HBV相关肝细胞癌肿瘤组织中热休克蛋白mRNA表达水平与肿瘤分期的相关性分析
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摘要
目的分析肝细胞癌(HCC)肿瘤组织中热休克蛋白(HSP)mRNA表达水平与HCC肿瘤分期的相关性。方法从NCBI网站的基因表达数据库(GEO)下载GSE14520数据集。从GSE14520基因数据库中获取HSP基因25种,通过与数据库下载的临床资料比对,纳入具有HSP基因mRNA表达水平和有对应临床资料的220例HCC患者。提取220例患者癌组织HSP基因的mRNA表达水平及对应的TNM分期及BCLC分期并进行相关性分析。采用Kruskal-Wallis H非参数检验进行多组间比较,采用单因素及多因素logistic回归分析HSP与HCC肿瘤分期的相关性。结果 HSPA12A、HSPA5、HSP90AA1与HSPA13 mRNA随着TNM分期增高,表达逐渐升高(P值均<0.05);HSP90AA1 mRNA随着BCLC分期增高,表达逐渐升高(P<0.05)。HSPA4L(OR=1.019,P=0.005)、HSPA12A(OR=1.077,P=0.026)与HSP90AA1(OR=1.001,P=0.002)是影响TNM分期的危险因素;HSPA9 mRNA升高与HCC患者TNM分期呈负相关(OR=0.995,P=0.011)。HSPH1(OR=1.005,P=0.041)、HSPA1B(OR=1.002,P=0.048)与HSPA5(OR=1.000,P=0.001)是影响BCLC分期的危险因素;HSPA9 mRNA升高与肝癌BCLC分期呈负相关(OR=0.995,P=0.005)。结论 HSP与HCC患者肿瘤临床分期存在一定相关性。
Objective To investigate the correlation between mRNA expression of heat shock protein(HSP) and tumor stage in patients with HBV-related hepatocellular carcinoma(HCC).Methods The GSE14520 data set was downloaded from gene expression omnibus in the website of the National Center of Biotechnology Information.A total of 25 HSP genes were obtained from the GSE14520 data,and after the comparison with the clinical data downloaded from the database,220 HCC patients with mRNA expression of HSP and corresponding clinical data were enrolled.The mRNA expression of HSP in tumor tissues was measured,the TNM stage and Barcelona Clinic Liver Cancer(BCLC) stage were determined for each patient,and a correlation analysis was performed.The Kruskal-Wallis H non-parametric test was used for comparison between multiple groups,and univariate and multivariate logistic regression analyses were used to investigate the correlation between HSP and HCC tumor stage.Results With the increase in TNM stage,the expression of HSPA12 A,HSPA5,HSP90AA1,and HSPA13 gradually increased(all P<0.05),while the expression of HSP90AA1 gradually increased with the increase in BCLC stage(P<0.05).HSPA4L(OR=1.019,P=0.005),HSPA12A(OR=1.077,P=0.026),and HSP90AA1(OR=1.001,P=0.002) were risk factors for TNM stage.HSPA9 was negatively correlated with TNM stage(OR=0.995,P=0.011).HSPH1(OR=1.005,P=0.041),HSPA1B(OR=1.002,P=0.048),and HSPA5(OR=1.000,P=0.001) were risk factors for BCLC stage,and HSPA9 was negatively correlated with BCLC stage(OR=0.995,P=0.005).Conclusion There is a certain correlation between HSPs and tumor stage in HCC patients.
Objective To investigate the correlation between mRNA expression of heat shock protein(HSP) and tumor stage in patients with HBV-related hepatocellular carcinoma(HCC).Methods The GSE14520 data set was downloaded from gene expression omnibus in the website of the National Center of Biotechnology Information.A total of 25 HSP genes were obtained from the GSE14520 data,and after the comparison with the clinical data downloaded from the database,220 HCC patients with mRNA expression of HSP and corresponding clinical data were enrolled.The mRNA expression of HSP in tumor tissues was measured,the TNM stage and Barcelona Clinic Liver Cancer(BCLC) stage were determined for each patient,and a correlation analysis was performed.The Kruskal-Wallis H non-parametric test was used for comparison between multiple groups,and univariate and multivariate logistic regression analyses were used to investigate the correlation between HSP and HCC tumor stage.Results With the increase in TNM stage,the expression of HSPA12 A,HSPA5,HSP90AA1,and HSPA13 gradually increased(all P<0.05),while the expression of HSP90AA1 gradually increased with the increase in BCLC stage(P<0.05).HSPA4L(OR=1.019,P=0.005),HSPA12A(OR=1.077,P=0.026),and HSP90AA1(OR=1.001,P=0.002) were risk factors for TNM stage.HSPA9 was negatively correlated with TNM stage(OR=0.995,P=0.011).HSPH1(OR=1.005,P=0.041),HSPA1B(OR=1.002,P=0.048),and HSPA5(OR=1.000,P=0.001) were risk factors for BCLC stage,and HSPA9 was negatively correlated with BCLC stage(OR=0.995,P=0.005).Conclusion There is a certain correlation between HSPs and tumor stage in HCC patients.
引文
[1]WU SH,CHENG J,ZHENG YJ.Relationship between heat shock protein family and hepatocellular carcinoma[J].World Chin JDig,2005,13(14):1725-1730.(in Chinese)吴顺华,成军,郑玉建.热休克蛋白家族与肝癌的关系[J].世界华人消化杂志,2005,13(14):1725-1730.
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[3]YANG Z,ZHUANG L,SZATMARY P,et al.Upregulation of heat shock proteins(HSPA12A,HSP90B1,HSPA4,HSPA5 and HSPA6)in tumour tissues is associated with poor outcomes from HBV-related early-stage hepatocellular carcinoma[J].Int JMed Sci,2015,12(3):256-263.
[4]YANG Z,YE P,XU Q,et al.Elevation of serum GGT and LDHlevels,together with higher BCLC staging are associated with poor overall survival from hepatocellular carcinoma:a retrospective analysis[J].Discov Med,2015,19(107):409-418.
[5]ROESSLER S,JIA HL,BUDHU A,et al.A unique metastasis gene signature enables prediction of tumor relapse in early-stage hepatocellular carcinoma patients[J].Cancer Res,2010,70(24):10202-10212.
[6]International Union Against Cancer(UICC).TNM classification of malignant tumours[S].6th ed.Hoboken,NJ:John Wiley&Sons,2002.
[7]LLOVET JM,BRU C,BRUIX J.Prognosis of hepatocellular carcinoma:the BCLC staging classification[J].Semin Liver Dis,1999,9:329-338.
[8]YAO DF,DONG ZZ,YAO M.Specific molecular markers in hepatocellular carcinoma[J].Hepatobiliary Pancreat Dis Int,2007,6(3):241-247.
[9]LIM SO,PARK SG,YOO JH,et al.Expression of heat shock proteins(HSP27,HSP60,HSP70,HSP90,GRP78,GRP94)in hepatitis B virus-related hepatocellular carcinomas and dysplastic nodules[J].World J Gastroenterol,2005,11(14):2072-2079.
[10]CUI N,XU YP,CAO ZH,et al.Effects of heat stress on the level of heat shock protein 70 on the surface of hepatocellular carcinoma Hep G2 cells:implications for the treatment of tumors[J].Tumor Biol,2013,34(2):743-748.
[11]LUO SM,GAO J.Research advances in heat shock protein 70 and hepatocellular carcinoma[J].Chongqing Med,2008,37(2):188-190.(in Chinese)罗善明,高建.热休克蛋白70与肝细胞肝癌的研究进展[J].重庆医学,2008,37(2):188-190.
[12]JIANG YG,WANG YM,LI QF.Expression significance of heat shock protein 27,70,90αin hepatocellular carcinoma[J].World Chin J Dig,2001,9(7):755-758.(in Chinese)蒋业贵,王宇明,李奇芬.肝细胞癌热休克蛋白27,70,90α的表达意义[J].世界华人消化杂志,2001,9(7):755-758.
[13]LI RK.Expressions of HSP90α,HSP70,HSP60 incolon cancer tissue and the relationship between the expressions of HSP90α,HSP70,HSP60 and the extent of tissue differentiation[J].J Clin Exp Med,2015,14(9):721-723.(in Chinese)李如凯.结肠癌组织中的HSP90α、HSP70、HSP60表达及其与组织分化程度的关系[J].临床和实验医学杂志,2015,14(9):721-723.
[14]HU PZ,YANG SJ,MA FC,et al.Expression of heat shock protein70 mRNA in human primary hepatocarcinoma[J].Chin J Diagn Pathol,2001,8(4):220-221.(in Chinese)胡沛臻,杨守京,马福成,等.人原发性肝细胞癌中热休克蛋白70mRNA的表达[J].诊断病理学杂志,2001,8(4):220-221.
[15]YIN YM,QIN QL,ZHAGN W,et al.Overexpression of heat shock protein 70 and spontaneous cancer cell apoptosis in hepatocellular carcinoma[J].Chin J Hepatol,2001,9(2):84-85.(in Chinese)尹燕明,秦庆亮,张伟,等.肝细胞癌热休克蛋白70过表达与自发性癌细胞凋亡[J].中华肝脏病杂志,2001,9(2):84-85.
[16]WANG X,SONG X,ZHUO W,et al.The regulatory mechanism of HSP90alpha secretion and its function in tumor malignancy[J].Proc Natl Acad Sci U S A,2009,106(50):21288-21293.
[17]LI H,LI WH,ZHANG ZX,et al.Expression of heat shock protein90αin HBV-related hepatocellular carcinoma[J].Acad J Guangzhou Med Col,2014,42(6):21-24.(in Chinese)李慧,李卫华,张志翔,等.热休克蛋白90α在HBV相关性肝细胞癌中表达的意义[J].广州医科大学学报,2014,42(6):21-24.
[18]SU XQ,YAO DF.Relationship between abnormal expression of heat shock protein 90 and malignant transformation of hepatocytes[J].Chin J Hepatol,2006,14(4):314-317.(in Chinese)苏小琴,姚登福.热休克蛋白90家族异常表达与肝细胞癌变关系的研究进展[J].中华肝脏病杂志,2006,14(4):314-317.
[19]JOLLY C,MORIMOTO RI.Role of the heat shock response and molecular chaperones in oncogenesis and cell death[J].J Natl Cancer Inst,2000,92(19):1564-1572.
[20]KONG QQ,ZOU ZQ.Research advances in the association between heat shock protein 90αand primary liver cancer[J].J Binzhou Med Univ,2016,39(4):289-290.(in Chinese)孔巧巧,邹志强.热休克蛋白90α与原发性肝癌关系的研究进展[J].滨州医学院学报,2016,39(4):289-290.
[21]CHEN Y,DING J.Heat shock protein 90:novel target for cancer therapy[J].Chin J Cancer,2004,23(8):968-974.(in Chinese)陈奕,丁健.热休克蛋白90-癌症治疗的新靶点[J].癌症,2004,23(8):968-974.
[22]SUN SP,WU SL,GENG ZM,et al.Expression of heat shock protein90αin hepatocellular carcinoma and its significance[J].Chin J Bases Clin Gen Surg,2003,10(3):243-245.(in Chinese)孙水平,吴胜利,耿智敏,等.肝细胞肝癌中Hsp90α的表达及意义[J].中国普外基础与临床杂志,2003,10(3):243-245.
[23]LUO HM,SUN W,YIN JY,et al.Progress in the study of heat shock protein 90 inhibitors[J].Acta Pharm Sin,2010,45(7):813-820.(in Chinese)罗浩铭,孙薇,尹建元,等.热休克蛋白90抑制剂的研究进展[J].药学学报,2010,45(7):813-820.
[24]WADHWA R,TAKANO S,KAUR K,et al.Upregulation of mortalin/mthsp70/Grp75 contributes to human carcinogenesis[J].Int J Cancer,2006,118(120):2973-2980.
[25]PENG C,YANG P,CUI Y,et al.HSPA9 overexpression inhibits apoptin-induced apoptosis in the Hep G2 cell line[J].Oncol Rep,2013,29(6):2431-2437.
[26]YI X,LUK JM,LEE NP,et al.Association of mortalin(HSPA9)with liver cancer metastasis and prediction for early tumor recurrence[J].Mol Cell Proteomics,2008,7(2):315-325.
[27]LUO X.Heat shock proteins with transmembrane protein CD151 Mortalin and mechanism of interaction in hepatocellular carcinoma[D].Kunming:Kunming Med Univ,2015.(in Chinese)罗旭.热休克蛋白Mortalin与四跨膜蛋白CD151在肝癌中的相互作用及机制研究[D].昆明:昆明医科大学,2015.
[2]GAO JL,YANG ZG,CHEN XR,et al.Analysis of association between HSP70 expression in tumor tissues and clinicopathological characteristics of HBV-related hepatocellular carcinoma[J].JClin Hepatol,2015,31(5):733-736.(in Chinese)高加林,杨宗国,陈晓蓉,等.热休克蛋白70的表达与HBV相关肝细胞癌临床病理学特征的相关性分析[J].临床肝胆病杂志,2015,31(5):733-736.
[3]YANG Z,ZHUANG L,SZATMARY P,et al.Upregulation of heat shock proteins(HSPA12A,HSP90B1,HSPA4,HSPA5 and HSPA6)in tumour tissues is associated with poor outcomes from HBV-related early-stage hepatocellular carcinoma[J].Int JMed Sci,2015,12(3):256-263.
[4]YANG Z,YE P,XU Q,et al.Elevation of serum GGT and LDHlevels,together with higher BCLC staging are associated with poor overall survival from hepatocellular carcinoma:a retrospective analysis[J].Discov Med,2015,19(107):409-418.
[5]ROESSLER S,JIA HL,BUDHU A,et al.A unique metastasis gene signature enables prediction of tumor relapse in early-stage hepatocellular carcinoma patients[J].Cancer Res,2010,70(24):10202-10212.
[6]International Union Against Cancer(UICC).TNM classification of malignant tumours[S].6th ed.Hoboken,NJ:John Wiley&Sons,2002.
[7]LLOVET JM,BRU C,BRUIX J.Prognosis of hepatocellular carcinoma:the BCLC staging classification[J].Semin Liver Dis,1999,9:329-338.
[8]YAO DF,DONG ZZ,YAO M.Specific molecular markers in hepatocellular carcinoma[J].Hepatobiliary Pancreat Dis Int,2007,6(3):241-247.
[9]LIM SO,PARK SG,YOO JH,et al.Expression of heat shock proteins(HSP27,HSP60,HSP70,HSP90,GRP78,GRP94)in hepatitis B virus-related hepatocellular carcinomas and dysplastic nodules[J].World J Gastroenterol,2005,11(14):2072-2079.
[10]CUI N,XU YP,CAO ZH,et al.Effects of heat stress on the level of heat shock protein 70 on the surface of hepatocellular carcinoma Hep G2 cells:implications for the treatment of tumors[J].Tumor Biol,2013,34(2):743-748.
[11]LUO SM,GAO J.Research advances in heat shock protein 70 and hepatocellular carcinoma[J].Chongqing Med,2008,37(2):188-190.(in Chinese)罗善明,高建.热休克蛋白70与肝细胞肝癌的研究进展[J].重庆医学,2008,37(2):188-190.
[12]JIANG YG,WANG YM,LI QF.Expression significance of heat shock protein 27,70,90αin hepatocellular carcinoma[J].World Chin J Dig,2001,9(7):755-758.(in Chinese)蒋业贵,王宇明,李奇芬.肝细胞癌热休克蛋白27,70,90α的表达意义[J].世界华人消化杂志,2001,9(7):755-758.
[13]LI RK.Expressions of HSP90α,HSP70,HSP60 incolon cancer tissue and the relationship between the expressions of HSP90α,HSP70,HSP60 and the extent of tissue differentiation[J].J Clin Exp Med,2015,14(9):721-723.(in Chinese)李如凯.结肠癌组织中的HSP90α、HSP70、HSP60表达及其与组织分化程度的关系[J].临床和实验医学杂志,2015,14(9):721-723.
[14]HU PZ,YANG SJ,MA FC,et al.Expression of heat shock protein70 mRNA in human primary hepatocarcinoma[J].Chin J Diagn Pathol,2001,8(4):220-221.(in Chinese)胡沛臻,杨守京,马福成,等.人原发性肝细胞癌中热休克蛋白70mRNA的表达[J].诊断病理学杂志,2001,8(4):220-221.
[15]YIN YM,QIN QL,ZHAGN W,et al.Overexpression of heat shock protein 70 and spontaneous cancer cell apoptosis in hepatocellular carcinoma[J].Chin J Hepatol,2001,9(2):84-85.(in Chinese)尹燕明,秦庆亮,张伟,等.肝细胞癌热休克蛋白70过表达与自发性癌细胞凋亡[J].中华肝脏病杂志,2001,9(2):84-85.
[16]WANG X,SONG X,ZHUO W,et al.The regulatory mechanism of HSP90alpha secretion and its function in tumor malignancy[J].Proc Natl Acad Sci U S A,2009,106(50):21288-21293.
[17]LI H,LI WH,ZHANG ZX,et al.Expression of heat shock protein90αin HBV-related hepatocellular carcinoma[J].Acad J Guangzhou Med Col,2014,42(6):21-24.(in Chinese)李慧,李卫华,张志翔,等.热休克蛋白90α在HBV相关性肝细胞癌中表达的意义[J].广州医科大学学报,2014,42(6):21-24.
[18]SU XQ,YAO DF.Relationship between abnormal expression of heat shock protein 90 and malignant transformation of hepatocytes[J].Chin J Hepatol,2006,14(4):314-317.(in Chinese)苏小琴,姚登福.热休克蛋白90家族异常表达与肝细胞癌变关系的研究进展[J].中华肝脏病杂志,2006,14(4):314-317.
[19]JOLLY C,MORIMOTO RI.Role of the heat shock response and molecular chaperones in oncogenesis and cell death[J].J Natl Cancer Inst,2000,92(19):1564-1572.
[20]KONG QQ,ZOU ZQ.Research advances in the association between heat shock protein 90αand primary liver cancer[J].J Binzhou Med Univ,2016,39(4):289-290.(in Chinese)孔巧巧,邹志强.热休克蛋白90α与原发性肝癌关系的研究进展[J].滨州医学院学报,2016,39(4):289-290.
[21]CHEN Y,DING J.Heat shock protein 90:novel target for cancer therapy[J].Chin J Cancer,2004,23(8):968-974.(in Chinese)陈奕,丁健.热休克蛋白90-癌症治疗的新靶点[J].癌症,2004,23(8):968-974.
[22]SUN SP,WU SL,GENG ZM,et al.Expression of heat shock protein90αin hepatocellular carcinoma and its significance[J].Chin J Bases Clin Gen Surg,2003,10(3):243-245.(in Chinese)孙水平,吴胜利,耿智敏,等.肝细胞肝癌中Hsp90α的表达及意义[J].中国普外基础与临床杂志,2003,10(3):243-245.
[23]LUO HM,SUN W,YIN JY,et al.Progress in the study of heat shock protein 90 inhibitors[J].Acta Pharm Sin,2010,45(7):813-820.(in Chinese)罗浩铭,孙薇,尹建元,等.热休克蛋白90抑制剂的研究进展[J].药学学报,2010,45(7):813-820.
[24]WADHWA R,TAKANO S,KAUR K,et al.Upregulation of mortalin/mthsp70/Grp75 contributes to human carcinogenesis[J].Int J Cancer,2006,118(120):2973-2980.
[25]PENG C,YANG P,CUI Y,et al.HSPA9 overexpression inhibits apoptin-induced apoptosis in the Hep G2 cell line[J].Oncol Rep,2013,29(6):2431-2437.
[26]YI X,LUK JM,LEE NP,et al.Association of mortalin(HSPA9)with liver cancer metastasis and prediction for early tumor recurrence[J].Mol Cell Proteomics,2008,7(2):315-325.
[27]LUO X.Heat shock proteins with transmembrane protein CD151 Mortalin and mechanism of interaction in hepatocellular carcinoma[D].Kunming:Kunming Med Univ,2015.(in Chinese)罗旭.热休克蛋白Mortalin与四跨膜蛋白CD151在肝癌中的相互作用及机制研究[D].昆明:昆明医科大学,2015.