过氧化物酶体增殖物激活受体γ在HBV、HCV感染肝细胞癌组织中的表达
详细信息    本馆镜像全文|  推荐本文 |  |   获取CNKI官网全文
摘要
目的探讨过氧化物酶体增殖物激活受体γ在HBV、HCV感染的肝细胞癌组织及相应癌旁组织中的表达情况。
     方法收集2008年10月至2010年9月湖南省人民医院、中南大学湘雅二医院及南华大学附属第一医院肝胆外科经手术切除且有完整临床病理资料的40例HBV阳性的肝细胞癌组织及相应癌旁组织、16例HCV阳性的肝细胞癌组织及相应癌旁组织标本,采用免疫组织化学法检测HBV、HCV阳性的肝细胞癌组织及相应癌旁组织中PPAR-γ的表达,用图像分析系统测定PPAR-γ的灰度值(gray scale)并分析其与临床病理资料的关系。
     结果HBV阳性肝细胞癌组织及其相应癌旁组织中PPAR-γ的灰度平均值分别为91.13+3.28、114.18+3.27,HCV阳性肝细胞癌组织及其相应癌旁组织中PPAR-γ的灰度平均值分别为99.75±4.99、117.69±4.91,两者间比较均具有显著性差异(P <0.05)。HCC组织中PPAR-y的表达程度与患者性别、年龄、肿瘤大小、血清AFP水平、门/腔静脉癌栓有无等因素无关(P>0.05),而与组织分化程度及肝炎病毒感染有关(P<0.05)。
     结论1、PPAR-y在HBV及HCV阳性的肝细胞癌组织表达高于相应癌旁组织中的表达。
     2、PPAR-γ在低分化的HCC中的表达高于在高分化的HCC中的表达,检测PPAR-γ对判断其恶性程度有一定参考价值。
     3、PPAR-γ可能参与HBV、HCV阳性的HCC的发生、发展过程,可能是引起HBV阳性的HCC较HCV阳性的HCC发病率高、进展快的影响因素之
Objective:To investigate the different expression of peroxisome proliferator-activated receptor-gamma in Human Hepatocellular Carcinoma tissues and the corresponding adjacent nontumoral liver tissues with HBV-Related and HCV-Related infections.
     Methods:Collect 40 cases of Hepatocellular Carcinoma tissues and the correspo-nding adjacent nontumoral liver tissues with HBV-Related infection,16 cases of Hepatocellular Carcinoma tissues and the corresponding adjacent nontumoral liver tissues with HCV-Related infection which were treated by surgical resecting and had complete clinicopathological informations from October 2008 to September 2010 in Hunan Provincial People's Hospital and The Second Xiangya Hospital of Central South University and The First Affiliated Hospital of Nanhua University. Detect the expression of PPAR-gamma in the cases of Hepatocellular Carcinoma tissues and the corresponding adjacent nontumoral liver tissues with HBV-Related and HCV-Related infections by immunohistochemistry, And make a quantitative analysis of the expression of PPAR-gamma by accessing their mean gray scale with Motic Image Advanced 3.2 color imaging analysis system,then analyse the relationship between PPAR-gamma and the clinicopathological informations.
     Results:The mean gray scale of HCC tissues and the corresponding adjacent nontumoral liver tissues with HBV-Related infection were respectively 91.13±3.28 and 114.18±3.27, the mean gray scale of HCC tissues and the corresponding adjacent nontumoral liver tissues with HCV-Related infection were respectively 99.75±4.99 and 117.69±4.91,the differences between them are very significant(P<0.05).The express degree of PPAR-gamma in HCC tissues was not associated with sex,age,tumor size,serum AFP levels,tumor embolus of portal vein or vena cana(P> 0.05),but with differentiation degree and hepatitis virus infection(P<0.05).
     Conclusions:
     1.The expression of PPAR-gamma in HCC tissues with HBV-Related and HCV-Related infections is higher than their corresponding adjacent nontumoral liver tissues.
     2. The expression of PPAR-gamma in poor-differentiated HCC is higher than its in well-differentiated HCC. Detection of PPAR-gamma is valuable for evaluating malignancy extent.
     3. PPAR-gamma may involve in the development of HCC with HBV-Related and HCV-Related infections.It may be one of the influencing factors which lead to HCC with HBV-Related infection having a high incidence and a fast progress than HCC with HCV-Related infection.
引文
[1]D.Max Parkin,MD,Freddie Bray,et al.Global cancer statistics,2002[J].CA Cancer J Clin,2005;55(2):74-108.
    [2]Shijian Liu,Jiaxin Xie,Jianhua Yin,et al.A Matched Case-Control Study of Hepatitis B Virus Mutations in the PreS and Core Promoter Regions Associated Independently With Hepatocellular Ccrcinoma[J]. Journal of Medical Virology,20 11,83:45-53.
    [3]孙爱武,陈园生.乙型病毒性肝炎和原发性肝细胞癌[J].中国疫苗和免疫,2010,16(2):173-177.
    [4]Kitamura T,Watanabe S,Sato N.Liver regeneration,liver cancers and cyclins[J].J Gastroenterol Hepatol,1998,13:S96-99.
    [5]Ishtiaq Qadri,Kaneez Fatima,Hany Abdel-Hafiz.Hepatitis B virus X protein impedes the DNA repair its association with transcription factor,TFIIH[J].BMC Microbiology,2011,11:48-63.
    [6]Hoofnagle JH.Course and outcome of hepatitis C[J].Hepatology,2002,36(5 Suppl 1):s21-29.
    [7]郭红伟,陈江,张丽萍,等.丙型肝炎病毒感染合并肝细胞癌64例临床分析[J].中国癌症杂志,2009,19(9):708-711.
    [8]小池克郎.乙型肝炎病毒所致肝癌[J].日本医学介绍,1999,20(5):212-214.
    [9]殷欣,张博恒,陈晓泓,等.乙型肝炎及丙型肝炎病毒对肝细胞癌临床病理特征及预后的影响[J].中国临床医学,2010,17(2):195-198
    [10]张利宁,曹英林,宋静,等.原发性肝细胞癌中HBV各基因片段整合基因、抑癌基因表达的相关研究[J].中华肝脏病杂志,1999,7(3):138-139.
    [11]Issemann I,Green S.Activation of a number of the steroid hormone receptor superfamily by peroxisome proliferators [J]. Nature,1990,347(6294):645-650.
    [12]Theocharis S,Margeli A,Vielh P,et al.Peroxisome proliferator-activated receptor-gamma ligands as cell-cycle modulators [J]. Cancer Treat Rev,2004,30 (6): 545-554.
    [13]Yoshizawa K,Cioca DP,Kawa S,et al.Peroxisome proliferator-activated receptor gamma ligand troglitazone induces cell cycle arrest and apoptosis of hepatocell- ular carcinoma cell lines[J].Cancer,2002,95(10):2243-2251.
    [14]Takeuchi S,Okumura T,Motomura W,et,al.Troglitazone induces G1 arrest by p27 (Kipl) induction that mediated by inhibition of proteasome in human gastric cancer cells[J].Jpn J Cancer Res,2002,93(7):774-782.
    [15]Shimada T,Kojima K,Yoshiura K,et al.Characteristics of the peroxisome proliferator-activated receptor gamma (PPARgamma) ligand induced apoptosis in colon cancer cells.[J].Gut,2002,50(5):658-664.
    [16]张剑,何生,李茂德.肝细胞癌中iNOS和p53蛋白的表达及其与肿瘤血管形成的关系[J].中国普外基础与临床杂志,2004,11(5):396-398.
    [17]郑鹏飞P21ras、PIK3CA、P-AKT在肝癌、肝硬化中的表达及意义[D].甘肃:兰州大学,2010.
    [18]吴孟超,吴在德.黄家驷外科学[M].人民卫生出版社,2008:1692.
    [19]Grimaldi PA.The roles of PPARs in adipocyte differentiation [J].Prog Lipid Research,2001,40(4):269-281.
    [20]Berthiaume M,Sell H, Lalonde J,et al.Actions of PPAR gamma agonism on adipose tissue remodeling,insulin sensitivity,and lipemia in absence of glucocorticoids[J].Am J Physiol Regul Integr Comp Physiol,2004,287(5):R1116-1123.
    [21]Sato H,Ishihara S,Kawashima K,et al.Expression of peroxisome proliferator-acti-vated receptor gamma in gastric cancer and inhibitory effects of PPAR gamma agonists[J].Br J Cancer,2000,83(10):1394-1400.
    [22]Nicholas P.Evans,Sarah A.Misyak,Eva M.Schmelz,et al.Conjugated Linoleic Acid Ameliorates Inflammation-induced Colorectal Cancer in Mice through Activation of PPARy[J].The Journal of Nutrition,2010,140 (3):515-521.
    [23]Tsubouchi Y,Sano H,Kawahito Y,et al.Inhibition of human lung cancer cell growth by the peroxisome proliferator-activated receptor-gamma agonists through induction of apoptosis[J].Biochem Biophys Res Commun,2000,270(2):400-405.
    [24]Yu-Wei Dong,Xing-Peng Wang,Kai Wu.Suppression of pancreatic carcinoma growth growth by activating peroxisome proliferator-activated receptor yinvolves angiogenesis inhibition[J].World Gastroenterology,2009,15 (4):441-448
    [25]李传凤,李军,吕愈敏.过氧化物酶体增殖物激活受体γ在大肠肿瘤中的表达及意义[J].肿瘤防治研究,2008,35(1),23-26.
    [26]Sahin M,Allard BL,Yates M,et al. PPAR gamma staining as a surrogate for PAX8/PPAR gamma fusion oncogene expression in follicular neoplasms: clinicopathological correlation and histopathological diagnostic value[J].J Clin Endocrinol Metab,2005,90(1):463-468.
    [27]郭鸣雷,李锦军,李宏年,等.过氧化物酶体增殖激活性受体y (PPARy)在肝癌组织中的差异性表达[J].肿瘤,2005,25(5):413-415.
    [28]Schaefer KL,Wada K,Takahashi H,et al.Peroxisome proliferator-activated receptor gamma inhibition prevents adhesion to the extracellular matrix and induces anoikis in hepatocellular carcinoma cells[J].Cancer Res,2005,65(6):2251-2259.
    [29]杨风光,师长进,张志文,等.过氧化物酶体增殖激活物受体-γ在肾细胞癌中的表达及其意义[J].中华实验外科杂志,2004,21(9):1107-1108.
    [30]何晓燕,张敏,陈智超,等PPARy在肺癌中的表达及在肺癌凋亡中的作用研究[J].中国肺癌杂志,2006,9(1):35-39.
    [31]夏启松,修瑞娟,孙仁宇,等.过氧化物酶体增殖物激活受体Y途径抑制肿瘤血管生成的研究进展[J].肿瘤防治研究,2009,36(5):443-447.
    [32]Toyoda M,Takagi H,Horiguchi N,et al.A ligand for peroxisime proliferator activated receptor gamma inhibits cell growth and induces apoptosis in human liver cancer cells[J].Gut,2002,50(4):563-567.
    [33]Han C,Demetris AJ,Michalopoulos GK,et al.PPARgamma ligands inhibit cholangiocarcinoma cell growth through p53-dependent GADD45 and p21 pathway[J].Hepatology,2003,38(1):167-177.
    [34]Markus Schwab,Veerle Reynders,Stefan Loitsch,et al.PPARy is involved in mesalazine-mediated induction of apoptosis and inhibition of cell growth in colon cancer cells[J].Carcinogeneses,2008,29(7):1407-1414.
    [35]孟爱国,刘春艳,石峻等.过氧化物酶体激活物活化受体γ活化对人胃癌细胞周期的影响.肿瘤.2007,27(11):874-877.
    [36]Qin C,Burghardt R,Smith R,et al.Peroxisome proliferator-activated receptor gamma agonists induce proteasome-dependent degradation of cyclinD1 and estrogen receptor alpha in MCF-7 breast cancer cells[J].Cancer Res,2003,63(5):9 58-964.
    [37]Toyota M,Miyazaki Y, Kitamura S,et al.Peroxisome proliferator-activated receptor gamma reduces the growth rate of pancreatic cancer cells through the reduction of cyclin D1[J].Life Sci,2002,70(13):1565-1575.
    [38]Yang FQZhang Z W,Xin DQ,et al. Peroxisome proliferator-actived receptor-gamma ligand troglitazone induces apoptosis in renal cell carcinoma[J].Beijing Da Xue Xue Bao,2004,36(2):173-176.
    [39]Christine LChaffer,David M Thomas,Erik W Thompson,et al.PPARy-independent induction of growth arrest and apoptosis in prostate and bladder carcinoma[J].BMC Cancer,2006,6:1-13.
    [40]Xu HE,Lambert MH,Montana VG,et al.Molecular recognition of fatty acids by peroxisome proliferator-adtivated receptors[J].Mol Cell,1999,3(3):397-403.
    [41]Nagy L,Tontonoz P,Alvarez JG,et al.Oxidized LDL regulates macrophage gene expression through ligand activation of PPARgamma[J].Cell,1998,93(2):229-240.
    [42]阿仙姑·哈斯木.PPARγ、COX-2和bel-2在子宫颈上皮瘤样变及子宫颈癌中的表达及意义[D].乌鲁木齐:新疆医科大学,2007.
    [43]Suzuki T,Hayashi S,Miki Y,et al.Peroxisome proliferator-activated receptor gamma in human breast carcinoma:a modulator of estrogenic actions [J].Endocr Relat Cancer,2006,13(1):233-250.
    [44]Green S.Peroxisome proliferators:a model for receptor mediated carecinogenesis [J].Cancet surv,1992,14:221-232.
    [45]Park IY,Sohn BH,Yu E,et al.Aberrant epigenetic modifications in hepatocarcinog-enesis induced by hepatitis B virus x protein[J].Gastroenterology,2007,132(4):1476-1494.
    [46]Tang H, Oishi N,Kaneko S,et al.Molecular functions and biological roles of hepatitis B virus x protein[J].Cancer Sci,2006,97(10):977-983.
    [47]毕杨,黄佳祎,吴明军,等.稳定表达HBx的HepG2细胞对罗格列酮敏感性的影响及其机制研究[J].肿瘤,2008,28(12):1034-1038.
    [1]Issemann I, Green S. Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators [J]. Nature,1990,347(6294):645-650.
    [2]Inoue H,Jiang XF,Katayama T,et al.Brain protection by resveratrol and fenofibrate against stroke requires pemxisome proliferator-activated receptor alpha in mice[J].Neuroscience Letters,2003,352(3):203-206.
    [3]Vamecq J,Latruffe N.Medical significance of peroxisome proliferentiator -activated receptors[J].Lancet,1999;354(9173):141-148.
    [4]Gilde AJ,Van der Lee KA,Willemsen PH,et al.Peroxisome proliferator activated-receptor (PPAR)alpha and PPARbeta/delta,but not PPARgamma,mo-dulate the expression of genes involved in cardiac lipid metabolism[J].Circ Res,2003,92(5):518-524.
    [5]Meirhaeghe A,Fajas L,Gouilleux F,et al.A functional polymorphism in a STAT5B site of human PPAR gamma 3 gene promoter affects height and lipid metabolism in a French population[J].Arterioscler Thromb Vasc Biol,2003,23( 2):289-294.
    [6]Paul A Grimaldi.The roles of PPARs in adipocyte differentiation [J].Progress Lipid Research,2001,40(4):269-281.
    [7]Theocharis S,Margeli A,Vielh P,et al.Peroxisome proliferator-activated receptor-gamma ligands as cell-cycle modulators[J].Cancer Treat Rev,2004,30 (6):545-554.
    [8]Lee HJ,Choi SS,Park MK,et al.Fenofibrate lowers abdominal and skeletal adiposity and improves insulin sensitivity in OLETF rats[J].Biochem Biophys Res Commun,2002,296 (2):293-299.
    [9]Kliewer SA, Umesono K,Noonan DJ,et al.Convergence of 9-cis retinoic acid and peroxisome proliferator signalling pathways through heterodimer formation of their receptors[J].Nature,1992,358(6389):771-774.
    [10]Yang WS,Jeng CY,Wu TJ,et al.Synthetic peroxisome proliferator-activated receptor-gamma agonist,rosiglitazone,increases plasma levels of adiponectin in type 2 diabetic patients[J].Diabetes Care,2002,25(2):376-380.
    [11]Nanjii AA,Jokelainen K,Rahemtulla A,et al.Activation of nuclear factor kappa B and cytokine imbalance in experimental alcoholic liver disease in the rat[J].Hepatology,1999;30(4):934-943.
    [12]Neuschwander-Tetri BA,Caldwell SH.Nonalcoholic steatohepatitis:summary of an AASLD Single Topic Conference[J].Hepatology,2003;37(5):1202-1219.
    [13]Sidhu JS,Kaski JC.Peroxisome proliferator activated receptor gamma:a potential therapeutic target in the management of ischaemic heart disease[J]. Heart,2001,86(3):255-258.
    [14]柳万千,王晓丽PPARy配体对急性心肌梗死心室重构炎症因子的影响[J].心血管病学进展,2008,29(4):616-618.
    [15]Wang AC,Dai X,Luu B,et al.Peroxisome proliferator-activated receptor-gamma regulates airway epithelial cell activation[J].Am J Respir Cell Mol Biol,2001,24(6):688-693.
    [16]Li M,Pascual G,Glass CK.Peroxisome proliferator-activated receptor gamma-dependent repression of the inducible nitric oxide synthase gene[J].Mol Cell Biol,2000,20(13):4699-4707.
    [17]Su CG,Wen X, Bailey ST, et al.A novel therapy for colitis utilizing PPAR-gamma ligands to inhibit the epithelial inflammatory response[J].J Clin Invest.1999;104(4):383-389.
    [18]Ferruzzi P,Ceni E,Tarocchi M,et al.Thiazolidinediones inhibit growth and invasiveness of the human adrenocortical cancer cell line H295R[J].J Clin Endocrinol Metab,2005,90(3):1332-1339.
    [19]Han C,Demetris AJ,Michalopoulos GK,et al.PPARgamma ligands inhibit cholangiocarcinoma cell growth through p53-dependent GADD45 and p21 pathway[J].Hepatology,2003,38(1):167-177.
    [20]程文,程南生,熊先泽,等PPAR-y在肝门部胆管癌中的表达及其配体激活后对胆管癌细胞的作用[J].四川大学学报(医学版),2006,37(5):745-749.
    [21]Yoshizawa K,Cioca DP,Kawa S,et al.Peroxisome proliferator-activated receptor gamma ligand troglitazone induces cell cycle arrest and apoptosis hepatocellular carcinoma cell lines[J].Cancer,2002,95(10):2243-2251.
    [22]Yoshida K,Tanabe K,Fujii D,et al.Induction mechanism of apoptosis by troglitazone through peroxisome proliferators-activated receptor-gamma in gastric carcinoma cells[J].Anticancer Res,2003,23(1 A):267-273.
    [23]Kitamura S,Miyazaki Y,Shinomura Y,et al.Peroxisome proliferator-activated receptor gamma induces growth arrest and differentiation markers of human colon cancer cells[J].Jpn J Cancer Res,1999;90(1):75-80.
    [24]Itami A,Watanabe G,Shimada Y,et al.Ligands for peroxisome proliferator- activated receptor gamma inhibit growth of pancreatic cancers both in vitro and in vivo[J].Int J Cancer,2001;94(3):370-376.
    [25]Fujii D, Yoshida K,Tanabe K,et al.The ligands of peroxisome proliferator-activated receptor(PPAR)gamma inhibit growth of human esophageal carcinoma cells throrgh induction of apoptosis and cycle arrest[J].Anticancer Res,2004;24 (3a):1409-1416.
    [26]Zander T,Kraus JA,Grommes C,et al.Induction of apoptosis in human and rat glioma by agonists of the nuclear receptor PPARgamma[J].J Neurochem,2002, 81(5):1052-1060.
    [27]杨风光,张志文,辛殿祺,等.曲格列酮诱导肾癌细胞的凋亡[J].北京大学学报(医学版),2004,36(2):173-176.
    [28]Li MY, Deng H,Zhao JM, et al.PPARgamma pathway activation results in apoptosis and cox-2 inhibition in HepG2 cells [J]. World J Gastroenterol,2003, 9(6):1220-1224.
    [29]Panigrahy D,Singer S,Shen LQ,et al.PPARgamma ligands inhibit primary tumor growth and metastasis by inhibiting angiogenesis[J].J Clin Invest,2002, 110(7):923-932.
    [30]Sunami E,Tsuno NH,Kitayama J,et al.Decreased synthesis of matrix metalloproteinase-7 and adhesion to extracellular matrix proteins of human colon cancer cells treated with troglitazone[J].Surg Today,2002,32(4):343-350.
    [31]Hashimoto K,Ethridge RT,Evers BM.Peroxisome proliferator-activated receptor gamma ligand inhibits cell growth and invasion of human pancreatic cancer cells[J].Int J Gastrointest Cancer,2002,32(1):7-22.
    [32]曹良启,汪谦,陈锡林,等.过氧化物酶增殖物激活受体γ活化抑制肝癌细胞迁移的研究[J].中华普通外科学文献(电子版),2007,1(2):85-88.
    [33]Tontonoz P,Nagy L,Alvarez JG,et al.PPARgamma promotes monocyte/macr-ophage differentiation and uptake of oxidized LDL[J].Cell,1998,93(2):241-252.
    [34]Mercedes Ricote,Jannet Huang,Luis Fajas,et al.Expression of the peroxisome proliferator-activated receptor y(PPARy)in human atherosclerosis and regulation in macrophages by colony stimulating factors and oxidized low density lipoprotein[J].Proc.Natl.Acad.Sci USA,1998,95:7614-7619.
    [35]Wang N,Verna L,Chen NG,et al.Constitutive activation of peroxisome proliferator-activated receptor-gamma suppresses pro-inflammatory adhesion molecules in human vascular endothelial cells[J].J Biol Chem,2002,277(37): 34176-34181.
    [36]胡莲美,郑文岭,朴英杰,等.过氧化物酶体增殖物激活受体的医学重要性[J].医学分子生物学杂志,2005,2(2):140-142.
    [37]Bluher M,Lubben QPaschke R.Analysis of the relationship between the Prol2Ala variant in the PPAR-gamma2 gene and the response rate to therapy with pioglitazone in patients with type 2 diabetes[J].Diabetes Care,2003,26(3): 825-831.
    [38]Schoonjans K,Watanabe M,Suzuki H,et al.Induction of the acyl-coenzyme A synthetase gene by fibrates and fatty acids is mediated by a peroxisome proliferator response element in the C promoter[J].J Biol Chem,1995,270(33): 19269-19276.
    [39]Everett L,Galli A,Grabb D.The role of hepatic peroxisome proliferator-activated receptors(PPARs) in health and disease[J].Liver,2000,20 (3):191-199.
    [40]Lee SS,Chan WY,Lo CK,et al.Requirement of PPAR alpha in maintaining phospholipid and triacylglycerol homeostasis during energy deprivation[J].J Lipid Res,2004,45(11):2025-2037.
    [41]Okuno A,Tamemoto H,Tobe K,et al.Troglitazone increases the number of small adipocyte without the change of white adipose tissue mass in obese Zucker rats[J].J Clin Invest,1998,101(6):1354-1361.
    [42]Barroso I,Gurnell M,Crowley VE,et al.Dominant negative mutations in huaman PPARgamma associated with severe insulin resistance,diabetes mellitus and hypertention[J].Nature,1999,402(6764):880-883.