PTEN在肝纤维化中的研究进展
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摘要
肝纤维化是指肝在修复各种致病因子所致肝损伤时出现的肝内弥漫性细胞外基质过度沉积。近年来,越来越多证据表明第10号染色体缺失的磷酸酶张力蛋白同源物基因(phosphatase and tensin homology deleted on chromosome ten,PTEN)参与肝纤维化进程。本文就PTEN调控肝纤维化的机制研究进行综述。
Liver fibrosis is caused due to excessive deposition of diffuse extracellular matrix in the liver during repair of liver injury caused by various pathogenic factors. In recent years, an increasing body of evidence has suggested that the phosphatase and tensin homology deleted on chromosome 10(PTEN) is involved in the development of liver fibrosis. We therefore reviewed the regulatory mechanism of PTEN in liver fibrosis.
Liver fibrosis is caused due to excessive deposition of diffuse extracellular matrix in the liver during repair of liver injury caused by various pathogenic factors. In recent years, an increasing body of evidence has suggested that the phosphatase and tensin homology deleted on chromosome 10(PTEN) is involved in the development of liver fibrosis. We therefore reviewed the regulatory mechanism of PTEN in liver fibrosis.
引文
[1] Pellicoro A,Ramachandran P,Iredale JP.Liver fibrosis and repair:immune regulation of wound healing in a solid organ [J].Nat Rev Immunol,2014,14(3):181-194.
[2] Zhang CY,Yuan WG,He P,et al.Liver fibrosis and hepatic stellate cells:Etiology,pathological hallmarks and therapeutic targets [J].World J Gastroenterol,2016,22(48):10512-10522.
[3] Omar R,Yang J,Liu H,et al.Hepatic stellate cells in liver fibrosis and siRNA-based therapy [J].Rev Physiol Biochem Pharmacol,2016,172:1-37.
[4] Li J,Yen C,Liaw D,et al.PTEN,a putative protein tyrosine phosphatase gene mutated in human brain,breast,and prostate cancer [J].Science,1997,275(5308):1943-1947.
[5] Lee YR,Chen M.The functions and regulation of the PTEN tumour suppressor:new modes and prospects [J].Nat Rev Mol Cell Biol,2018,19(9):547-562.
[6] Chen L.The functions of tumor suppressor PTEN in innate and adaptive immunity [J].Cell Mol Immunol,2017,14(7):581-589.
[7] Kechagioglou P,Papi RM,Provatopoulou X,et al.Tumor suppressor PTEN in breast cancer:heterozygosity,mutations and protein expression [J].Anticancer Res,2014,34(3):1387-1400.
[8] Wise HM,Hermida MA.Prostate cancer,PI3K,PTEN and prognosis [J].Clin Sci (Lond),2017,131(3):197-210.
[9] Roa I,de Toro G,Fernández F,et al.Inactivation of tumor suppressor gene pten in early and advanced gallbladder cancer [J].Diagn Pathol,2015,10:148.
[10] Garcia-Cao I,Song MS,Hobbs RM,et al.Systemic elevation of PTEN induces a tumor-suppressive metabolic state [J].Cell,2012,149(1):49-62.
[11] Zhou J,Zhong J,Lin S,et al.Inhibition of PTEN activity aggravates post renal fibrosis in mice with ischemia reperfusion-induced acute kidney injury [J].Cell Physiol Biochem,2017,43(5):1841-1854.
[12] Yu F,Chen B,Dong P.HOTAIR epigenetically modulates PTEN expression via microRNA-29b:a novel mechanism in regulation of liver fibrosis [J].Mol Ther,2017,25(1):205-217.
[13] Parapuram SK,Thompson K,Tsang M,et al.Loss of PTEN expression by mouse fibroblasts results in lung fibrosis through a CCN2-dependent mechanism [J].Matrix Biol,2015,43:35-41.
[14] Matsuda S,Kobayashi M.Roles for PI3K/AKT/PTEN pathway in cell signaling of nonalcoholic fatty liver disease [J].ISRN Endocrinol,2013,2013:472432.
[15] Pradere JP,Kluwe J,De Minicis S,et al.Hepatic macrophages but not dendritic cells contribute to liver fibrosis by promoting the survival of activated hepatic stellate cells in mice [J].Hepatology,2013,58(4):1461-1473.
[16] Ma PF,Gao CC,Yi J,et al.Cytotherapy with M1-polarized macrophages ameliorates liver fibrosis by modulating immune microenvironment in mice [J].J Hepatol,2017,67(4):770-779.
[17] 郝礼森,张晓岚,李玉林,等.大鼠纤维化肝组织中PTEN的动态表达及其与肝星状细胞增殖和活化的关系[J].中华肝脏病杂志,2008,16(10):743-747.
[18] Ruan W,Pan R,Shen X,et al.CDH11 promotes liver fibrosis via activation of hepatic stellate cells [J].Biochem Biophys Res Commun,2018,508(2):543-549.
[19] An J,Zheng L,Xie S,et al.Regulatory effects and mechanism of adenovirus-mediated PTEN gene on hepatic stellate cells [J].Dig Dis Sci,2016,61(4):1107-1120.
[20] Hao LS,Zhang XL,An JY,et al.PTEN expression is down-regulated in liver tissues of rats with hepatic fibrosis induced by biliary stenosis [J].APMIS,2009,117(9):681-691.
[21] An J,Zheng L,Xie S,et al.Down-regulation of focal adhesion kinase by short hairpin RNA increased apoptosis of rat hepatic stellate cells [J].APMIS,2011,119(6):319-329.
[22] 魏月,郝礼森,任昌镇,等.PTEN过表达及突变对活化肝星状细胞黏着斑激酶信号转导的影响研究[J].中国全科医学,2016,19(29):3562-3566.
[23] Kumar P,Raeman R,Chopyk DM,et al.Adiponectin inhibits hepatic stellate cell activation by targeting the PTEN/AKT pathway [J].Biochim Biophys Acta Mol Basis Dis,2018,1864(10):3537-3545.
[24] Li WX,Chen X,Yang Y,et al.Hesperitin derivative-11 suppress hepatic stellate cell activation and proliferation by targeting PTEN/AKT pathway [J].Toxicology,2017,381:75-86.
[25] Huang YH,Kuo HC,Yang YL.MicroRNA-29a is a key regulon that regulates BRD4 and mitigates liver fibrosis in mice by inhibiting hepatic stellate cell activation [J].Int J Med Sci,2019,16(2):212-220.
[26] Jiang X.Long noncoding RNA:a new contributor and potential therapeutic target in fibrosis [J].Epigenomics,2017,9(9):1233-1241.
[27] Bangen JM,Hammerich L,Sonntag R,et al.Targeting CCl4-induced liver fibrosis by RNA interference-mediated inhibition of cyclin E1 in mice [J].Hepatology,2017,66(4):1242-1257.
[28] Caviglia JM,Yan J,Jang MK,et al.MicroRNA-21 and Dicer are dispensable for hepatic stellate cell activation and the development of liver fibrosis [J].Hepatology,2018,67(6):2414-2429.
[29] Wei J,Feng L,Li Z,et al.MicroRNA-21 activates hepatic stellate cells via PTEN/Akt signaling [J].Biomed Pharmacother,2013,67(5):387-392.
[30] Zheng J,Wu C,Xu Z,et al.Hepatic stellate cell is activated by microRNA-181b via PTEN/Akt pathway [J].Mol Cell Biochem,2015,398(1-2):1-9.
[31] Kaimori A,Potter J,Kaimori JY,et al.Transforming growth factor-beta1 induces an epithelial-to-mesenchymal transition state in mouse hepatocytes in vitro [J].J Biol Chem,2007,282(30):22089-22101.
[32] Chen YL,Zhang X,Bai J,et al.Sorafenib ameliorates bleomycin-induced pulmonary fibrosis:potential roles in the inhibition of epithelial-mesenchymal transition and fibroblast activation [J].Cell Death Dis,2013,4:e665.
[33] Osawa Y,Seki E,Adachi M,et al.Role of acid sphingomyelinase of Kupffer cells in cholestatic liver injury in mice [J].Hepatology,2010,51(1):237-245.
[34] Tacke F.Macrophage heterogeneity in liver injury and fibrosis [J].J Hepatol,2014,60(5):1090-1096.
[35] Hyam SR,Lee IA,Gu W,et al.Arctigenin ameliorates inflammation in vitro and in vivo by inhibiting the PI3K/AKT pathway and polarizing M1 macrophages to M2-like macrophages [J].Eur J Pharmacol,2013,708(1-3):21-29.
[36] Yue S,Rao J,Zhu J,et al.Myeloid PTEN deficiency protects livers from ischemia reperfusion injury by facilitating M2 macrophage differentiation [J].J Immunol,2014,192(11):5343-5353.
[37] Cheng Y,Tian Y,Xia J,et al.The role of PTEN in regulation of hepatic macrophages activation and function in progression and reversal of liver fibrosis [J].Toxicol Appl Pharmacol,2017,317:51-62.
[38] Li N,Qin JF,Han X,et al.miR-21a negatively modulates tumor suppressor genes PTEN and miR-200c and further promotes the transformation of M2 macrophages [J].Immunol Cell Biol,2018,96(1):68-80.
[39] Ghesquière B,Wong BW,Kuchnio A.Metabolism of stromal and immune cells in health and disease [J].Nature,2014,511(7508):167-176.
[40] Thwe PM.The role of nitric oxide in metabolic regulation of Dendritic cell immune function [J].Cancer Lett,2018,412:236-242.
[41] Pearce EL.Metabolic pathways in immune cell activation and quiescence [J].Immunity,2013,38(4):633-643.
[42] Saha S,Shalova IN.Metabolic regulation of macrophage phenotype and function [J].Immunol Rev,2017,280(1):102-111.
[43] Artyomov MN,Sergushichev A.Integrating immunometabolism and macrophage diversity [J].Semin Immunol,2016,28(5):417-424.
[44] Ortega-Molina A.PTEN in cancer,metabolism,and aging [J].Trends Endocrinol Metab,2013,24(4):184-189.
[45] Qiu W,Federico L,Naples M,et al.Phosphatase and tensin homolog (PTEN) regulates hepatic lipogenesis,microsomal triglyceride transfer protein,and the secretion of apolipoprotein B-containing lipoproteins [J].Hepatology,2008,48(6):1799-1809.
[46] Linke M,Fritsch SD,Sukhbaatar N,et al.mTORC1 and mTORC2 as regulators of cell metabolism in immunity [J].FEBS Lett,2017,591(19):3089-3103.
[2] Zhang CY,Yuan WG,He P,et al.Liver fibrosis and hepatic stellate cells:Etiology,pathological hallmarks and therapeutic targets [J].World J Gastroenterol,2016,22(48):10512-10522.
[3] Omar R,Yang J,Liu H,et al.Hepatic stellate cells in liver fibrosis and siRNA-based therapy [J].Rev Physiol Biochem Pharmacol,2016,172:1-37.
[4] Li J,Yen C,Liaw D,et al.PTEN,a putative protein tyrosine phosphatase gene mutated in human brain,breast,and prostate cancer [J].Science,1997,275(5308):1943-1947.
[5] Lee YR,Chen M.The functions and regulation of the PTEN tumour suppressor:new modes and prospects [J].Nat Rev Mol Cell Biol,2018,19(9):547-562.
[6] Chen L.The functions of tumor suppressor PTEN in innate and adaptive immunity [J].Cell Mol Immunol,2017,14(7):581-589.
[7] Kechagioglou P,Papi RM,Provatopoulou X,et al.Tumor suppressor PTEN in breast cancer:heterozygosity,mutations and protein expression [J].Anticancer Res,2014,34(3):1387-1400.
[8] Wise HM,Hermida MA.Prostate cancer,PI3K,PTEN and prognosis [J].Clin Sci (Lond),2017,131(3):197-210.
[9] Roa I,de Toro G,Fernández F,et al.Inactivation of tumor suppressor gene pten in early and advanced gallbladder cancer [J].Diagn Pathol,2015,10:148.
[10] Garcia-Cao I,Song MS,Hobbs RM,et al.Systemic elevation of PTEN induces a tumor-suppressive metabolic state [J].Cell,2012,149(1):49-62.
[11] Zhou J,Zhong J,Lin S,et al.Inhibition of PTEN activity aggravates post renal fibrosis in mice with ischemia reperfusion-induced acute kidney injury [J].Cell Physiol Biochem,2017,43(5):1841-1854.
[12] Yu F,Chen B,Dong P.HOTAIR epigenetically modulates PTEN expression via microRNA-29b:a novel mechanism in regulation of liver fibrosis [J].Mol Ther,2017,25(1):205-217.
[13] Parapuram SK,Thompson K,Tsang M,et al.Loss of PTEN expression by mouse fibroblasts results in lung fibrosis through a CCN2-dependent mechanism [J].Matrix Biol,2015,43:35-41.
[14] Matsuda S,Kobayashi M.Roles for PI3K/AKT/PTEN pathway in cell signaling of nonalcoholic fatty liver disease [J].ISRN Endocrinol,2013,2013:472432.
[15] Pradere JP,Kluwe J,De Minicis S,et al.Hepatic macrophages but not dendritic cells contribute to liver fibrosis by promoting the survival of activated hepatic stellate cells in mice [J].Hepatology,2013,58(4):1461-1473.
[16] Ma PF,Gao CC,Yi J,et al.Cytotherapy with M1-polarized macrophages ameliorates liver fibrosis by modulating immune microenvironment in mice [J].J Hepatol,2017,67(4):770-779.
[17] 郝礼森,张晓岚,李玉林,等.大鼠纤维化肝组织中PTEN的动态表达及其与肝星状细胞增殖和活化的关系[J].中华肝脏病杂志,2008,16(10):743-747.
[18] Ruan W,Pan R,Shen X,et al.CDH11 promotes liver fibrosis via activation of hepatic stellate cells [J].Biochem Biophys Res Commun,2018,508(2):543-549.
[19] An J,Zheng L,Xie S,et al.Regulatory effects and mechanism of adenovirus-mediated PTEN gene on hepatic stellate cells [J].Dig Dis Sci,2016,61(4):1107-1120.
[20] Hao LS,Zhang XL,An JY,et al.PTEN expression is down-regulated in liver tissues of rats with hepatic fibrosis induced by biliary stenosis [J].APMIS,2009,117(9):681-691.
[21] An J,Zheng L,Xie S,et al.Down-regulation of focal adhesion kinase by short hairpin RNA increased apoptosis of rat hepatic stellate cells [J].APMIS,2011,119(6):319-329.
[22] 魏月,郝礼森,任昌镇,等.PTEN过表达及突变对活化肝星状细胞黏着斑激酶信号转导的影响研究[J].中国全科医学,2016,19(29):3562-3566.
[23] Kumar P,Raeman R,Chopyk DM,et al.Adiponectin inhibits hepatic stellate cell activation by targeting the PTEN/AKT pathway [J].Biochim Biophys Acta Mol Basis Dis,2018,1864(10):3537-3545.
[24] Li WX,Chen X,Yang Y,et al.Hesperitin derivative-11 suppress hepatic stellate cell activation and proliferation by targeting PTEN/AKT pathway [J].Toxicology,2017,381:75-86.
[25] Huang YH,Kuo HC,Yang YL.MicroRNA-29a is a key regulon that regulates BRD4 and mitigates liver fibrosis in mice by inhibiting hepatic stellate cell activation [J].Int J Med Sci,2019,16(2):212-220.
[26] Jiang X.Long noncoding RNA:a new contributor and potential therapeutic target in fibrosis [J].Epigenomics,2017,9(9):1233-1241.
[27] Bangen JM,Hammerich L,Sonntag R,et al.Targeting CCl4-induced liver fibrosis by RNA interference-mediated inhibition of cyclin E1 in mice [J].Hepatology,2017,66(4):1242-1257.
[28] Caviglia JM,Yan J,Jang MK,et al.MicroRNA-21 and Dicer are dispensable for hepatic stellate cell activation and the development of liver fibrosis [J].Hepatology,2018,67(6):2414-2429.
[29] Wei J,Feng L,Li Z,et al.MicroRNA-21 activates hepatic stellate cells via PTEN/Akt signaling [J].Biomed Pharmacother,2013,67(5):387-392.
[30] Zheng J,Wu C,Xu Z,et al.Hepatic stellate cell is activated by microRNA-181b via PTEN/Akt pathway [J].Mol Cell Biochem,2015,398(1-2):1-9.
[31] Kaimori A,Potter J,Kaimori JY,et al.Transforming growth factor-beta1 induces an epithelial-to-mesenchymal transition state in mouse hepatocytes in vitro [J].J Biol Chem,2007,282(30):22089-22101.
[32] Chen YL,Zhang X,Bai J,et al.Sorafenib ameliorates bleomycin-induced pulmonary fibrosis:potential roles in the inhibition of epithelial-mesenchymal transition and fibroblast activation [J].Cell Death Dis,2013,4:e665.
[33] Osawa Y,Seki E,Adachi M,et al.Role of acid sphingomyelinase of Kupffer cells in cholestatic liver injury in mice [J].Hepatology,2010,51(1):237-245.
[34] Tacke F.Macrophage heterogeneity in liver injury and fibrosis [J].J Hepatol,2014,60(5):1090-1096.
[35] Hyam SR,Lee IA,Gu W,et al.Arctigenin ameliorates inflammation in vitro and in vivo by inhibiting the PI3K/AKT pathway and polarizing M1 macrophages to M2-like macrophages [J].Eur J Pharmacol,2013,708(1-3):21-29.
[36] Yue S,Rao J,Zhu J,et al.Myeloid PTEN deficiency protects livers from ischemia reperfusion injury by facilitating M2 macrophage differentiation [J].J Immunol,2014,192(11):5343-5353.
[37] Cheng Y,Tian Y,Xia J,et al.The role of PTEN in regulation of hepatic macrophages activation and function in progression and reversal of liver fibrosis [J].Toxicol Appl Pharmacol,2017,317:51-62.
[38] Li N,Qin JF,Han X,et al.miR-21a negatively modulates tumor suppressor genes PTEN and miR-200c and further promotes the transformation of M2 macrophages [J].Immunol Cell Biol,2018,96(1):68-80.
[39] Ghesquière B,Wong BW,Kuchnio A.Metabolism of stromal and immune cells in health and disease [J].Nature,2014,511(7508):167-176.
[40] Thwe PM.The role of nitric oxide in metabolic regulation of Dendritic cell immune function [J].Cancer Lett,2018,412:236-242.
[41] Pearce EL.Metabolic pathways in immune cell activation and quiescence [J].Immunity,2013,38(4):633-643.
[42] Saha S,Shalova IN.Metabolic regulation of macrophage phenotype and function [J].Immunol Rev,2017,280(1):102-111.
[43] Artyomov MN,Sergushichev A.Integrating immunometabolism and macrophage diversity [J].Semin Immunol,2016,28(5):417-424.
[44] Ortega-Molina A.PTEN in cancer,metabolism,and aging [J].Trends Endocrinol Metab,2013,24(4):184-189.
[45] Qiu W,Federico L,Naples M,et al.Phosphatase and tensin homolog (PTEN) regulates hepatic lipogenesis,microsomal triglyceride transfer protein,and the secretion of apolipoprotein B-containing lipoproteins [J].Hepatology,2008,48(6):1799-1809.
[46] Linke M,Fritsch SD,Sukhbaatar N,et al.mTORC1 and mTORC2 as regulators of cell metabolism in immunity [J].FEBS Lett,2017,591(19):3089-3103.