S100A4、Survivin及COX-2在胰腺癌中的表达及意义的研究
|
摘要
目的：通过检测钙离子结合蛋白S100A4、生存素(Survivin)及环氧化酶2(COX-2)在胰腺癌中的表达情况,探讨三者在胰腺癌中的表达与临床病理因素及预后的关系,进一步阐明S100A4在胰腺癌组织中的作用机制,为进一步应用干预S100A4活性的方法治疗胰腺癌提供实验依据。
方法：①采用免疫组化二步法(PV法)检测63例手术切除的原发性胰腺导管腺癌组织及11例癌旁正常胰腺组织中S100A4、Survivin及COX-2的表达情况。②应用x2检验的统计学方法分析胰腺癌组织S100A4、Survivin及COX-2蛋白表达与临床病理因素的关系及对患者预后的影响;用Kaplan-Meier法分析生存曲线；多变量Cox北例风险回归模型筛选影响患者生存的独立预后因素。
结果：①63例标本中S100A4和(?) Survivin及COX-2阳性率分别为74.6%(47/63),69.8%(44/63),73%(46/63)。②S100A4、Survivin蛋白过表达存在显著相关性(r=0.570,P=0.000);S100A4与COX-2蛋白过表达存在显著相关性(r=0.385,P=0.002)；Survivin与COX-2蛋白过表达也存在显著相关性(r=0.613,P=0.000)。③S100A4表达与肿瘤的TNM分期(P=0.002)、淋巴结转移(P=0.002)及远处转移(P=0.007)显著相关;Survivin表达与肿瘤的TNM分期(P=0.034)、淋巴结转移(P=0.020)及分化程度(P=0.000)显著相关；COX-2的表达与肿瘤大小(P=0.013)、分化程度(P=0.001)、TNM分期(P=0.021)、远处转移(P=0.031)及淋巴结转移(P=0.022)显著相关。④S100A4阴性/Survivin阴性组患者(11例)中位生存时间(大于36个月)明显大于S100A4阳性/SurvivinP日性组患者(37例)中位生存时间(9个月)(Log-rank检验,x2=17.754,P=0.000)；S100A4阴性/COX-2阴性组患者(8例)中位生存时间(大于36个月)明显大于S100A4阳性/COX-2阳性组患者(37例)中位生存时间(9个月)(Log-rank检验,x2=44.969, P=0.000); Survivin阴性/COX-2阴性组患者(9例)中位生存时间(大于36个月)也明显大于Survivin阳性/COX-2阳性组患者(38例)中位生存时间(9个月)(Log-rank检验,x2=34.128,P=0.000)。⑤分化程度(P=0.002)、TNM分期(P=0.002)、S100A4过表达(P=0.001)、Survivin过表达(P=0.024)及COX-2过表达P=0.002)是影响胰腺癌预后的独立因素。
结论：S100A4、Survivin和COX-2的高表达与胰腺癌的临床病理参数密切相关,在胰腺癌的生长浸润过程中,三者可能协同抑制肿瘤细胞凋亡、促进肿瘤细胞增殖及血管生成的作用,其高表达提示患者预后不良,联合检测S100A4与Survivin和COX-2表达可预测胰腺癌发生转移的危险性及患者预后情况。胰腺癌组织细胞的抗凋亡、促进增殖及血管生成的作用与S100A4的表达有关,S100A4可能成为胰腺癌基因治疗的新靶点,这为进一步应用干预S100A4活性的方法治疗胰腺癌提供实验依据。
Objective:To detect the expression of calcium-binding protein S100A4, Survivin and COX-2 in pancreatic carcinoma (PC) and their correlation with clinicopathological parameters and prognosis of pancreatic carcinoma patients, investigate the mechanism of action of protein S100A4 in PC, to provide academic and experimental evidence of the treatment of PC by the intervention of S100A4.
Methods:①he expressions of S100A4, Survivin and COX-2 were examined in 63 surgical specimens of primary pancreatic carcinoma and 11 surgical specimens of non-pancreatic carcinoma with immunohistochemistry PV method.②The relationship between S100A4, Survivin, COX-2, clinicopathological parameters and prognosis of PC was analyzed by X2 test in 63 cases of PC. Kaplan-Meier and multivariate Cox proportional hazards regression model analysis were applied to compare the survival curves and screen the independent prognosis factors respectively.
Results:①Forty-seven of 63(74.6%)specimens of PC were positive for S100A4, Forty-four of 63(69.8%)pancreatic carcinoma specimens showed positive expressions of Survivin and Forty-six of 63(73.0%)specimens of PC were positive for COX-2 according to immunohistochemistry detection.②he positive expressions of S100A4 and Survivin were significantly correlated with PC (r= 0.570, P=0.000), The correlation was significant between S100A4 and COX-2 in PC (r=0.385, P=0.002), The positive expressions of Survivin and COX-2 were also significantly correlated with PC (r=0.613, P=0.000).③he expressions of S100A4 significantly correlated with TNM stages (P=0.002), lymph node metastasis (P=0.002)and distant metastasis (P=0.007); The expression of Survivin had a significant correlation with TNM stages(P=0.034), lymph node metastasis (P=0.020)and differentiation(P=0.000); The expressions of COX-2 significantly correlated with turner size (P=0.013), differentiation (P=0.001), TNM stages (P=0.021), lymph node metastasis (P=0.022) and distant metastasis (P=0.031).④he median survival time(>36 months) of 11 patients with S100A4(-)/Survivin (-) was significantly longer than that of the 37 patients with S100A4(+)/Survivin(+) (9 months, x 2=17.754, P=0.000); The median survival time(>36 months) of 8 patients with S100A4(-)/COX-2 (-) was significantly longer than that of the 37 patients with S100A4(+)/COX-2(+) (9 months, x 2=44.969, P=0.000); The median survival time(>36 months) of 9 patients with Survivin (-)/COX-2 (-) was significantly longer than that of the 38 patients with S100A4(+)/COX-2(+)(9 months, x 2=34.128, P=0.000).⑤The differentiation(P=0.002), TNM stages (P=0.002), S100A4(+)Expression (P=0.001), Survivin (+) expression(P=0.024) and COX-2(+) Expression (P=0.002) were the independent prognostic factors for pancreatic cancer.
Conclusion:This study indicated that the expression of S100A4, Survivin and COX-2 proteins were related with clinicopathological parameters of pancreatic cancer patients, S100A4 combined with Survivin and COX-2 could cooperatively inhibit the cells into apoptosis, promote the proliferation and angiogensis in the process of growth and invasion in pancreatic cancer, over-expressions of S100A4, Survivin and COX-2 proteins maybe predict the poor prognostic of pancreatic cancer patients, They may be the potential indicators of metastasis and prognosis in pancreatic cancer. S100A4 expression in PC tissiue is related with the inhibition of cells apoptosis, promotion of the proliferation and angiogensis, S100A4 may be a new target for the treatment of PC, to provide academic and experimental evidence of the treatment of PC by the intervention of S100A4.
方法：①采用免疫组化二步法(PV法)检测63例手术切除的原发性胰腺导管腺癌组织及11例癌旁正常胰腺组织中S100A4、Survivin及COX-2的表达情况。②应用x2检验的统计学方法分析胰腺癌组织S100A4、Survivin及COX-2蛋白表达与临床病理因素的关系及对患者预后的影响;用Kaplan-Meier法分析生存曲线；多变量Cox北例风险回归模型筛选影响患者生存的独立预后因素。
结果：①63例标本中S100A4和(?) Survivin及COX-2阳性率分别为74.6%(47/63),69.8%(44/63),73%(46/63)。②S100A4、Survivin蛋白过表达存在显著相关性(r=0.570,P=0.000);S100A4与COX-2蛋白过表达存在显著相关性(r=0.385,P=0.002)；Survivin与COX-2蛋白过表达也存在显著相关性(r=0.613,P=0.000)。③S100A4表达与肿瘤的TNM分期(P=0.002)、淋巴结转移(P=0.002)及远处转移(P=0.007)显著相关;Survivin表达与肿瘤的TNM分期(P=0.034)、淋巴结转移(P=0.020)及分化程度(P=0.000)显著相关；COX-2的表达与肿瘤大小(P=0.013)、分化程度(P=0.001)、TNM分期(P=0.021)、远处转移(P=0.031)及淋巴结转移(P=0.022)显著相关。④S100A4阴性/Survivin阴性组患者(11例)中位生存时间(大于36个月)明显大于S100A4阳性/SurvivinP日性组患者(37例)中位生存时间(9个月)(Log-rank检验,x2=17.754,P=0.000)；S100A4阴性/COX-2阴性组患者(8例)中位生存时间(大于36个月)明显大于S100A4阳性/COX-2阳性组患者(37例)中位生存时间(9个月)(Log-rank检验,x2=44.969, P=0.000); Survivin阴性/COX-2阴性组患者(9例)中位生存时间(大于36个月)也明显大于Survivin阳性/COX-2阳性组患者(38例)中位生存时间(9个月)(Log-rank检验,x2=34.128,P=0.000)。⑤分化程度(P=0.002)、TNM分期(P=0.002)、S100A4过表达(P=0.001)、Survivin过表达(P=0.024)及COX-2过表达P=0.002)是影响胰腺癌预后的独立因素。
结论：S100A4、Survivin和COX-2的高表达与胰腺癌的临床病理参数密切相关,在胰腺癌的生长浸润过程中,三者可能协同抑制肿瘤细胞凋亡、促进肿瘤细胞增殖及血管生成的作用,其高表达提示患者预后不良,联合检测S100A4与Survivin和COX-2表达可预测胰腺癌发生转移的危险性及患者预后情况。胰腺癌组织细胞的抗凋亡、促进增殖及血管生成的作用与S100A4的表达有关,S100A4可能成为胰腺癌基因治疗的新靶点,这为进一步应用干预S100A4活性的方法治疗胰腺癌提供实验依据。
Objective:To detect the expression of calcium-binding protein S100A4, Survivin and COX-2 in pancreatic carcinoma (PC) and their correlation with clinicopathological parameters and prognosis of pancreatic carcinoma patients, investigate the mechanism of action of protein S100A4 in PC, to provide academic and experimental evidence of the treatment of PC by the intervention of S100A4.
Methods:①he expressions of S100A4, Survivin and COX-2 were examined in 63 surgical specimens of primary pancreatic carcinoma and 11 surgical specimens of non-pancreatic carcinoma with immunohistochemistry PV method.②The relationship between S100A4, Survivin, COX-2, clinicopathological parameters and prognosis of PC was analyzed by X2 test in 63 cases of PC. Kaplan-Meier and multivariate Cox proportional hazards regression model analysis were applied to compare the survival curves and screen the independent prognosis factors respectively.
Results:①Forty-seven of 63(74.6%)specimens of PC were positive for S100A4, Forty-four of 63(69.8%)pancreatic carcinoma specimens showed positive expressions of Survivin and Forty-six of 63(73.0%)specimens of PC were positive for COX-2 according to immunohistochemistry detection.②he positive expressions of S100A4 and Survivin were significantly correlated with PC (r= 0.570, P=0.000), The correlation was significant between S100A4 and COX-2 in PC (r=0.385, P=0.002), The positive expressions of Survivin and COX-2 were also significantly correlated with PC (r=0.613, P=0.000).③he expressions of S100A4 significantly correlated with TNM stages (P=0.002), lymph node metastasis (P=0.002)and distant metastasis (P=0.007); The expression of Survivin had a significant correlation with TNM stages(P=0.034), lymph node metastasis (P=0.020)and differentiation(P=0.000); The expressions of COX-2 significantly correlated with turner size (P=0.013), differentiation (P=0.001), TNM stages (P=0.021), lymph node metastasis (P=0.022) and distant metastasis (P=0.031).④he median survival time(>36 months) of 11 patients with S100A4(-)/Survivin (-) was significantly longer than that of the 37 patients with S100A4(+)/Survivin(+) (9 months, x 2=17.754, P=0.000); The median survival time(>36 months) of 8 patients with S100A4(-)/COX-2 (-) was significantly longer than that of the 37 patients with S100A4(+)/COX-2(+) (9 months, x 2=44.969, P=0.000); The median survival time(>36 months) of 9 patients with Survivin (-)/COX-2 (-) was significantly longer than that of the 38 patients with S100A4(+)/COX-2(+)(9 months, x 2=34.128, P=0.000).⑤The differentiation(P=0.002), TNM stages (P=0.002), S100A4(+)Expression (P=0.001), Survivin (+) expression(P=0.024) and COX-2(+) Expression (P=0.002) were the independent prognostic factors for pancreatic cancer.
Conclusion:This study indicated that the expression of S100A4, Survivin and COX-2 proteins were related with clinicopathological parameters of pancreatic cancer patients, S100A4 combined with Survivin and COX-2 could cooperatively inhibit the cells into apoptosis, promote the proliferation and angiogensis in the process of growth and invasion in pancreatic cancer, over-expressions of S100A4, Survivin and COX-2 proteins maybe predict the poor prognostic of pancreatic cancer patients, They may be the potential indicators of metastasis and prognosis in pancreatic cancer. S100A4 expression in PC tissiue is related with the inhibition of cells apoptosis, promotion of the proliferation and angiogensis, S100A4 may be a new target for the treatment of PC, to provide academic and experimental evidence of the treatment of PC by the intervention of S100A4.
引文
[1]Jemal A, Siegel R, Ward E, et al.Cancer statistics 2006. CACancer J Clin,2006,56:106-130.
[2]Lowenfels AB, Sullivan T, Fioranti J. The epidemiology and important of pancreat disease in the United States[J]. Curr Castroenterol Rep,2005,7(2):90-95.
[3]沈魁.我国胰腺癌诊断治疗的进展[J].外科理论与实践,1998,2：67-69.
[4]Spinelli GP, Zullo A, Romiti A, et al. Long-term survival in metastatic pancreatic cancer.A case report and review of the literature[J]. JOP,2006,7(5):486-491.
[5]Garrett SC, Varney KM, Weber DJ, et al. S100A4, a mediator of metastasis[J]. J Biol Chem,2006, 281(2):677-680.
[6]Donato R. S100:a multigenic family of calcium-modulated proteins of the EF-hand type with intracellular and extracellnlar funetional roles[J]. Int J Bioehem Cell Biol,2001,33:637-668.
[7]Sehafer BW, Wicki R, Engelkamp D, et al. Isolation of a YAC clone covering a cluster of nine S100 genes on human chromosome lq21:rationale for a new nomenclature of the S100 calcium-binding protein family[J]. Genomics,1995,25(3):638-643.
[8]Oida Y, Yamazaki H, Tobita K, et al. Increased S100A4 expression combined with decreased E-cadherin expression predicts a poor outcome of patients with pancreatic cancer[J]. Oncol Rep, 2006,16(3):457-463.
[9]Rosty C, Ueki T, Argani P, et al. Overexpression of S100A4 in pancreatic ductal adenocarcinomas is associated with poor differentiation and DNA hypomethylation[J]. Am J Pathol,2002,160(1): 45-50.
[10]Ai KX, Lu LY. Huang XY, et al. Prognostic significance of S100A4 and vascular endothelial growth factor expression in pancreatic cancer[J]. World J Gastroenterol 2008,14(12):1931-1935.
[11]李春生,倪灿荣.S100A4和E-Cadherin在胰腺癌组织中的表达及相关性研究[J].临床肝胆病杂志,2006,22：207-208.
[12]Mazzucchelli L. Protein S100A4:too long overlooked by pathologists?[J]. Am JPathol,2002, 160(1):7-13.
[13]Shin S, Sung BJ, Cho YS, et al. An anti-apoptotic protein human surviving is a direct inhibitor of caspase-3 and 7[J]. Biochem,2001,40(4):1117-1123.
[14]唐忠辉,池正忠,蔡庆发,等DPC4、survivin基因在胃癌中的表达及其与微血管形成和预后的关系[J].中国临床实用医学,2007,1(10)：18-21.
[15]Delvaeye M, De Vriese A, Zwerts F, et al. Role of the 2 zebrafish survivin genes in vasculo-angiogenesis, neurogenesis, cardiogenesis and hematopoiesis [J]. BMC Dev Biol,2009,9:25.
[16]Xu JH, Wang AX, Huang HZ, et al. Survivin shRNA induces caspase-3-dependent apoptosis and enhances cisplatin sensitivity in squarnous cell carcinoma of the tongue [J]. Oncol Res,2010,18(8): 377-385.
[17]Brenes O, Arce F, Gatjens-Boniche O, et al. Characterization of cell death events induced by anti-neoplastic drugs cisplatin, paclitaxel and 5-fluorouracil on human hepatoma cell lines:Possible mechanisms of cell resistance [J]. Biomed Pharmacother,2007,61(6):347-355.
[18]Pratt MA, Niu MY, Renart LI. Regulation of survivin by retinoic acid and its role in paclitaxel-mediated cytotoxicity in MCF-7 breast cancer cells [J]. Apoptosis,2006,11 (4):589-605.
[19]Caldas H, Jaynes FO, Boyer MW, et al. Survivin and Granzyme B-induced apoptosis, a novel anticancer therapy [J]. Mol Cancer Ther,2006,5(3):693-703.
[20]Satoh K, Kaneko K, Hirota M, et al. Expression of survivin is correlated with cancer cell apoptosis and is involved in the developed in the development of human pancreatic duct cell tumor[J]. Cancer, 2001,92(2) 273-278.
[21]Sarela AI, Verbeke CS, Ramsdale J, et al. Expression of survivin, a novel inhibitor of apoptesis and cell cycle regulatory protein, in pancreatic adenocarcinoma [J]. Br J Cancer,2002, 86(6):886-892.
[22]Eberhart CE, Coffey RJ, Radhika A,et al.UP-regulation of cyclooxygenase-2 gene expression in human colorectal adenomas and adenocarcinomas[J]. Gastroenterology,1994,107(4):1183-1188.
[23]刘江伟,李开宗,窦科峰.环氧化酶-2和血管内皮生长因子在胰腺癌组织中的表达及其相关性研究[J].中国普外科基础与临床杂志,2003,10(6)：539-541.
[24]文明波,姚红兵.环氧化酶-2与消化道肿瘤研究进展[J].华南国防医学杂志.2006,20(1)：33-37.
[25]Zhou HN, Ivanov VN, Gillespie J, et al. Mechanism of radiation-induced bystander effect:Role of the cyclooxygenase-2 signaling pathway[J].Proc Nat Acad Sci USA,2005,102(41):14641-14646.
[26]Pai R, Soreghan B, Szabo IL, et al. Prostaglandin E2 transactivates EGF receptor:A novel mechanism for promoting colon cancer growth and gastrointestinal hypertrophy[J]. Nat Med,2002, 8(3):289-293.
[27]Xu M, Jin YL, Fu J,et al.The abnormal expression of retinoic acid receptor-beta,53 and Ki67 protein in normal, premalignant and malignant esophageal tissues[J]. World J Gastroenterol,2002, 8(2):200-202.
[28]Pedersen KB, Andersen K, Fodstad O, et al. Sensitization of interferon-γ induced apoptosis in human osteosarcoma cells by extracellular S100A4[J]. BMC Cancer.2004,4:52.
[29]Schmidt-Hansen B, Klingelhofer J, Grum-Schwensen B, et al. Functional significance of metastasis-inducing S100A4(Mtsl) in tumor-stroma interplay[J]. J Biol Chem.2004,279(23):24498-24504.
[30]Grigorian M, Andresen S, Tulchinsky E, et al. Tumor suppressor p53 protein is a new target for the metastasis-associated Mtsl/S100A4 protein:functional consequences of their interaction[J]. J Biol Chem,2001,276(25):22699-708
[31]Tabata T, Tsukamoto N, Fooladi AA, et al. RNA interference targeting against S100A4 suppresses cell growth and motility and induces apoptosis in human pancreatic cancer cells[J]. Biochem Biophys Res Commun,2009.390 (3):475-480.
[32]Radestock Y, Willing C, Kehien A, et al. Relaxin enhances S100A4 and promotes growth of human thyroid carcinoma cell xenografts[J]. Mol Cancer Res,2010.8(4):494-506.
[33]Tang Y, Wang L, Goloubeva O, et al. The relationship of neuroendocrine carcinomas to anti-tumor therapies in TRAMP mice[J]. Prostate,2009,69(16):1763-1773.
[34]吴爱国,马雷,纪术峰,等.短发夹RNA沉默S100A4基因表达对乳腺癌MCF-7细胞生长和侵袭能力的影响[J].肿瘤,2009,29(8)：715-721.
[35]Mahon PC, Baril P, Bhakta V, et al. S100A4 Contributes to the Suppression of BNIP3 Expression, Chemoresistance, and Inhibition of Apoptosis in Pancreatic Cancer[J]. Cancer Res,2007, 67(14):6786-6795.
[36]樊洁,唐峰等.胰腺癌淋巴结转移与P53、Ki67表达及预后的关系[J].中国临床医学,2007,]4(6)：825-828.
[37]Semov A, Moreno MJ, Onichtchenko A, et al. Metastasis-associated protein S100A4 induces angiogenesis through interaction with Annexin Ⅱ and accelerated plasmin formation[J]. Biol Chem, 2005,280(21):20833-20841.
[38]Schmidt-Hansen B, Ornas D, Grigorian M, et al. Extracellular S100A4 (mtsl) stimulates invasive growth ofmouse endothelial cells andmodulates MMP-13 matrix metalloproteinase activity[J]. Oncogene,2004,23(32):5487-5495.
[39]Sobin LH, Wittekind CH. UICC TNM classification of malignant tumors. (M).5th ed, new york: Wile Liss,1997:66-69.
[40]Lu CD, Altieri DC. Tanigawa N. Expression of a novel antiapoptosis gene, survivin, correlated with tumor cell apoptosis and P53 accumulation in gastric carcinomas. Cancer Res,1998,58:1808-1812.
[41]Hida T, Yatabe Y, Achiwa H, et al. Inreased expression of cyclooxygenase-2 occurs frequently in huan lung cancers, specifically in adenocarinoma[J]. Cancer Res,1998,58(17):3761-3764.
[42]Weidner N, Semple J P, Welch WR, et al. Tumor angiogenesis and metastasis correlation in invasive breast carcinoma[J]. New Engl J Med,1991.324 (1):1-8.
[43]Sherbet GV, Lakshmi MS. S100A4(MTS1)calcium binding protein in cancer growth, invasion and metastasis[J].Anticancer Res,1998,18(4A):2415-2421.
[44]Cajone F, Sherbet GV. Statnmin is involved in S100A4 mediated regulation of cell cycle progression[J]. Clin ExpMetastasis,1999,17(10):865-871.
[45]Ryu B,Jones J, Blades NJ, et al. Relationships and differentially expressed genes among pancreatic cancers examined by large-scale serial analysis of gene expression[J]. Cancer Res,2002, 62(3):819-826.
[46]Lee WY, Su WC, Lin PW, et al. Expression of S100A4 and Met:potential predictors for metastasis and survival in earlystage breast cancer[J]. Oncology,2004,66(6):429-438.
[47]Kimura K, Endo Y, Yonemura Y, et al. Clinical significance of S100A4 and E-cadherin-related adhesion molecules in nonsmall cell lung cancer[J]. Int J Oncol,2000,16(6):1125-1131.
[48]Davies BR, O Donnell M, Durkan GC, et al. Expression of S100A4 protein is associated with metastasis and reduced survival in human bladder cancer[J]. J Pathol,2002,196(1):292-299.
[49]Mazzocca A, Carloni V. The metastatic process:methodological advances and pharmacological challenges [J]. Curr Med Chem,2009,16 (14):1704-1717.
[50]Kami K, Doi R, Koizumi M, et al. Survivin expression is a prognostic marker in pancreatic cancer patients[J]. Surgery,2004,136(2):443-448.
[51]刘江伟,李开宗,窦科峰.COX-2在胰腺癌组织中的表达及其与p53的相关性研究[J].世界华人消化杂志,2003,11(2)：229-232.
[52]Juuti A, Louhimo J, Nordling S, et al. Cyclooxygenase-2 expression correlates with poor prognosis in pancreatic cancer[J]. J Clin Pathol,2006,59(4):382-386.
[53]刘江伟,李开宗窦科峰iNOS、COX-2在胰腺癌组织中的表达及其临床意义[J].肿瘤防治杂志,2003,30(5)：361-363.
[54]Kiryushko D, Novitskaya V, Soroka V, et al. Molecular mechanisms of Ca(2+)signaling in neurons induced by the S100A4 protein[J]. Mol Cell Biol,2006,26(9):3625-3638.
[55]Ambartsumian N, Klingelhofer J, Grigorian M, et al.The metastasis-associated Mts1(S100A4) protein could act as an angiogenic factor[J]. Oncogene,2001,20(34):4685-4695.
[56]Ambartsumian N, Grigorian M, Lukanidin E. Genetically modified mouse models to study the role of metastasis-promoting S100A4(mts1) protein in metastatic mammary cancer[J]. J Dairy Res, 2005,72(S1):27-33.
[57]Wang TY, QianXP, Liu BR. Survivin:potential role in diaguosis, prognosis and targeted therapy ofgastric cancer[J]. World J Gastroenterol,2007,13(20):2784-2790.
[58]Capalbo G, Rodel C, Stauber RH, et al. The role of survivin for radiation therapy[J]. Strahlenther Onkol,2007,183(11):593-599.
[59]Akyuek N, Memis L, Ekinci O, et al. Survivin expression in pre-invasive lesions and non-small cell lung carcinoma[J]. Virchows Arch,2006,449(2):164-170.
[60]Lee MA, Park GS,Lee HJ, et al. Survivin expression and its clinical significance in pancreatic cancer [J]. BMC Cancer,2005,5(127):1-6.
[61]Sarela AI, Macadam RC, Farmery SM, et al. Expression of the antiapoptosis gene, survivin, predicts death from recurrent colorectal carcinoma[J]. Gut,2000,46(5):645-650.
[62]Li H, Niederkorn JY, Neelam S, et al. Downregnlation of survivin expression enhances sensitivity of cultured uveal melanoma cells to cisplatin treatment[J]. Exp Eye Res,2006,83(1):176-182.
[63]刘江伟,李开宗,窦科峰,等.胰腺癌组织Survivin和COX-2表达的相关性[J].第四军医大学学报,2004.,25(7)：635-636.
[1]Taylor S, Herrington S, Prime W, et al.S100A4 (p9Ka) protein in colon carcinoma and livermetastases: association with carcinoma cells and T-lymphocytes[J]. Br J Cancer,2002,86(3):409-416.
[2]Mazzucchelli L. Protein S100A4:too long overlooked by pathologists?[J]. Am J Pathol,2002,160(1): 7-13.
[3]Sherbet GV, Lakshmi MS. S100A4 (MTS1) calcium binding protein in cancer growth, invasion and metastasis[J]. Anticancer Res,1998,18(4A):2415-2421.
[4]Yao R, Davidson DD, Lopez-Beltran A, et al.The S100 proteins for screening and prognostic grading of bladder cancer [J]. Histol Histopathol,2007,22(9):1025.
[5]Gribenko AV, Hopper J E, Makhatadze GI, et al. Molecular characterization and tissue distribution of a novel member of the S100 family of EF-hand proteins[J]. Biochemistry,2001,40:1553-15548.
[6]Donato R. S100:a multigenic family of calcium-modulated proteins of the EF-hand type with intracellular and extracellular functional roles[J].Int J Biochem Cell Biol,2001,33(7):637.
[7]Tarabykina S, Scott DJ, Herzyk P, et al. The dimerization interface of the metastasis-associated protein S100A4 (Mts1):in vivo and in vitro studies[J]. J Biol Chem,2001,276(26):24212-24222.
[8]Platt-Higgins AM, Renshaw CA, West CR, et al. Comparison of the metastasis inducing protein S100A4(p9Ka) with other prognostic markers in human breast cancer[J].Int J Cancer,2000,89(2):198.
[9]Ninomiya I, Ohta T, Fushida S, et al. Increased expression of S100A4 and its prognostic significance in esophagealsquamous cell carcinoma[J].Int J Oncol,2001,18:715.
[10]Yonemura Y, Endou Y, kimura K, et al.Inverse expression of S100A4 and E-cadherin is associated with metastatic potential in gastric cancer[J]. Clin Cancer Res,2000,6(11):4234.
[11]Endo Y, Yonemura Y, Heizmann CW, et al. Clinical significance of S100A4 and E-cadherin related adhesion molecules in nonsmall cell lung cancer[J].Int J Oncol.2000,16(6):1125
[12]Ryu B,Jones J,Blades NJ,et al.Relationships and differentially expressed genes among pancreatic cancers examined by large-scale serial analysis of gene expression[J].Cancer Res,2002,62(3):819.
[13]Lloyd BH, Platt-Higgins A, Rudland PS, et al. Human S100A4 (p9Ka)induces the metastatic phenotype upon benign tumour cells[J].Oncogene,1998,17(4):465-473
[14]Gao XN,Tang SQ, Zhang XF. S100A4 antisense oligodeoxynucleotide suppresses invasive potential of neuroblastoma cells[J].J Pediatr Surg,2005,40(4):648-652.
[15]Kiryushko D, Novitskaya V. Soroka V, et al.Molecular mechanisms of Ca(2+)signaling in neurons induced by the S100A4 protein.Mol Cell Biol,2006,26(9):3625
[16]Cajone F, Sherbet GV. Stathmin is involved in S100A4 mediated regulation of cell cycle progression[J]. Clin ExpMetastasis,1999,17(10):865-871.
[17]Lee WY, Su WC, Lin PW, et al. Expression of S100A4 and Met:potential predictors for metastasis and survival in earlystage breast cancer[J]. Oncology,2004,66(6):429-438.
[18]Kimura K, Endo Y, Yonemura Y, et al. Clinical significance of S100A4 and E-cadherin-related adhesion molecules in nonsmall cell lung cancer[J]. Int J Oncol,2000,16(6):1125-1131.
[19]Davies BR, O Donnell M, Durkan GC, et al. Expression of S100A4 protein is associated with metastasis and reduced survival in human bladder cancer[J]. J Pathol,2002,196(1):292-299.
[20]Ambartsumian N, Klingelhofer J, Grigorian M, et al. The metastasis-associated Mts1(S100A4) protein could act as an angiogenic factor[J]. Oncogene.2001,20(34):4685-4695.
[21]Ambartsumian N, Grigorian M, Lukanidin E. Genetically modified mouse models to study the role of metastasis-promoting S100A4(mts1) protein in metastatic mammary cancer[J]. J Dairy Res,2005, 72(S1):27-33.
[22]Endo H, Takenaga K, Kanno T, et al. Methionine aminopeptidase 2 is a new target for the metastasis-associated protein, S100A4[J]. J Biol Chem,2002,277:26396-26402.
[23]Schmidt-Hansen B, Klingelh J, et al. Functional significance of metastasis-inducing S100A4(Mtsl) in tumor-stroma interplay. J Biol Chem,2004,279(23):24498
[24]Schmidt-Hansen B, Ornas D, Grigorian M, et al. Extracellular S100A4 (mts1) stimulates invasive growth ofmouse endothelial cells andmodulates MMP-13 matrix metallo proteinase activity[J]. Oncogene,2004,23(32):5487-5495.
[25]Bromn LF, Berse B, Jackman RW, et al. Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in adenocarcinomas of the gastrointestinal tract [J].CancerRes,1993,53(19):4727-4735.
[26]鲁林源,艾开兴,黄新余,等,S100A4、VEGF的表达与胰腺癌预后的关系[J].肿瘤,2008,28(4)：326-329.
[27]Semov A, Moreno MJ, Onichtchenko A, et al. Metastasis-associated protein S100A4 induces angiogenesis through interaction with Annexin Ⅱ and accelerated plasmin formation[J]. J Biol Chem,2005,280(21):20833-20841.
[1]Yao R, Davidson DD, Lopez-Beltran A, et al.The S100 proteins for screening and prognostic grading of bladder cancer [J].Histol Histopathol,2007,22(9):1025.
[2]Guo X, Cui Z. Current diagnosis and treat ment of pancreatic cancer in china[J]. Pancreas,2005,31: 13-22.
[3]Wang L, rang GH, Li H, et al. The changing pancreatic cancer mortality in China (1991-2000) [J]. Zhonghua Nei Ke Za Zhi,2005,44:509-513 (In Chinese).
[4]Li C, Heidt DG, Dalrba P, et al. Identification of pancreatic cancerl stem cell[J]. Cancer Res,2007, 67:1030-1037.
[5]Rodfiguez JA, Li M, Yao Q, et al. Gene overexp ression in pancreatic adenocareinoma:diagnostic and therapeuticimp lications [J]. World J Surg,2005,29:297-305.
[6]Garrett SC, Varney KM, Weber DJ, et al. S100A4, a mediator of metastasis[J]. J Biol Chem,2006, 281(2):677-680.
[7]Taylor S, Herrington S, Prime W, et al. S100A4 (p9Ka) protein in colon carcinoma and liver metastases:association with carcinoma cells and T-lymphocytes[J].Br J Cancer,2002,86(3):409-416.
[8]Mazzucchelli L. Protein S100A4:too long overlooked by pathologists?[J]. Am J Pathol,2002,160 (1):7-13.
[9]Platt-Higgins AM, Renshaw CA, West CR, et al.Comparison of the metastasis inducing protein S100A4(p9Ka) with other prognostic markers in human breast cancer [J].Int J Cancer,2000,89(2):198.
[10]Ninomiya I, Ohta T, Fushida S, et al.Increased expression of S100A4 and its prognostic significance in esophageal squamous cell carcinoma[J].Int J Oncol,2001,18:715.
[11]Yonemura Y, Endou Y, kimura K, et al.Inverse expression of S100A4 and E-cadherin is associated with metastatic potential in gastric cancer[J]. Clin Cancer Res,2000,6(11):4234.
[12]Endo Y, Yonemura Y, Heizmann CW, et al. Clinical significance of S100A4 and E-cadherin-related adhesion molecules in nonsmall cell lung cancer[J].Int J Oncol,2000,16(6):1125.
[13]Ryu B, Jones J, Blades NJ, et al. Relationships and differentially expressed genes among pancreatic cancers examined by large-scale serial analysis of gene expression[J].Cancer Res,2002,62(3):819.
[14]Gribenko AV, Hopper J E, Makhatadze GI, et al. Molecular characterization and tissue distribution of a novel member of the S100 family of EF-hand proteins[J]. Biochemistry,2001,40:1553815548.
[15]Donato R. S100:a multigenic family of calcium-modulated proteins of the EF-hand type with intracellular and extracellular functional roles[J].Int J Biochem Cell Biol,2001,33(7):637.
[16]Tarabykina S, Scott DJ, Herzyk P, et al.The dimerization interface of the metastasis-associated protein S100A4 (Mts1):in vivo and in vitro studies[J].J Biol Chem,2001,276(26):24212-24222.
[17]Jang JY, Park YC, Song YS, et al. Increased K-ras mutation and expression of S100A4 and MUC2 protein in the malignant intraductal papillary mucinous tumor of the pancreas. J Hepatobiliary Pancreat Surg.2009;16(5):668-674.
[18]Rosty C, Ueki T, Argani P, et al. Overexpression of S100A4 in pancreatic ductal adenoearcinomas is associated with poor differention and DNA hypomethylation. AM J Pathol,2002,160(1):45-50
[19]Ai KX, Lu LY, Huang XY, et al. Chen Prognostic significance of S100A4 and vascular endothelial growth factor expression in pancreatic cancer[J]. World J Gastroenterol,2008; 14: 1931-1935
[20]Naoki Ikenaga, et. al. S100A4 mRNA is a Diagnostic and Prognostic Marker in Pancreatic Carcinoma[J]. J Gastrointest Surg.2009,13:1852-1858
[21]Mahon, P.C.,Baril,P,Bhakta,V, et al.S100A4 Contributes to the Suppression of BNIP3 Expression, Chemoresistance, and Inhibition of Apoptosis in Pancreatic Cancer[J]. Cancer Res,2007,67(14): 6786-6795.
[22]Vande Velde C, Cizeau J, Dubik D, et al. BNIP3 and genetic control of necrosis-like cell death through the mitochondrial permeability transition pore[J]. Mol Cell Biol,2000,20:5454-5468.
[23]. Tabata T, Tsukamoto N, Fooladi AA, et al. RNA interference targeting against S100A4 suppresses cell growth and motility and induces apoptosis in human pancreatic cancer cells[J]. Biochem Biophys Res Commun,2009,18; 390 (3):475-480.
[24]Bromn LF, Berse B, Jackman RW, et al. Expression of vascular permeability factor(vascular endothelial growth factor) and its receptors in adenoearcinomas of the gastrointestinal tract[J]. CancerRes,1993,53(19):4727-4735
[25]贾富鑫,张东,刘江伟.S100A4蛋白与肿瘤血管生成的研究进展[J].现代生物医学进展,2010,2(10)：389-391.
[26]arrett SC, Varney KM, Weber DJ, Bresnick AR. S100A4, a mediator of metastasis[J]. J Biol Chem,2006,281:677-680.
[27]李春生,倪灿荣.S100A4和E-Cadherin在胰腺癌组织中的表达及与相关性研究[J].临床肝胆病杂志,2006,3(22)207-208
[28]刘苗,董春燕,邹多武,等S100mRNA在胰腺癌中的表达及其意义[J].胰腺病学,2006,6(4)：230-232.
[29]Tarabykina S, Griffiths TR, Tulchinsky E, et al. Metastasis-associated protein S100A4:spotlight on its role in cell migration[J].Curr Cancer Drug Targets,2007,7(3):217
[30]Oida Y, Yamazaki H, Tobita K, et al. Increased S100A4 expression combined with decreased E-cadherin expression predicts a poor outcome of patients with pancreatic cancer[J]. Oncol Rep,2006, 16(3):457-463.
[31]onemura Y, Endou Y, Kimura K, et al. Inverse expression of S100A4 and E-cadherin is associated with metastatic potential in gastric cancer[J]. Clin Cancer Res,2000,6:4234-4242.
[32]Logsdon CD, Simeone DM, Binkley C, et al. Molecular profiling of pancreatic adenocarcinoma and chronic pancreatitis identifies multiple genes differentially regulated in pancreatic cancer[J]. Cancer Res,2003,63:2649-2657.
[33]Lowe AW, Olsen M, Hao Y, et al. Gene expression patterns in pancreatic tumors, cells and tissues[J]. PLoS ONE,2007,2:e323.
[34]Eibl G, Takata Y, Boros LG, et al. Growth stimulation of COX-2 negative pancreatic cancer by a selective COX-2 inhibitor[J]. Cancer Res,2005,65:982-990.
[35]Baril P, Gangeswaran R, Mahon PC, et al. Periostin promotes invasiveness and resistance of pancreatic cancer cells to hypoxia-induced cell death:role of the β4 integrin and the PI3k pathway[J]. Oncogene,2007,26:2082-2094.
[36]Akada M, Crnogorac-Jurcevic T, Lattimore S, et al. Intrinsic chemoresistance to gemcitabine is associated with decreased expression of BNIP3 in pancreatic cancer[J]. Clin Cancer Res,2005,11: 3094-3101.
[37]刘江伟,李开宗,窦科峰,等.COX-2抑制剂联合顺铂对胰腺癌细胞增生和凋亡的影响[J].世界华人消化杂志,2004,12(5)：1193-1143.
[2]Lowenfels AB, Sullivan T, Fioranti J. The epidemiology and important of pancreat disease in the United States[J]. Curr Castroenterol Rep,2005,7(2):90-95.
[3]沈魁.我国胰腺癌诊断治疗的进展[J].外科理论与实践,1998,2：67-69.
[4]Spinelli GP, Zullo A, Romiti A, et al. Long-term survival in metastatic pancreatic cancer.A case report and review of the literature[J]. JOP,2006,7(5):486-491.
[5]Garrett SC, Varney KM, Weber DJ, et al. S100A4, a mediator of metastasis[J]. J Biol Chem,2006, 281(2):677-680.
[6]Donato R. S100:a multigenic family of calcium-modulated proteins of the EF-hand type with intracellular and extracellnlar funetional roles[J]. Int J Bioehem Cell Biol,2001,33:637-668.
[7]Sehafer BW, Wicki R, Engelkamp D, et al. Isolation of a YAC clone covering a cluster of nine S100 genes on human chromosome lq21:rationale for a new nomenclature of the S100 calcium-binding protein family[J]. Genomics,1995,25(3):638-643.
[8]Oida Y, Yamazaki H, Tobita K, et al. Increased S100A4 expression combined with decreased E-cadherin expression predicts a poor outcome of patients with pancreatic cancer[J]. Oncol Rep, 2006,16(3):457-463.
[9]Rosty C, Ueki T, Argani P, et al. Overexpression of S100A4 in pancreatic ductal adenocarcinomas is associated with poor differentiation and DNA hypomethylation[J]. Am J Pathol,2002,160(1): 45-50.
[10]Ai KX, Lu LY. Huang XY, et al. Prognostic significance of S100A4 and vascular endothelial growth factor expression in pancreatic cancer[J]. World J Gastroenterol 2008,14(12):1931-1935.
[11]李春生,倪灿荣.S100A4和E-Cadherin在胰腺癌组织中的表达及相关性研究[J].临床肝胆病杂志,2006,22：207-208.
[12]Mazzucchelli L. Protein S100A4:too long overlooked by pathologists?[J]. Am JPathol,2002, 160(1):7-13.
[13]Shin S, Sung BJ, Cho YS, et al. An anti-apoptotic protein human surviving is a direct inhibitor of caspase-3 and 7[J]. Biochem,2001,40(4):1117-1123.
[14]唐忠辉,池正忠,蔡庆发,等DPC4、survivin基因在胃癌中的表达及其与微血管形成和预后的关系[J].中国临床实用医学,2007,1(10)：18-21.
[15]Delvaeye M, De Vriese A, Zwerts F, et al. Role of the 2 zebrafish survivin genes in vasculo-angiogenesis, neurogenesis, cardiogenesis and hematopoiesis [J]. BMC Dev Biol,2009,9:25.
[16]Xu JH, Wang AX, Huang HZ, et al. Survivin shRNA induces caspase-3-dependent apoptosis and enhances cisplatin sensitivity in squarnous cell carcinoma of the tongue [J]. Oncol Res,2010,18(8): 377-385.
[17]Brenes O, Arce F, Gatjens-Boniche O, et al. Characterization of cell death events induced by anti-neoplastic drugs cisplatin, paclitaxel and 5-fluorouracil on human hepatoma cell lines:Possible mechanisms of cell resistance [J]. Biomed Pharmacother,2007,61(6):347-355.
[18]Pratt MA, Niu MY, Renart LI. Regulation of survivin by retinoic acid and its role in paclitaxel-mediated cytotoxicity in MCF-7 breast cancer cells [J]. Apoptosis,2006,11 (4):589-605.
[19]Caldas H, Jaynes FO, Boyer MW, et al. Survivin and Granzyme B-induced apoptosis, a novel anticancer therapy [J]. Mol Cancer Ther,2006,5(3):693-703.
[20]Satoh K, Kaneko K, Hirota M, et al. Expression of survivin is correlated with cancer cell apoptosis and is involved in the developed in the development of human pancreatic duct cell tumor[J]. Cancer, 2001,92(2) 273-278.
[21]Sarela AI, Verbeke CS, Ramsdale J, et al. Expression of survivin, a novel inhibitor of apoptesis and cell cycle regulatory protein, in pancreatic adenocarcinoma [J]. Br J Cancer,2002, 86(6):886-892.
[22]Eberhart CE, Coffey RJ, Radhika A,et al.UP-regulation of cyclooxygenase-2 gene expression in human colorectal adenomas and adenocarcinomas[J]. Gastroenterology,1994,107(4):1183-1188.
[23]刘江伟,李开宗,窦科峰.环氧化酶-2和血管内皮生长因子在胰腺癌组织中的表达及其相关性研究[J].中国普外科基础与临床杂志,2003,10(6)：539-541.
[24]文明波,姚红兵.环氧化酶-2与消化道肿瘤研究进展[J].华南国防医学杂志.2006,20(1)：33-37.
[25]Zhou HN, Ivanov VN, Gillespie J, et al. Mechanism of radiation-induced bystander effect:Role of the cyclooxygenase-2 signaling pathway[J].Proc Nat Acad Sci USA,2005,102(41):14641-14646.
[26]Pai R, Soreghan B, Szabo IL, et al. Prostaglandin E2 transactivates EGF receptor:A novel mechanism for promoting colon cancer growth and gastrointestinal hypertrophy[J]. Nat Med,2002, 8(3):289-293.
[27]Xu M, Jin YL, Fu J,et al.The abnormal expression of retinoic acid receptor-beta,53 and Ki67 protein in normal, premalignant and malignant esophageal tissues[J]. World J Gastroenterol,2002, 8(2):200-202.
[28]Pedersen KB, Andersen K, Fodstad O, et al. Sensitization of interferon-γ induced apoptosis in human osteosarcoma cells by extracellular S100A4[J]. BMC Cancer.2004,4:52.
[29]Schmidt-Hansen B, Klingelhofer J, Grum-Schwensen B, et al. Functional significance of metastasis-inducing S100A4(Mtsl) in tumor-stroma interplay[J]. J Biol Chem.2004,279(23):24498-24504.
[30]Grigorian M, Andresen S, Tulchinsky E, et al. Tumor suppressor p53 protein is a new target for the metastasis-associated Mtsl/S100A4 protein:functional consequences of their interaction[J]. J Biol Chem,2001,276(25):22699-708
[31]Tabata T, Tsukamoto N, Fooladi AA, et al. RNA interference targeting against S100A4 suppresses cell growth and motility and induces apoptosis in human pancreatic cancer cells[J]. Biochem Biophys Res Commun,2009.390 (3):475-480.
[32]Radestock Y, Willing C, Kehien A, et al. Relaxin enhances S100A4 and promotes growth of human thyroid carcinoma cell xenografts[J]. Mol Cancer Res,2010.8(4):494-506.
[33]Tang Y, Wang L, Goloubeva O, et al. The relationship of neuroendocrine carcinomas to anti-tumor therapies in TRAMP mice[J]. Prostate,2009,69(16):1763-1773.
[34]吴爱国,马雷,纪术峰,等.短发夹RNA沉默S100A4基因表达对乳腺癌MCF-7细胞生长和侵袭能力的影响[J].肿瘤,2009,29(8)：715-721.
[35]Mahon PC, Baril P, Bhakta V, et al. S100A4 Contributes to the Suppression of BNIP3 Expression, Chemoresistance, and Inhibition of Apoptosis in Pancreatic Cancer[J]. Cancer Res,2007, 67(14):6786-6795.
[36]樊洁,唐峰等.胰腺癌淋巴结转移与P53、Ki67表达及预后的关系[J].中国临床医学,2007,]4(6)：825-828.
[37]Semov A, Moreno MJ, Onichtchenko A, et al. Metastasis-associated protein S100A4 induces angiogenesis through interaction with Annexin Ⅱ and accelerated plasmin formation[J]. Biol Chem, 2005,280(21):20833-20841.
[38]Schmidt-Hansen B, Ornas D, Grigorian M, et al. Extracellular S100A4 (mtsl) stimulates invasive growth ofmouse endothelial cells andmodulates MMP-13 matrix metalloproteinase activity[J]. Oncogene,2004,23(32):5487-5495.
[39]Sobin LH, Wittekind CH. UICC TNM classification of malignant tumors. (M).5th ed, new york: Wile Liss,1997:66-69.
[40]Lu CD, Altieri DC. Tanigawa N. Expression of a novel antiapoptosis gene, survivin, correlated with tumor cell apoptosis and P53 accumulation in gastric carcinomas. Cancer Res,1998,58:1808-1812.
[41]Hida T, Yatabe Y, Achiwa H, et al. Inreased expression of cyclooxygenase-2 occurs frequently in huan lung cancers, specifically in adenocarinoma[J]. Cancer Res,1998,58(17):3761-3764.
[42]Weidner N, Semple J P, Welch WR, et al. Tumor angiogenesis and metastasis correlation in invasive breast carcinoma[J]. New Engl J Med,1991.324 (1):1-8.
[43]Sherbet GV, Lakshmi MS. S100A4(MTS1)calcium binding protein in cancer growth, invasion and metastasis[J].Anticancer Res,1998,18(4A):2415-2421.
[44]Cajone F, Sherbet GV. Statnmin is involved in S100A4 mediated regulation of cell cycle progression[J]. Clin ExpMetastasis,1999,17(10):865-871.
[45]Ryu B,Jones J, Blades NJ, et al. Relationships and differentially expressed genes among pancreatic cancers examined by large-scale serial analysis of gene expression[J]. Cancer Res,2002, 62(3):819-826.
[46]Lee WY, Su WC, Lin PW, et al. Expression of S100A4 and Met:potential predictors for metastasis and survival in earlystage breast cancer[J]. Oncology,2004,66(6):429-438.
[47]Kimura K, Endo Y, Yonemura Y, et al. Clinical significance of S100A4 and E-cadherin-related adhesion molecules in nonsmall cell lung cancer[J]. Int J Oncol,2000,16(6):1125-1131.
[48]Davies BR, O Donnell M, Durkan GC, et al. Expression of S100A4 protein is associated with metastasis and reduced survival in human bladder cancer[J]. J Pathol,2002,196(1):292-299.
[49]Mazzocca A, Carloni V. The metastatic process:methodological advances and pharmacological challenges [J]. Curr Med Chem,2009,16 (14):1704-1717.
[50]Kami K, Doi R, Koizumi M, et al. Survivin expression is a prognostic marker in pancreatic cancer patients[J]. Surgery,2004,136(2):443-448.
[51]刘江伟,李开宗,窦科峰.COX-2在胰腺癌组织中的表达及其与p53的相关性研究[J].世界华人消化杂志,2003,11(2)：229-232.
[52]Juuti A, Louhimo J, Nordling S, et al. Cyclooxygenase-2 expression correlates with poor prognosis in pancreatic cancer[J]. J Clin Pathol,2006,59(4):382-386.
[53]刘江伟,李开宗窦科峰iNOS、COX-2在胰腺癌组织中的表达及其临床意义[J].肿瘤防治杂志,2003,30(5)：361-363.
[54]Kiryushko D, Novitskaya V, Soroka V, et al. Molecular mechanisms of Ca(2+)signaling in neurons induced by the S100A4 protein[J]. Mol Cell Biol,2006,26(9):3625-3638.
[55]Ambartsumian N, Klingelhofer J, Grigorian M, et al.The metastasis-associated Mts1(S100A4) protein could act as an angiogenic factor[J]. Oncogene,2001,20(34):4685-4695.
[56]Ambartsumian N, Grigorian M, Lukanidin E. Genetically modified mouse models to study the role of metastasis-promoting S100A4(mts1) protein in metastatic mammary cancer[J]. J Dairy Res, 2005,72(S1):27-33.
[57]Wang TY, QianXP, Liu BR. Survivin:potential role in diaguosis, prognosis and targeted therapy ofgastric cancer[J]. World J Gastroenterol,2007,13(20):2784-2790.
[58]Capalbo G, Rodel C, Stauber RH, et al. The role of survivin for radiation therapy[J]. Strahlenther Onkol,2007,183(11):593-599.
[59]Akyuek N, Memis L, Ekinci O, et al. Survivin expression in pre-invasive lesions and non-small cell lung carcinoma[J]. Virchows Arch,2006,449(2):164-170.
[60]Lee MA, Park GS,Lee HJ, et al. Survivin expression and its clinical significance in pancreatic cancer [J]. BMC Cancer,2005,5(127):1-6.
[61]Sarela AI, Macadam RC, Farmery SM, et al. Expression of the antiapoptosis gene, survivin, predicts death from recurrent colorectal carcinoma[J]. Gut,2000,46(5):645-650.
[62]Li H, Niederkorn JY, Neelam S, et al. Downregnlation of survivin expression enhances sensitivity of cultured uveal melanoma cells to cisplatin treatment[J]. Exp Eye Res,2006,83(1):176-182.
[63]刘江伟,李开宗,窦科峰,等.胰腺癌组织Survivin和COX-2表达的相关性[J].第四军医大学学报,2004.,25(7)：635-636.
[1]Taylor S, Herrington S, Prime W, et al.S100A4 (p9Ka) protein in colon carcinoma and livermetastases: association with carcinoma cells and T-lymphocytes[J]. Br J Cancer,2002,86(3):409-416.
[2]Mazzucchelli L. Protein S100A4:too long overlooked by pathologists?[J]. Am J Pathol,2002,160(1): 7-13.
[3]Sherbet GV, Lakshmi MS. S100A4 (MTS1) calcium binding protein in cancer growth, invasion and metastasis[J]. Anticancer Res,1998,18(4A):2415-2421.
[4]Yao R, Davidson DD, Lopez-Beltran A, et al.The S100 proteins for screening and prognostic grading of bladder cancer [J]. Histol Histopathol,2007,22(9):1025.
[5]Gribenko AV, Hopper J E, Makhatadze GI, et al. Molecular characterization and tissue distribution of a novel member of the S100 family of EF-hand proteins[J]. Biochemistry,2001,40:1553-15548.
[6]Donato R. S100:a multigenic family of calcium-modulated proteins of the EF-hand type with intracellular and extracellular functional roles[J].Int J Biochem Cell Biol,2001,33(7):637.
[7]Tarabykina S, Scott DJ, Herzyk P, et al. The dimerization interface of the metastasis-associated protein S100A4 (Mts1):in vivo and in vitro studies[J]. J Biol Chem,2001,276(26):24212-24222.
[8]Platt-Higgins AM, Renshaw CA, West CR, et al. Comparison of the metastasis inducing protein S100A4(p9Ka) with other prognostic markers in human breast cancer[J].Int J Cancer,2000,89(2):198.
[9]Ninomiya I, Ohta T, Fushida S, et al. Increased expression of S100A4 and its prognostic significance in esophagealsquamous cell carcinoma[J].Int J Oncol,2001,18:715.
[10]Yonemura Y, Endou Y, kimura K, et al.Inverse expression of S100A4 and E-cadherin is associated with metastatic potential in gastric cancer[J]. Clin Cancer Res,2000,6(11):4234.
[11]Endo Y, Yonemura Y, Heizmann CW, et al. Clinical significance of S100A4 and E-cadherin related adhesion molecules in nonsmall cell lung cancer[J].Int J Oncol.2000,16(6):1125
[12]Ryu B,Jones J,Blades NJ,et al.Relationships and differentially expressed genes among pancreatic cancers examined by large-scale serial analysis of gene expression[J].Cancer Res,2002,62(3):819.
[13]Lloyd BH, Platt-Higgins A, Rudland PS, et al. Human S100A4 (p9Ka)induces the metastatic phenotype upon benign tumour cells[J].Oncogene,1998,17(4):465-473
[14]Gao XN,Tang SQ, Zhang XF. S100A4 antisense oligodeoxynucleotide suppresses invasive potential of neuroblastoma cells[J].J Pediatr Surg,2005,40(4):648-652.
[15]Kiryushko D, Novitskaya V. Soroka V, et al.Molecular mechanisms of Ca(2+)signaling in neurons induced by the S100A4 protein.Mol Cell Biol,2006,26(9):3625
[16]Cajone F, Sherbet GV. Stathmin is involved in S100A4 mediated regulation of cell cycle progression[J]. Clin ExpMetastasis,1999,17(10):865-871.
[17]Lee WY, Su WC, Lin PW, et al. Expression of S100A4 and Met:potential predictors for metastasis and survival in earlystage breast cancer[J]. Oncology,2004,66(6):429-438.
[18]Kimura K, Endo Y, Yonemura Y, et al. Clinical significance of S100A4 and E-cadherin-related adhesion molecules in nonsmall cell lung cancer[J]. Int J Oncol,2000,16(6):1125-1131.
[19]Davies BR, O Donnell M, Durkan GC, et al. Expression of S100A4 protein is associated with metastasis and reduced survival in human bladder cancer[J]. J Pathol,2002,196(1):292-299.
[20]Ambartsumian N, Klingelhofer J, Grigorian M, et al. The metastasis-associated Mts1(S100A4) protein could act as an angiogenic factor[J]. Oncogene.2001,20(34):4685-4695.
[21]Ambartsumian N, Grigorian M, Lukanidin E. Genetically modified mouse models to study the role of metastasis-promoting S100A4(mts1) protein in metastatic mammary cancer[J]. J Dairy Res,2005, 72(S1):27-33.
[22]Endo H, Takenaga K, Kanno T, et al. Methionine aminopeptidase 2 is a new target for the metastasis-associated protein, S100A4[J]. J Biol Chem,2002,277:26396-26402.
[23]Schmidt-Hansen B, Klingelh J, et al. Functional significance of metastasis-inducing S100A4(Mtsl) in tumor-stroma interplay. J Biol Chem,2004,279(23):24498
[24]Schmidt-Hansen B, Ornas D, Grigorian M, et al. Extracellular S100A4 (mts1) stimulates invasive growth ofmouse endothelial cells andmodulates MMP-13 matrix metallo proteinase activity[J]. Oncogene,2004,23(32):5487-5495.
[25]Bromn LF, Berse B, Jackman RW, et al. Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in adenocarcinomas of the gastrointestinal tract [J].CancerRes,1993,53(19):4727-4735.
[26]鲁林源,艾开兴,黄新余,等,S100A4、VEGF的表达与胰腺癌预后的关系[J].肿瘤,2008,28(4)：326-329.
[27]Semov A, Moreno MJ, Onichtchenko A, et al. Metastasis-associated protein S100A4 induces angiogenesis through interaction with Annexin Ⅱ and accelerated plasmin formation[J]. J Biol Chem,2005,280(21):20833-20841.
[1]Yao R, Davidson DD, Lopez-Beltran A, et al.The S100 proteins for screening and prognostic grading of bladder cancer [J].Histol Histopathol,2007,22(9):1025.
[2]Guo X, Cui Z. Current diagnosis and treat ment of pancreatic cancer in china[J]. Pancreas,2005,31: 13-22.
[3]Wang L, rang GH, Li H, et al. The changing pancreatic cancer mortality in China (1991-2000) [J]. Zhonghua Nei Ke Za Zhi,2005,44:509-513 (In Chinese).
[4]Li C, Heidt DG, Dalrba P, et al. Identification of pancreatic cancerl stem cell[J]. Cancer Res,2007, 67:1030-1037.
[5]Rodfiguez JA, Li M, Yao Q, et al. Gene overexp ression in pancreatic adenocareinoma:diagnostic and therapeuticimp lications [J]. World J Surg,2005,29:297-305.
[6]Garrett SC, Varney KM, Weber DJ, et al. S100A4, a mediator of metastasis[J]. J Biol Chem,2006, 281(2):677-680.
[7]Taylor S, Herrington S, Prime W, et al. S100A4 (p9Ka) protein in colon carcinoma and liver metastases:association with carcinoma cells and T-lymphocytes[J].Br J Cancer,2002,86(3):409-416.
[8]Mazzucchelli L. Protein S100A4:too long overlooked by pathologists?[J]. Am J Pathol,2002,160 (1):7-13.
[9]Platt-Higgins AM, Renshaw CA, West CR, et al.Comparison of the metastasis inducing protein S100A4(p9Ka) with other prognostic markers in human breast cancer [J].Int J Cancer,2000,89(2):198.
[10]Ninomiya I, Ohta T, Fushida S, et al.Increased expression of S100A4 and its prognostic significance in esophageal squamous cell carcinoma[J].Int J Oncol,2001,18:715.
[11]Yonemura Y, Endou Y, kimura K, et al.Inverse expression of S100A4 and E-cadherin is associated with metastatic potential in gastric cancer[J]. Clin Cancer Res,2000,6(11):4234.
[12]Endo Y, Yonemura Y, Heizmann CW, et al. Clinical significance of S100A4 and E-cadherin-related adhesion molecules in nonsmall cell lung cancer[J].Int J Oncol,2000,16(6):1125.
[13]Ryu B, Jones J, Blades NJ, et al. Relationships and differentially expressed genes among pancreatic cancers examined by large-scale serial analysis of gene expression[J].Cancer Res,2002,62(3):819.
[14]Gribenko AV, Hopper J E, Makhatadze GI, et al. Molecular characterization and tissue distribution of a novel member of the S100 family of EF-hand proteins[J]. Biochemistry,2001,40:1553815548.
[15]Donato R. S100:a multigenic family of calcium-modulated proteins of the EF-hand type with intracellular and extracellular functional roles[J].Int J Biochem Cell Biol,2001,33(7):637.
[16]Tarabykina S, Scott DJ, Herzyk P, et al.The dimerization interface of the metastasis-associated protein S100A4 (Mts1):in vivo and in vitro studies[J].J Biol Chem,2001,276(26):24212-24222.
[17]Jang JY, Park YC, Song YS, et al. Increased K-ras mutation and expression of S100A4 and MUC2 protein in the malignant intraductal papillary mucinous tumor of the pancreas. J Hepatobiliary Pancreat Surg.2009;16(5):668-674.
[18]Rosty C, Ueki T, Argani P, et al. Overexpression of S100A4 in pancreatic ductal adenoearcinomas is associated with poor differention and DNA hypomethylation. AM J Pathol,2002,160(1):45-50
[19]Ai KX, Lu LY, Huang XY, et al. Chen Prognostic significance of S100A4 and vascular endothelial growth factor expression in pancreatic cancer[J]. World J Gastroenterol,2008; 14: 1931-1935
[20]Naoki Ikenaga, et. al. S100A4 mRNA is a Diagnostic and Prognostic Marker in Pancreatic Carcinoma[J]. J Gastrointest Surg.2009,13:1852-1858
[21]Mahon, P.C.,Baril,P,Bhakta,V, et al.S100A4 Contributes to the Suppression of BNIP3 Expression, Chemoresistance, and Inhibition of Apoptosis in Pancreatic Cancer[J]. Cancer Res,2007,67(14): 6786-6795.
[22]Vande Velde C, Cizeau J, Dubik D, et al. BNIP3 and genetic control of necrosis-like cell death through the mitochondrial permeability transition pore[J]. Mol Cell Biol,2000,20:5454-5468.
[23]. Tabata T, Tsukamoto N, Fooladi AA, et al. RNA interference targeting against S100A4 suppresses cell growth and motility and induces apoptosis in human pancreatic cancer cells[J]. Biochem Biophys Res Commun,2009,18; 390 (3):475-480.
[24]Bromn LF, Berse B, Jackman RW, et al. Expression of vascular permeability factor(vascular endothelial growth factor) and its receptors in adenoearcinomas of the gastrointestinal tract[J]. CancerRes,1993,53(19):4727-4735
[25]贾富鑫,张东,刘江伟.S100A4蛋白与肿瘤血管生成的研究进展[J].现代生物医学进展,2010,2(10)：389-391.
[26]arrett SC, Varney KM, Weber DJ, Bresnick AR. S100A4, a mediator of metastasis[J]. J Biol Chem,2006,281:677-680.
[27]李春生,倪灿荣.S100A4和E-Cadherin在胰腺癌组织中的表达及与相关性研究[J].临床肝胆病杂志,2006,3(22)207-208
[28]刘苗,董春燕,邹多武,等S100mRNA在胰腺癌中的表达及其意义[J].胰腺病学,2006,6(4)：230-232.
[29]Tarabykina S, Griffiths TR, Tulchinsky E, et al. Metastasis-associated protein S100A4:spotlight on its role in cell migration[J].Curr Cancer Drug Targets,2007,7(3):217
[30]Oida Y, Yamazaki H, Tobita K, et al. Increased S100A4 expression combined with decreased E-cadherin expression predicts a poor outcome of patients with pancreatic cancer[J]. Oncol Rep,2006, 16(3):457-463.
[31]onemura Y, Endou Y, Kimura K, et al. Inverse expression of S100A4 and E-cadherin is associated with metastatic potential in gastric cancer[J]. Clin Cancer Res,2000,6:4234-4242.
[32]Logsdon CD, Simeone DM, Binkley C, et al. Molecular profiling of pancreatic adenocarcinoma and chronic pancreatitis identifies multiple genes differentially regulated in pancreatic cancer[J]. Cancer Res,2003,63:2649-2657.
[33]Lowe AW, Olsen M, Hao Y, et al. Gene expression patterns in pancreatic tumors, cells and tissues[J]. PLoS ONE,2007,2:e323.
[34]Eibl G, Takata Y, Boros LG, et al. Growth stimulation of COX-2 negative pancreatic cancer by a selective COX-2 inhibitor[J]. Cancer Res,2005,65:982-990.
[35]Baril P, Gangeswaran R, Mahon PC, et al. Periostin promotes invasiveness and resistance of pancreatic cancer cells to hypoxia-induced cell death:role of the β4 integrin and the PI3k pathway[J]. Oncogene,2007,26:2082-2094.
[36]Akada M, Crnogorac-Jurcevic T, Lattimore S, et al. Intrinsic chemoresistance to gemcitabine is associated with decreased expression of BNIP3 in pancreatic cancer[J]. Clin Cancer Res,2005,11: 3094-3101.
[37]刘江伟,李开宗,窦科峰,等.COX-2抑制剂联合顺铂对胰腺癌细胞增生和凋亡的影响[J].世界华人消化杂志,2004,12(5)：1193-1143.