Journal
HEPATOLOGY
Volume 52, Issue 2, Pages 644-655Publisher
WILEY-BLACKWELL
DOI: 10.1002/hep.23703
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Funding
- NCATS NIH HHS [UL1 TR000005] Funding Source: Medline
- NCI NIH HHS [R01 CA106280, R01 CA102325, R03 CA137729, CA102325, CA134568, CA137729, CA106280, R01 CA134568] Funding Source: Medline
- NIDDK NIH HHS [R01 DK077776, DK077776, R01 DK077776-03, R56 DK077776] Funding Source: Medline
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Hepatocellular carcinoma often develops in the setting of abnormal hepatocyte growth associated with chronic hepatitis and liver cirrhosis. Transforming growth factor beta (TGF-beta) is a multifunctional cytokine pivotal in the regulation of hepatic cell growth, differentiation, migration, extracellular matrix production, stem cell homeostasis, and hepatocarcinogenesis. However, the mechanisms by which TGF-beta influences hepatic cell functions remain incompletely defined. We report herein that TGF-beta regulates the growth of primary and transformed hepatocytes through concurrent activation of Smad and phosphorylation of cytosolic phospholipase A(2)alpha (cPLA(2)alpha), a rate-limiting key enzyme that releases arachidonic acid for the production of bioactive eicosanoids. The interplays between TGF-beta and cPLA(2)alpha signaling pathways were examined in rat primary hepatocytes, human hepatocellular carcinoma cells, and hepatocytes isolated from newly developed cPLA(2)alpha transgenic mice. Conclusion: Our data show that cPLA(2)alpha activates peroxisome proliferator-activated receptor gamma (PPAR-gamma) and thus counteracts Smad2/3-mediated inhibition of cell growth. Therefore, regulation of TGF-beta signaling by cPLA(2)alpha and PPAR-gamma may represent an important mechanism for control of hepatic cell growth and hepatocarcinogenesis. (HEPATOLOGY 2010;52:644-655)
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