ expression that in turn led to increased tumorigenesis. Pharmacological activation of PPARγ in a mouse model of liver cancer exacerbated tumor formation; in contrast, treatment with a PPARγ inhibitor had positive therapeutic effects.
Taken together, these findings demonstrate a role for PPARγ in the metabolic pathway disturbances that promote liver tumorigenesis and reveal that PPARγ is a potential target for anti-tumor therapies to treat liver cancers.
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TITLE: Hepatocyte nuclear factor 1α suppresses steatosis- associated liver cancer by inhibiting PPARγ transcription
AUTHOR CONTACT:
Ganna Panasyuk
Institut Necker-Enfants Malades
INSERM U1151/CNRS UMR 8253 <
a href="mailto:ganna.panasyuk@inserm.fr">ganna.panasyuk@inserm.fr
View this article at: http://www.jci.org/articles/view/90327?key=f53576a87fd0165f5cb7
Journal of Clinical Investigation