Differential expression of PTEN in hepatic tissue and hepatic stellate cells during rat liver fibrosis and its reversal

Zheng,Libo; Chen,Xiuli; Guo,Jinbo; Sun,Huicong; Liu,Lei; Shih,David  Q.; Zhang,Xiaolan

doi:10.3892/ijmm.2012.1151

Differential expression of PTEN in hepatic tissue and hepatic stellate cells during rat liver fibrosis and its reversal

Authors:
- Libo Zheng
- Xiuli Chen
- Jinbo Guo
- Huicong Sun
- Lei Liu
- David Q. Shih
- Xiaolan Zhang
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Affiliations: Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Shijiazhuang, Hebei 050000, P.R. China, Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
Published online on: October 5, 2012 https://doi.org/10.3892/ijmm.2012.1151
Pages: 1424-1430

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Abstract

To evaluate the change in phosphatase and tensin homology deleted on chromosome ten (PTEN) expression in liver fibrogenesis, particularly the reversal of fibrogenic liver tissues, and to investigate the relation with the proliferation and apoptosis of hepatic stellate cells (HSCs) in vivo, a rat model of hepatic fibrosis was established by hypodermic injection of carbon tetrachloride (CCl4) mixed with olive oil at the concentration of 40% for 5 weeks (2 ml/kg, twice a week). Reversal of fibrosis was achieved with normal feedings for 4 weeks after CCl4 injection for 5 weeks. The expression of PTEN was measured by immunofluorescence, western blot analysis and real-time PCR. Co-expression of α-smooth muscle actin (α-SMA) with PTEN and α-SMA with terminal deoxynucleotidyltransferase-mediated dUTP nick end labelling (TUNEL) were assessed by confocal laser scanning microscopy. The results displayed that the expression of PTEN was reduced with fibrosis in both rat liver tissues and activated HSCs. By contrast, PTEN expression was increased with the reversal of liver fibrosis. Compared to the fibrogenic state, there were increased numbers of apoptotic activated HSCs during reversal of fibrosis. These data suggest that the dynamic expression of PTEN in rat liver tissues is negatively correlated with liver fibrosis and activated HSCs and is positively correlated with reversal of fibrosis and apoptotic activated HSCs. Modulation of PTEN expression may be an effective and novel method for the treatment of liver fibrosis.

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1.	D PoveroC BuslettaE NovoLV di BonzoS CannitoC PaternostroM ParolaLiver fibrosis: a dynamic and potentially reversible processHistol Histopathol2510751091201020552556
2.	SL FriedmanMechanisms of hepatic fibrogenesisGastroenterology13416551669200810.1053/j.gastro.2008.03.00318471545
3.	SL FriedmanHepatic stellate cells: protean, multifunctional, and enigmatic cells of the liverPhysiol Rev88125172200810.1152/physrev.00013.200718195085
4.	AM LaknerTL WallingIH McKillopLW SchrumAltered aquaporin expression and role in apoptosis during hepatic stellate cell activationLiver Int314251201110.1111/j.1478-3231.2010.02356.x20958918
5.	T KisselevaDA BrennerHepatic stellate cells and the reversal of fibrosisJ Gastroenterol Hepatol21Suppl 3S84S87200610.1111/j.1440-1746.2006.04584.x
6.	J LiC YenD LiawPTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancerScience27519431947199710.1126/science.275.5308.19439072974
7.	ES WhiteRG AtraszB HuNegative regulation of myofibroblast differentiation by PTEN (phosphatase and tensin homolog deleted on chromosome 10)Am J Respir Crit Care Med173112121200610.1164/rccm.200507-1058OC16179636
8.	LS HaoXL ZhangJY AnPTEN expression is down-regulated in liver tissues of rats with hepatic fibrosis induced by biliary stenosisAPMIS117681691200910.1111/j.1600-0463.2009.02515.x19703128
9.	LS HaoXL ZhangJY AnAdenoviral transduction of PTEN induces apoptosis of cultured hepatic stellate cellsChin Med J (Engl)12229072911200920092800
10.	I MontfortR Perez-TamayoCollagenase in experimental carbon tetrachloride cirrhosis of the liverAm J Pathol924114201978209692
11.	SJ CotlerN HayH XieML ChenPZ XuTJ LaydenG GuzmanImmunohistochemical expression of components of the Akt-mTORC1 pathway is associated with hepatocellular carcinoma in patients with chronic liver diseaseDig Dis Sci53844849200810.1007/s10620-007-9934-x17763954
12.	JP LaiS BaoIC DavisDL KnoellInhibition of the phosphatase PTEN protects mice against oleic acid-induced acute lung injuryBr J Pharmacol156189200200910.1111/j.1476-5381.2008.00020.x19134000
13.	M PeyrouL BourgoinM FotiPTEN in non-alcoholic fatty liver disease/non-alcoholic steatohepatitis and cancerDig Dis28236246201010.1159/00028209520460918
14.	VR DasariK KaurKK VelpulaUpregulation of PTEN in glioma cells by cord blood mesenchymal stem cells inhibits migration via downregulation of the PI3K/Akt pathwayPLoS One5e10350201010.1371/journal.pone.001035020436671
15.	S BuY AsanoA BujorK HighlandF HantM TrojanowskaDihydrosphingosine 1-phosphate has a potent antifibrotic effect in scleroderma fibroblasts via normalization of phosphatase and tensin homolog levelsArthritis Rheum6221172126201020309867
16.	H XiaW KhalilJ KahmJ JessurunJ KleidonCA HenkePathologic caveolin-1 regulation of PTEN in idiopathic pulmonary fibrosisAm J Pathol17626262637201010.2353/ajpath.2010.09111720395445
17.	W SatoY HorieE KataokaHepatic gene expression in hepatocyte-specific Pten deficient mice showing steatohepatitis without ethanol challengeHepatol Res34256265200610.1016/j.hepres.2006.01.00316490391
18.	M TakashimaCJ ParsonsK IkejimaS WatanabeES WhiteRA RippeThe tumor suppressor protein PTEN inhibits rat hepatic stellate cell activationJ Gastroenterol44847855200910.1007/s00535-009-0073-319436944
19.	A GeertsHistory, heterogeneity, developmental biology, and functions of quiescent hepatic stellate cellsSemin Liver Dis21311335200110.1055/s-2001-1755011586463
20.	R BatallerDA BrennerHepatic stellate cells as a target for the treatment of liver fibrosisSemin Liver Dis21437451200110.1055/s-2001-1755811586471
21.	SL FriedmanMolecular regulation of hepatic fibrosis, an integrated cellular response to tissue injuryJ Biol Chem27522472250200010.1074/jbc.275.4.224710644669
22.	MJ ArthurFibrogenesis II. Metalloproteinases and their inhibitors in liver fibrosisAm J Physiol Gastrointest Liver Physiol279G245G249200010915630
23.	RS NhoH XiaD DieboldJ KahmJ KleidonE WhiteCA HenkePTEN regulates fibroblast elimination during collagen matrix contractionJ Biol Chem2813329133301200610.1074/jbc.M60645020016963781
24.	T TianKJ NanH GuoPTEN inhibits the migration and invasion of HepG2 cells by coordinately decreasing MMP expression via the PI3K/Akt pathwayOncol Rep2315931600201020428814
25.	LQ CaoXL ChenQ WangUpregulation of PTEN involved in rosiglitazone-induced apoptosis in human hepatocellular carcinoma cellsActa Pharmacol Sin28879887200710.1111/j.1745-7254.2007.00571.x17506947
26.	DA BrennerMolecular pathogenesis of liver fibrosisTrans Am Clin Climatol Assoc120361368200919768189