PTEN基因与消化系统器官纤维化PTEN and Digestive Organ Fibrosis
张晓云;郝建宇;
ZHANG Xiao-yun;HAO Jian-yu;Department of Gastroenterology,Beijing Chaoyang Hospital Affiliated to Capital Medical University;
摘要(Abstract):
PTEN基因是目前发现的重要抑癌基因之一,其蛋白产物具有独特的蛋白磷酸酶及脂质磷酸酶双重活性。PTEN蛋白分布广泛、生物学功能复杂、调节方式多样,可通过多种信号转导途径对细胞的形态、增殖、分化、黏附、迁移等发挥调节作用。随着对PTEN基因的深入研究,揭示该基因与多种消化器官纤维化过程密切相关,并可能成为逆转及治疗纤维化的潜在靶点。
PTEN gene is one of the most important tumor suppressor gene,which acts through a unique protein phosphatase and lipid phosphates activity. PTEN protein has a wide distribution,complex biological function,and a variety of regulation modes,which can regulate the cell morphology,proliferation,differentiation,adhesion and migration through a variety of signaling pathways. With the further study of PTEN,it is found that the gene is closely related to the digestive process of many kinds of digestive organs,and may be a potential target for the reversing and treatment of fibrosis.
关键词(KeyWords):
PTEN;消化系统疾病;纤维化;细胞外基质
PTEN;digestive disease;fibrosis;extracellular matrix
基金项目(Foundation): 国家自然科学基金面上项目(81470888)
作者(Author):
张晓云;郝建宇;
ZHANG Xiao-yun;HAO Jian-yu;Department of Gastroenterology,Beijing Chaoyang Hospital Affiliated to Capital Medical University;
Email:
DOI:
参考文献(References):
- [1]Li J,Yen C,Liaw D,et al.PTEN.a putative protein tyrosine phesphatasc gene mutated in human brain,breastand prostate cancer[J].Science,1997,275:1943-1947.
- [2]Steck PA,Pershouse MA,Jasser SA,et al.Identification of a candidate tumour suppressor gene,MMAC1,at chromosome10q23.3 that is mutated in multiple advanced cancers[J].Nat Genet,1997,15:356-362.
- [3]Li DM,Sun H.TEP1,encoded by a candidate tumor suppressor locus,is a novel protein tyrosine phosphatase regulated by transforming growth factor beta[J].Cancer Res,1997,57:2124-2129.
- [4]Milella M,Falcone I,Conciatori F,et al.PTEN:multiple functions in human malignant tumors[J].Front Oncol,2015,5:24.
- [5]Lee JO,Yang H,Georgescu MM,et al.Crystal structure of the PTEN tumour suppressor:implications for its phosphoinositide phosphatase activity and membrane association[J].Cell,1999,99:323-334.
- [6]Maehama T,Dixon JE.The tumor suppressor,PTEN/MMAC1,dephosphorylates the lipid second messenger,phosphatidylinositol 3,4,5-trisphosphate[J].J Biol Chem,1998,273:13375-13378.
- [7]Stambolic V,Suzuki A,de la Pompa JL,et al.Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN[J].Cell,1998,95:29-39.
- [8]Conidi A,Cazzola S,Beets K,et al.Few Smad proteins and many Smad-interacting proteins yield multiple functions and action modes in TGFβ/BMP signaling in vivo[J].Cytokine Growth Factor Rev,2011,22:287-300.
- [9]Wang S,Cheng Z,Yang X,et al.Effect of wild type PTEN gene on proliferation and invasion of multiple myeloma[J].Int J Hematol,2010,92:83-94.
- [10]Song MS,Salmena L,Pandolfi PP.The functions and regulation of the PTEN tumour suppressor[J].Nat Rev Mol Cell Biol,2012,13:283-296.
- [11]White ES,Thannickal VJ,Carskadon SL,et al.Integrin alpha4beta1 regulates migration across basement membranes by lung fibroblasts:a role for phosphatase and tensin homologue deleted on chromosome 10[J].Am J Respir Crit Care Med,2003,168:436-442.
- [12]Parapuram SK,Shi-wen X,Elliott C,et al.Loss of PTEN expression by dermalfibroblasts causesskin fibrosis[J].J Invest Dermatol,2011,131:1996-2003.
- [13]Zheng L,Chen X,Guo J,et al.Differential expression of PTEN in hepatic tissue and hepatic stellate cells during rat liver fibrosis and its reversal[J].Int J Mol Med,2012,30:1424-1430.
- [14]Im E,Jung J,Pothoulakis C,et al.Disruption of Pten speeds onset and increases severity of spontaneous colitis in Il10(-/-)mice[J].Gastroenterology,2014,147:667-669.
- [15]Wang L,Zhang N,Wang Z,et al.Pseudogene PTENP1Functions as a Competing Endogenous RNA(ceRNA)to Regulate PTEN Expression by Sponging miR-499-5p[J].Biochemistry(Mosc),2016,81:739-747.
- [16]Vazquez F,Ramaswamy S,Nakamura N,et al.Phosphorylation of the PTEN tail regulates protein stability and function[J].Mol Cell Biol,2000,20:5010-5018.
- [17]Putz U,Mah S,Goh CP,et al.PTEN secretion in exosomes[J].Methods,2015,77-78:157-163.
- [18]Bian EB,Huang C,Ma TT,et al.DNMT1-mediated PTEN hypermethylation confers hepatic stellate cell activation and liver fibrogenesis in rats[J].Toxicol Appl Pharmacol,2012,264:13-22.
- [19]Lorenzen JM,Schauerte C,Hübner A,et al.Osteopontin is indispensible for AP1-mediated angiotensin II-related miR-21transcription during cardiac fibrosis[J].Eur Heart J,2015,36:2184-2196.
- [20]Zhong C,Wang K,Liu Y,et al.miR-19b controls cardiac fibroblast proliferation and migration[J].J Cell Mol Med,2016,20:1191-1197.
- [21]Kuninty PR,Bojmar L,Tjomsland V,et al.MicroRNA-199aand-214 as potential therapeutic targets in pancreatic stellate cells in pancreatic tumor[J].Oncotarget,2016,7:16396-16408.
- [22]Manning BD,Cantley LC.AKT/PKB signaling:navigating downstream[J].Cell,2007,129,1261-1274.
- [23]Schwock J,Dhani N,Hedley DW.Targeting focal adhesion kinase signaling in tumor growth and metastasis[J].Expert Opin Ther Targets,2010,14:77-94.
- [24]Xia H,Diebold D,Nho R,et al.Pathological integrin signaling enhances proliferation of primary lung fibroblasts from patients with idiopathic pulmonary fibrosis[J].J Exp Med2008,205:1659-1672.
- [25]Samarakoon R,Helo S,Dobberfuhl AD,et al.Loss of tumour suppressor PTEN expression in renal injury initiates SMAD3-and p53-dependent fibrotic responses[J].J Pathol,2015,236:421-432.
- [26]Gao Y,Chu M,Hong J,et al.Hypoxia induces cardiac fibroblast proliferation and phenotypic switch:a role for caveolae and caveolin-1/PTEN mediated pathway[J].J Thorac Dis,2014,6:1458-1468.
- [27]Danussi C,Petrucco A,Wassermann B,et al.EMILIN1-α4/α9 integrin interaction inhibits dermal fibroblast and keratinocyte proliferation[J].J Cell Biol,2011,195:131-145.
- [28]Eng FJ,Friedman SL,Fibrogenesis I.New insights into hepatic stellate cell activation:the simple becomes complex[J].Am J Physiol Gastrointest Liver Physiol,2000,279:G7-G11.
- [29]Reif S,Lang A,Lindquist JN,et al.The role of focal adhesion kinase-phosphatidylinositol 3-kinase-Akt signaling in hepatic stellate cell proliferation and type I collagen expression[J].J Biol Chem,2003,278:8083-8090.
- [30]Takashima M,Parsons CJ,Ikejima K,et al.The tumor suppressor protein PTEN inhibits rat hepatic stellate cell activation[J].J Gastroenterol,2009,44:847-855.
- [31]Hao LS,Zhang XL,An JY,et al.PTEN expression is downregulated in liver tissues of rats with hepatic fibrosis induced by biliary stenosis[J].APMIS,2009,117:681-691.
- [32]Zheng L,Chen X,Guo J,et al.Differential expression of PTEN in hepatic tissue and hepatic stellate cellsduring rat liver fibrosis and its reversal[J].Int J Mol Med,2012,30:1424-1430.
- [33]Stiles B,Wang Y,Stahl A,et al.Liver-specific deletion of negative regulator PTEN results in fatty liver and insulin hypersensitivity[corrected][J].Proc Natl Acad Sci U S A,2004,101:2082-2087.
- [34]Sato W,Horie Y,Kataoka E,et al.Hepatic gene expression in hepatocyte-specific PTEN deficient mice showing steatohepatitis without ethanol challenge[J].Hepatol Res,2006,34:256-265.
- [35]Mc Carroll JA,Phillips PA,Kumar RK,et al.Pancreatic stellate cell migration:role of the phosphatidylinositol 3-kinase(PI3-kinase)pathway[J].Biochem Pharmacol,2004,67:1215-1225.
- [36]Covey TM,Edes K,Fitzpatrick FA.Akt activation by arachidonic acid metabolism occurs via oxidation andinactivation of PTEN tumor suppressor[J].Oncogene,2007,26:5784-5792.
- [37]Vonlaufen A,Joshi S,Qu C,et al.Pancreatic stellate cells:Partners in crime with pancreatic cancer cells[J].Cancer Res,2008,68:2085-2093.
- [38]Gong H.Analysis of intercellular signal transduction in the tumor microenvironment[J].BMC Syst Biol,2013,7Suppl3:S5.
- [39]Ince MN,Elliott DE.Immunologic and molecular mechanisms in inflammatory bowel disease[J].Surg Clin North Am,2007,87:681-696.
- [40]Sheppard K,Kinross KM,Solomon B,et al.Targeting PI3kinase/AKT/m TOR signaling in cancer[J].Crit Rev Oncog,2012,17:69-95.
- [41]Nakanishi A,Wada Y,Kitagishi Y,et al.Link between PI3K/AKT/PTEN pathway and NOX protein in diseases[J].Aging Dis,2014,5:203-211.
- [42]Burke JP,Cunningham MF,Sweeney C,et al.N cadherin is overexpressed in Crohn's stricture fibroblasts and promotes intestinal fibroblast migration[J].Inflamm Bowel Dis,2011,17:1665-1673.