Cytosolic Phospholipase A2alpha and Peroxisome Proliferator-activated Receptor Gamma Signaling Pathway Counteracts Transforming Growth Factor Beta-mediated Inhibition of Primary and Transformed Hepatocyte Growth

Overview

Journal Hepatology

Specialty Gastroenterology

Date 2010 Aug 5

PMID 20683962

Citations 17

Authors

Chang Han

William C Bowen

Guiying Li

Anthony J Demetris

George K Michalopoulos

Tong Wu

Affiliations

Soon will be listed here.

Abstract

Unlabelled: 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.

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References

Wu T, Han C, Lunz 3rd J, Michalopoulos G, Shelhamer J, Demetris A . Involvement of 85-kd cytosolic phospholipase A(2) and cyclooxygenase-2 in the proliferation of human cholangiocarcinoma cells. Hepatology. 2002; 36(2):363-73. DOI: 10.1053/jhep.2002.34743. View

Hata A, Seoane J, Lagna G, Montalvo E, Hemmati-Brivanlou A, Massague J . OAZ uses distinct DNA- and protein-binding zinc fingers in separate BMP-Smad and Olf signaling pathways. Cell. 2000; 100(2):229-40. DOI: 10.1016/s0092-8674(00)81561-5. View

Wu T . Cyclooxygenase-2 and prostaglandin signaling in cholangiocarcinoma. Biochim Biophys Acta. 2005; 1755(2):135-50. DOI: 10.1016/j.bbcan.2005.04.002. View

Pawliczak R, Han C, Huang X, Demetris A, Shelhamer J, Wu T . 85-kDa cytosolic phospholipase A2 mediates peroxisome proliferator-activated receptor gamma activation in human lung epithelial cells. J Biol Chem. 2002; 277(36):33153-63. DOI: 10.1074/jbc.M200246200. View

Bedossa P, Peltier E, Terris B, Franco D, Poynard T . Transforming growth factor-beta 1 (TGF-beta 1) and TGF-beta 1 receptors in normal, cirrhotic, and neoplastic human livers. Hepatology. 1995; 21(3):760-6. View

Ito N, Kawata S, Tamura S, Takaishi K, Shirai Y, Kiso S . Elevated levels of transforming growth factor beta messenger RNA and its polypeptide in human hepatocellular carcinoma. Cancer Res. 1991; 51(15):4080-3. View

Xu L, Han C, Lim K, Wu T . Cross-talk between peroxisome proliferator-activated receptor delta and cytosolic phospholipase A(2)alpha/cyclooxygenase-2/prostaglandin E(2) signaling pathways in human hepatocellular carcinoma cells. Cancer Res. 2006; 66(24):11859-68. DOI: 10.1158/0008-5472.CAN-06-1445. View

Wu T . Cyclooxygenase-2 in hepatocellular carcinoma. Cancer Treat Rev. 2005; 32(1):28-44. DOI: 10.1016/j.ctrv.2005.10.004. View

Massague J, Blain S, Lo R . TGFbeta signaling in growth control, cancer, and heritable disorders. Cell. 2000; 103(2):295-309. DOI: 10.1016/s0092-8674(00)00121-5. View

10.

Seglen P . Preparation of isolated rat liver cells. Methods Cell Biol. 1976; 13:29-83. DOI: 10.1016/s0091-679x(08)61797-5. View

11.

Gupta R, DuBois R . Colorectal cancer prevention and treatment by inhibition of cyclooxygenase-2. Nat Rev Cancer. 2002; 1(1):11-21. DOI: 10.1038/35094017. View

12.

Derynck R, Zhang Y . Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature. 2003; 425(6958):577-84. DOI: 10.1038/nature02006. View

13.

Sanderson N, Factor V, Nagy P, Kopp J, Kondaiah P, Wakefield L . Hepatic expression of mature transforming growth factor beta 1 in transgenic mice results in multiple tissue lesions. Proc Natl Acad Sci U S A. 1995; 92(7):2572-6. PMC: 42260. DOI: 10.1073/pnas.92.7.2572. View

14.

Carr B, Hayashi I, Branum E, Moses H . Inhibition of DNA synthesis in rat hepatocytes by platelet-derived type beta transforming growth factor. Cancer Res. 1986; 46(5):2330-4. View

15.

Akhurst R, Derynck R . TGF-beta signaling in cancer--a double-edged sword. Trends Cell Biol. 2001; 11(11):S44-51. DOI: 10.1016/s0962-8924(01)02130-4. View

16.

SCHNUR J, Nagy P, Sebestyen A, Schaff Z, Thorgeirsson S . Chemical hepatocarcinogenesis in transgenic mice overexpressing mature TGF beta-1 in liver. Eur J Cancer. 2000; 35(13):1842-5. DOI: 10.1016/s0959-8049(99)00224-5. View

17.

Rosen E, Spiegelman B . PPARgamma : a nuclear regulator of metabolism, differentiation, and cell growth. J Biol Chem. 2001; 276(41):37731-4. DOI: 10.1074/jbc.R100034200. View

18.

Schaloske R, Dennis E . The phospholipase A2 superfamily and its group numbering system. Biochim Biophys Acta. 2006; 1761(11):1246-59. DOI: 10.1016/j.bbalip.2006.07.011. View

19.

Kanzler S, Meyer E, Lohse A, Schirmacher P, Henninger J, Galle P . Hepatocellular expression of a dominant-negative mutant TGF-beta type II receptor accelerates chemically induced hepatocarcinogenesis. Oncogene. 2001; 20(36):5015-24. DOI: 10.1038/sj.onc.1204544. View

20.

RUSSELL W, Coffey Jr R, Ouellette A, Moses H . Type beta transforming growth factor reversibly inhibits the early proliferative response to partial hepatectomy in the rat. Proc Natl Acad Sci U S A. 1988; 85(14):5126-30. PMC: 281701. DOI: 10.1073/pnas.85.14.5126. View