Cytosolic phospholipase A2alpha and peroxisome proliferator-activated receptor gamma signaling pathway counteracts transforming growth factor beta-mediated inhibition of primary and transformed hepatocyte growth.
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.


CONCLUSIONS
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.
Han
Chang
C
Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA. chan@tulane.edu
Bowen
William C
WC
Li
Guiying
G
Demetris
Anthony J
AJ
Michalopoulos
George K
GK
Wu
Tong
T
D000818:Animals; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D054513:Group IV Phospholipases A2 / Q000502:physiology*; D022781:Hepatocytes / Q000473:pathology*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D047495:PPAR gamma / Q000502:physiology*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000502:physiology*
D047495:PPAR gamma; D016212:Transforming Growth Factor beta; D054513:Group IV Phospholipases A2