Survivin、Bcl-2在口腔疣状癌的表达及相关性研究
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摘要
目的研究Survivin和Bcl-2蛋白在口腔疣状癌中的表达及其相关性,并与口腔鳞癌做比较,探讨其在口腔疣状癌发生、发展及预后中的作用。
     方法取15例口腔疣状癌(外生型疣状癌8例,囊肿/浸润型疣状癌7例),30例口腔鳞状细胞癌(高,中/低分化鳞癌各15例),15例正常口腔粘膜,应用免疫组织化学S-P法检测上述标本中Bcl-2,Survivin的表达和分布。
     结果
     1.Surivin蛋白的表达
     a口腔疣状癌和口腔鳞癌的癌组织中Surivin蛋白表达水平均高于正常的口腔粘膜组织(均为P<0.01)。口腔疣状癌与口腔鳞癌癌组织中Surivin蛋白的表达无显著差异(P>0.05)
     b.外生型疣状癌癌组织中Surivin蛋白表达水平低于囊肿/浸润型疣状癌、高分化鳞癌和中低分化鳞癌(p<0.05)。囊肿/浸润型疣状癌与高分化鳞癌、中/低分化鳞癌比较,癌组织中Surivin蛋白表达无显著差异(P>0.05)。
     c.口腔鳞癌中,Surivin蛋白的表达与病理分级、年龄、性别、发病部位和临床分期无关(P>0.05),而与有无淋巴结转移有关(p<0.01)。
     2.Bcl-2蛋白的表达
     a.口腔疣状癌和口腔鳞癌的癌组织中Bcl-2蛋白表达水平均高于正常的口腔粘膜组织(均为P<0.01)。口腔疣状癌与口腔鳞癌癌组织中Bcl-2蛋白的表达有显著差异(P<0.05)。
     b.外生型疣状癌癌组织中Bcl-2蛋白表达水平低于囊肿/浸润型疣状癌、高分化鳞癌和中低分化鳞癌(p<0.05)。囊肿/浸润型疣状癌与高分化鳞癌、中低分化鳞癌比较,癌组织中Bcl-2蛋白表达无显著差异(P>0.05)。
     c.口腔鳞癌中,Bcl-2蛋白的表达与病理分级、年龄、性别、发病部位和临床分期无关(P>0.05),而与有无淋巴结转移有关(p<0.01)。
     3.在口腔疣状癌组织中,Survivin蛋白和Bcl-2蛋白的表达呈正相关(r=0.591,P<0.05)。在口腔鳞癌组织中,Survivin蛋白和Bcl-2蛋白的表达呈正相关(r=0.539,p<0.05)
     结论
     1.survivin和Bcl-2可能在口腔疣状癌和口腔鳞癌的发生发展过程中发挥了重要作用。
     2.survivin和Bcl-2从蛋白水平说明,囊肿/浸润型口腔疣状癌有高于外生型口腔疣状癌甚至部分口腔高分化鳞癌的浸润转移潜能。
     3.Survivin基因与凋亡相关基因Bcl-2在口腔疣状癌和口腔鳞癌的发生发展过程中起协同作用。
Objective:To study the expression and the relationship of survivin and bcl-2 in oral verrucous carcinoma(OVC)and oral squamous cell carcinoma(OSCC)so as to investigate their role in the development and prognosis of OVC and OSCC.
     Methods:15 cases of oral normal mucosa(NM),15 cases of OVC(8 cases of exogenic type and 7case's of cystoid/infiltrative type)and 30 cases of OSCC(15cases wdSCC and 15 cases md/pdSCC)were used to detect the expression of survivin and bcl-2 by immunohistochemistry S-P method.
     Results:
     1.The protein expression of survivin
     a.The expression of survivin in OVC and OSCC were higher than in NM(both P<0.01).There was no difference of the expression of survivin between OVC and OSCC(P>0.05).
     b.The expression of survivin in exogenic type OVC was significantly lower than cystoid/infiltrative type OVC、wd-OSCC and md/pd-OSCC(P<0.05).There was no difference of the expression of survivin among cystoid/infiltrative type OVC、wd-SCC and md/pd-SCC(P>0.05).
     c.Survivin expression of OSCC was associated with lymph node metastasis(p<0.01),positive rates were higher in patients displaying lymph node metastasis than no metastasis.And there was no significant difference in age、sex of the patients,as well as the tumor sites、differentiated grades and clinical stages(p>0.05)
     2.The protein expression of Bcl-2
     a.The expression of Bcl-2 in OVC and OSCC were higher than in NM(both P<0.01).There was significant difference of the expression of Bcl-2 between OVC and OSCC(P<0.05).
     b.The expression of Bcl-2 in exogenic type OVC was significantly lower than cystoid/infiltrative type OVC、wd-OSCC and md/pd-OSCC (P>0.05).There was no difference of the prontein expression of Bcl-2 among cystoid/infiltrative type OVC、wd-OSCC and md/pd -OSCC (P>0.05).
     c.Bcl-2 expression of OSCC was.associated with lymph node metastasis(p<0.01),positive rate were higher in patients displaying lymph node metastasis than no metastasis.And there was no significant difference in age,sex of the patients,as well as the tumor sites, differentiated grades and clinical stages(p>0.05).
     3.In OVC and OSCC the expression of survivin was correlated with the expression ofBcl-2(OVC:r=0.591,p<0.05;OSCC:r=0.539,p<0.05)
     Conclusion
     1.Survivin and Bcl-2 may play a key role in the carcinogenesis and development of OVC and OSCC.
     2.And it also showed part of cystoid/infiltratie type OVC can have a higher potential of invade and metastasis than exogenic type OVC.
     3.Apoptosis related gene Bcl-2 may have a synergistic role with survivin in pathogenesis and progression of OVC and OSCC.
引文
[1]Ackerman LV.Verrucous carcinoma of the oral cavity[J].Surgery,1948,23:670-678
    [2]Spiro RH.Verrucous carcinoma,then and now.Am J Surg,1998,176(5):393-397
    [3]Bouquot JE.Oral verrucous carcinoma,Incidence in two US populations[J].Oral Surg Oral Med Oral Pathol Oral Radiol Endod,1998,86(3):318-324
    [4]唐瞻贵,李晋芸,苏彤,等.口腔疣状癌的临床研究[J].口腔领面外科杂志,2002,12(1):878
    [5]Kang CJ,Chang JT,Chen TM,et al.Surgical treatment of oral Verrucous carcinoma[J].Chang Gung Med J,2003,26(11):807-812
    [6]Salesiotis A,Soong R,Diasio RB,et al.Capecitabine induces rapid,sustained response in two patients with extensive oral verrucous carcinoma[J].Clin Cancer Res,2003,9(2):580-585
    [7]Strojan P,Soba E,Budihna M,et al.Radiochemotherapy with Vinblastine,Methotrexate,and Bleomycin in the treatment of verrucous carcinoma of the head and neck[J].Surg Oncol.2005,92(4):278-283
    [8]王瑛,吴奇光,郑麟蕃.口腔粘膜疣状癌的临床病理学研究[J].中华口腔科杂志,1985,20(2):65-68
    [9]Oliveira MC,Silveira EJ,Godoy GP,et al.Immunohistochemical evaluation of intermediate filament proteins in squamous papilloma and oral verrucous carcinoma[J].Oral Dis,2005,11(5):288-292
    [10]Eversole LR,Papillary lesions of the oral cavity:relationship to human papillomaviruses[J].Calif Dent Assoc,2000,28(12):922-927
    [11]Sakurai K,Urade M,Takahashi Y,et al.Increased expression of verrucous carcinoma of the oral mucosa[J].Cancer,2000,89(12):2597-2705.
    [12]Punnya V,Rekha K.Cyclin D1 expression in oral squamous cell carcinoma and verrucous carcinoma:correlation with histological differentiation[J].Oral Surg Oral Med Oral Pthol Oral Radiol Endod,2007,103(4):33-35
    [13]邹萍,唐瞻贵,冯德云,等.人乳头状瘤病毒16/18型、p53、p16蛋白在口腔疣状癌中的表达[J].口腔领面外科杂志,2003,13(3):211-215
    [14]唐瞻贵,邹萍,谢晓莉,等.E-cadherin基因蛋白在口腔疣状癌中的表达[J].湖 南医科大学学报,2003,28(3):206-208.
    [15]李晋芸,唐瞻贵,姚志刚,等.口腔疣状癌VEGF基因蛋白免疫电镜研究[J].临床口腔医学杂志,2003,19(7):399-401
    [16]唐瞻贵,张雷,全向娟,等.口腔疣状癌Maspin基因表达研究[J].中华口腔医学杂志,2005,40(4):279
    [17]唐瞻贵,邹萍,李晋芸,等.MDM_2在口腔疣状癌中的表达及意义[J].实用口腔医学杂志,2004,20(3):375-376
    [18]唐瞻贵,李金茂,洪珍珍,等.基质金属蛋白酶2 mRNA在口腔疣状癌中的表达研究[J].中南大学学报(医学版),2005,30(6):650-652
    [19]李晋芸,唐瞻贵,姚志刚,等.口腔疣状癌超微结构特征研究[J].临床口腔医学杂志,2003,19(11):673-674.
    [20]唐瞻贵,赵素萍,张雷,等.口腔疣状癌与口腔鳞癌差异基因表达对比分析[J].中华口腔医学杂志,2007,42(4):229-230.
    [21]唐瞻贵,赵素萍.口腔疣状癌差异基因表达及蛋白质组差异分析的研究.[博士学位论文].长沙,中南大学,2006.
    [22]TANG ZG,XIE XL,LI JY,et al.A clinic study on oral verrucous carcinoma phenotypes[J].The Chinese Journal of Dental Research,2005,8(3):53-61.
    [23]唐瞻贵,谢晓莉,李晋芸,等.口腔疣状癌的误诊研究[J].临床口腔医学杂志,2003,19(8):474-475.
    [24]Tsujimoto Y,Finger LR,Yunis J,et al.Cloning of the chromosome break point of neoplastic B cells with the t(14:18)chromosome translocation[J].Science,1984,226:1097.
    [25]Barinaga M.Death by dozens of cuts[J].Science,1998,280(5360):32-34
    [26]Sakuragi N,Ohkouchi T,Hareyama H,et al.Bcl-2 expression and prognosis of patients with endometrial carcinoma[J].Int J Cancer,1998,79(2):153-158
    [27]Ambrosini G,Adida C,Altieri DC.A novel anti-apoptosisgene,surviving,expressed in cancer and lymphoma[J].Nat Med,1997,3(8):917- 921
    [28]Pannone G,Bufo P,Serpico R,et al.Survivin phosphorylation and M-phase promoting factor in oral carcinogenesis[J].Histol Histopathol,2007,22(11):1241-9
    [29]Al-Joudi FS,Iskandar ZA,Imran AK,et al.Correlations in survivin expression with the expression of p53 and bcl-2 in invasive ductal carcinoma of the breast.Southeast Asian[J].Trop Med Public Health,2007,38(5):904-10
    [30]Gross M,Dexter TM.Growth factors in development,transformation,and tumorigenesis [J]. Cell, 1991, 64(2):271-280.
    [31] Conway EM, Pollefeyt S, Steiner-Mosonyi M, et al . Deficiency of survivin in transgenic mice exacerbates Fas induced apoptosis via mitochondrial pathways [J]. Gastroenterology ,2002,123:619-631.
    [32] Hay BA, Wassarman DA, Rubin GM. Drosophila homologs of baculovirus inhibitor of apoptosis proteins function to block cell death [J]. Cell, 1995; 83(7):1253-1262.
    [33] Ambrosini G, Adida C , sirugo G, et al. Induction of apoptosis and inhibition of cell proliferation by survivin gene targeting [ J ]. J Biol Chem ,1998 , 273 (18 ): 11171-11182.
    [34] Chantalat L, Skoufias D A, Kleman J P, et al. Crystal structure of human survivin reveals- a bow tie- shaped dimer with two unusual α- .helical extensions[J]. Molecular Cell, 2000, 6(1): 183-189.
    [35] Suzuki A, Ito T, Kawabo H, et al. Survivin initiates procaspase3/p21 complex formation as a result of interaction with Cdk4 to resist Fas-mediated cell death [J].Oncogene,2000,19(10):1346-53
    [36] O'Connor DS, Grossman D, Plescia J, et al. Regulation of apoptosis at cell division by p34cdc2 phosphorylation of survivin [J]. Proc Natl Acad Sci USA,2000,97(24): 13103-13107
    [37] Lo Muzio L ,Staibano S ,Pannone G, et al. Expression of the apoptosis inhibitor surviving in aggressive squamous cell carcinoma [J].Exp Mol Pathol ,2001 , 70 :249 - 254.
    [38] Lo Muzio L , Pannone G, Leonardi R ,et al. Survivin , a potential early predictor of tumor progression in the oral mucosa [J].Dent Res , 2003 ,82 (11) : 923 - 928
    [39] Tanaka C , Uzawa K, Shibahara T ,et al. Expression of an inhibitor of apoptosis, survivin, in oral carcinogenesis [J].Dent Res, 2003 ,82 (8) : 607 - 611
    [40] Lo Muzio L , Pannone G, Staibano S , et al. Survivin ex- pression in oral squamous cell carcinoma [J]. Br J Cancer, 2003 ,89 :2244 - 2248.
    [41] Dimitrakakis C, Konstadoulakis M, Messaris E, et al. Molecular markers in breast cancer: can we use c-erbB-2, p53, bcl-2 and bax gene expression as prognostic factors [ J].Breast,2002,11(4):279-285.
    [42] Hirvikoski P, Kumpulainen E, Virtaniemi J, et al. Enhanced apoptosis correlates with poor survival in patients with laryngeal cancer but not with cell proliferati- on, bcl-2 or p53 expression [ J] .Eur J Cancer, 1 999,35(2):231-237.
    [43] Jackel MC, Dorudian MA, Marx D, et al. Spontaneous apoptosis in laryngeal squamous cell carcinoma is in dependent of bcl-2 and bax protein expression [ J]. Cancer,1999,85(3):591-599
    [44] Kalogiannidis I, Bobos M, Papanikolaou A, et al. Immunohistochemical bcl-2 expression, p53 overexpression, PR and ER status in endometrial carcinoma and survival outcomes [J]. Eur J Gynaecol Oncol, 2008,29(1):19-25
    [45] Kristek J, Dmitrovic B, Kurbel S, et al. Tumor growth fraction, expression of estrogen and progesterone receptors, p53, bcl-2 and cathepsin D activity in primary ductal invasive breast carcinoma and their axillary lymph node metastases [J]. Coll Antropol, 2007 ,31(4):1043-1047.
    [46] Niedzielska G, Kocki. J. Evaluation of bcl-2 gene expression in papilloma of larynx in children [ J]. Int J Pediatr Otorhinolaryngol, 2 000,53(1):25-29
    [47] Pruneri G, Pignataro L, Carboni N, et al. Clinical relevance of p53 and bcl-2 Protein over-expression in laryngeal squamous-cel carcinoma [J] .Int J Cancer, 1998,79(3).263.
    [48] Islam A, Kageyama H, Takada N, et al. High expression of Survivin, Mapped to17q25, is significantly associated with poor prognostic factors and promotes Cell survivalin human neuroblastoma[J].Oncogene,2 000,19 (5 ): 617—623.
    [49] Popovi(?) B, Jeki_ B, Novakovi I, et al. Bcl-2 expression in oral squamous cell carcinoma. Ann N Y Acad Sci, 2007,1095:19-25
    [50] Kawasaki H , Altieri DC, Lu CD, et al .Inhibition of apoptosis by survivin predicts short survival rates in colorectal cancer [J].Cancer Res ,1998,58(22):5071-5074
    [51] Tanaka K, Iwamoto S, Gonq et al. Expression of survivin and relationship to loss of apoptosis in breast carcinomas [J].Clin Cancer Res,2000,6 (1):127-134
    [52] Kar R, Sen S, Singh A, Role of Apoptotic Regulators in Human Epithelial Ovarian Cancer [J].Cancer Biol Ther,2007 , 6(7):435-440
    [1] Grabowski P , Kuhnel T , Muhr - Wilkenshoff F , etal. Prognostic value of nuclear survivin expression in oesophageal squamous cell carcinoma[J]. Br J Cancer, 2003 ,88(1) : 115-119
    
    [2] Ambrosini G, Adida C , Altieri DC. A novel anti-apoptosisgene , survivin , expressed in cancer and lymphoma[J]. Nat Med ,1997 ,3 (8) : 917 - 921
    [3] Ambrosini G, Adida C , sirugo G, e ta 1. Induction of apoptosis and inhibition of cell p roliferation by survivingene targeting [ J ]. J Biol Chem ,1998 , 273 (18 ): 11171-11182.
    [4] Lacasse EC , Baird S , Korneluk, RG, et al. The inhibitors of apoptosis and their emerging role in cancer [J ]. Onco Gene ,1998 ,17 (25): 3247-3259.
    [5] Chantalat L, Skoufias D A, Kleman J P, et al. Crystal structure of human survivin reveals a bow tie- shaped dimer with two unusual a- helical extensions[J]. Molecular Cell, 2000,6(1): 183-189.
    [6] Kennedy SM , O'Driscoll L, Purcell R ,et al. Prognostic importance of survivin in breast cancer[J]. Br J Cancer, 2003 , 88 (7) : 1077 -1083
    [7] O'Connor DS , Scheduler J S , Adida C ,et al. Control of apoptosis during angiogenesis by survivin expression in endothelial cells[J].Am J Pathol ,2000,156(2) : 393-398
    [8] Papapetropoulos A ,Fulton D ,Mahboubi K, etal. Angiop- oietin -1 inhibits endothelial cell apoptosis via the Akt/ survivin pathway [J].Biol Chem ,2000 , 275(13): 9,102-9,105
    [9] Blanc - Brude OP , Yu J , Simosa H ,et al. Inhibitor of apoptosis protein survivin regulates vascular injury [J]. Nat Med ,2002 ,8(9) : 987- 994
    [10] Li F, Ling X. Survivin study: An update of "What is the next wave?" [J]. J Cellular Physiol, 2006,208(3): 476- 486.
    
    [11] Li F. Survivin study: what is the next wave?[J]. J Cell Physiol, 2003,197(1): 8- 29.
    
    [12] Vong Q P, Cao K, Li H Y, et al. Chromosome alignment and segregation regulated by ubiquitination of survivin [J]. Science, 2005, 310 (5753): 1499- 1504.
    
    [13] Sampath S C, Ohi R, Leismann O, etal. The chromosomal passenger complex is required for chromatin- induced microtubule stabilization and spindle assembly[J]. Cell, 2004,118(2): 187- 202.
    [14] Lo Muzio L ,Staibano S ,Pannone G, etal. Expression of the apoptosis inhibitor surviving in aggressive squamous cell carcinoma[J]. Exp Mol Pathol , 2001,70:249-254.
    [15] Lo Muzio L, Pannone G, Leonardi R ,et al. Survivin , a potential early predictor of tumor progression in the oral mucosa[J].Dent Res ,2003 ,82 (11) : 923 - 928
    [16] Tanaka C , Uzawa K, Shibahara T ,et al. Expression of an inhibitor of apoptosis , survivin, in oral carcinogenesis[J].Dent Res ,2003 ,82 (8) : 607 - 611
    [17] Lo Muzio L , Pannone G, Staibano S , et al. Survivin ex- pression in oral squamous cell carcinoma[J]. Br J Cancer, 2003 ,89 :2244 - 2248.
    [18] Grabowski P , Kuhnel T , Muhr2Wilkenshoff F , et al. Prognostic value of nuclear- survivin expression in oeso- phageal squamous cell carcinoma[J]. Br J Cancer ,2003 ,88: 115-119.
    [19] Dong Y,Sui L ,Watanabe Y, et al. Survivin expression in laryngeal squamous cell carcinomas and it s prognostic implications [J]. Anticancer Res ,2002 ,22 :2377 - 2383.
    [20] Ito Y, Yoshida H , Uruno T ,et al. Survivin expression is significantly linked to the dedifferentiation of thyroid carcinoma[J]. Oncol Rep , 2003 ,10 :1337 -1340.
    [21] Sugawara M ,Mat suzuka F , Fukata S , et al. Excessive survivin expression in thyroid lymphomas[J]. Hum Pathol, 2002 , 33 :524 - 5277.
    [22] Smith SD, Wheeler MA, Plescia J, et al. Urine detection of survivin and diagnosis of bladder cancer[J] JAMA, 2001,285(3):324-328.
    [23] Sharp J D, Hausladen DA, Maher MG, et al .Bladder cancer detection with urinary survivin, an in hibitor of apo- ptosis[J].Front Biosci,2002,7:e36-e41
    [24] Rohayem J, Diestelkoeter P et al. Antibody response to the tumor-associated inhibitor of apoptosis protein survivin in cancer patients[J].C ancer Res,2000, 60 (7) :1815 — 1817.
    [25] Lu, CD, Altieri DC, Tanigawa N, et al. Expression of a novel antiapoptosis gene, survivin, correlated with tumor cell apoptosis and p53 accumulation in gastric carcinomas[J]. Cancer Res,1998,58:1808-1812.
    [26] Adida C ,Haioun C ,et al .Prognostic significance of su- rvivin expression in diffuse Large B -cell lymphomas [J].B lood,2000,96(5):1921-1925.
    [27] Kawasaki H ,Altieri DC,Lu CD, et al. Inhibition of a- poptosis by survivin predicts shorter survival rates in colorectal cancer[J].Cancer Res,1998, 58(22): 5071-5074.
    [28] Islam A, Kageyama H, Hashizume K, et al. Role of survivin, whose gene is mapped to 17q25, in human neuroblastoma and identification of a novel domaint-negative isform, sur- vivin- beta/2B[J].Med Pediator Oncol,2000, 35(6) :550- 553.
    [29] Tanaka K, Iwamoto S, Gon G, et al. Expression of survivin and its relationship to loss of apoptosis in breast car- cinomas [J].Clin Cancer Res,2000,6(1):127-134.
    [30] Asanuma K, Moriai R ,Yajima T, et al. Survivin as a radio- resistance factor in pancreatic cancer[J] Jpn J Cancer Res,2000,91(11):1204-1209.
    [31] Sarela Al, Macadam RC, Farmery SM, et a 1. Expression of the anti-apoptosis gene, survivin , predicts death from recurrent colorectal carcinoma[J]. Gut,2000 ,46 (5): 645- 650.
    [32] Olie RA, Simoes Wust AP, Baumann B, et al. A novel antisense oligonucleotide targeting Survivin expression induces apoptosis and sensitizes lung cancer cell stochemotherapy [J].Cancer Res, 2000, 60(11):2805-2809.
    [33] Mesri M, Morales Ruiz M, Ackermann E J, et al. Suppression of vascular endothelial growth factor-mediated endothe- lial cell protection by survivin targeting [J].Am J Pathol, 2001,158(5):1757-1765.
    [34] Tsuruma T, Hata F, Torigoe T, et al. Phase I clinical study of anti-apoptosis protein, survivin derived peptide vacc- ine therapy for patients with advanced or recurrent color- rectal cancer [J]. J Trans 1 Med, 2004,2(1): 19.
    [35] Xiang R, Mizutani N, Luo Y, et al. ADNA vaccine targeting survivin combines apoptosis with suppression of angio- genesis in lung tumor radication [J]. Cancer Res, 2005, 65(2):553-561.
    [36] Jiang G, Li J, Zeng Z, Xian L. Lentivirus-mediated gene therapy by suppressing survivin in BALB/c nude mice bearing oral squamous cell carcinoma[J]. Cancer Biol Ther. 2006 Apr ;5(4):435-440.
    [37] Hunakova L, Chorvath M, Duraj J, et al. Radiation-induced apoptosis and cell cycle alterations in human carcinoma cell lines with different radiosensitivities [J]. Neopla- sma,2000,47(1): 25-31.
    [38] Asanuma K, Kobayashi D, Furuya D, et al. A role for sur- vivin radioresistance of pancreatic cancer cells [J]. Jpn J Cancer Res, 2002, 93(9): 1057-1062.
    [39] Rodel C, Haas J, G roth A, et al.Spontaneous and radiation- induced apoptosis in colorectal carcinoma cells with different intrinsic radiosensitivities: survivin as a radioresistance factor [J]. Int J Radiat Oncol Biol Phys, 2003, 55(5):1341-1347.
    
    [40] Beardsmore D M,Verbeke C S,Davies C L,et al. Apoptotic and proliferative indexes in esophageal cancer: predictors of response to neoadjuvant therapyapoptosis and prolife- ration in esophageal cancer[J]. J Gastrointest Surg, 2003,7(1):77-87.
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