FHIT，P16蛋白在口腔黏膜下纤维性变及其伴发口腔癌组织中的表达研究
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摘要
目的:
检测抑癌基因脆性组氨酸三联体(FHIT)、p16蛋白在口腔黏膜下纤维性病变(Oral Submucous Fibrosis,OSF)及其伴发口腔癌组织中的表达与分布情况,初步探讨FHIT、p16在OSF癌变发生,发展过程中的作用。
方法:
采用免疫组化SP法,用鼠抗人FHIT、p16单克隆抗体检测44例OSF组织、15例OSF伴发的口腔癌组织及8例正常对照者的口腔粘膜组织中FHIT、p16蛋白的表达及分布。
结果:
(1)FHIT蛋白阳性表达定位于细胞质,少数可见细胞核黄染。FHIT蛋白在正常口腔粘膜组织高表达率为87.5%,OSF组织中的高表达率为70.4%,两者之间没有显著性差异(P＞0.05);FHIT蛋白在正常口腔粘膜组织与OSF伴发口腔癌组织中的高表达率(40.0%)有显著性差异(P＜0.05);FHIT蛋白在OSF组织与OSF伴发口腔癌组织中的表达有显著性差异(P＜0.05)。
(2)p16蛋白在细胞核和细胞质均有表达,其在正常口腔粘膜组织高表达率为100.0%,在OSF组织中的高表达率72.7%,两者之间没有显著性差异(P＞0.05);p16蛋白在正常口腔粘膜组织与OSF伴发口腔癌组织中的高表达率(40.0%)有显著性差异(P＜0.05);p16蛋白在OSF组织与OSF伴发口腔癌组织中的表达有显著性差异(P＜0.05)。
(3)p16蛋白在各组病变组织中表达的平均灰度值均分别小于FHIT蛋白在各其病变组织中表达的平均灰度值,差别有统计学意义(P＜0.05)。FHIT蛋白和p16蛋白在不同病变组织中的表达显示二者正相关,其Person相关系数为0.970,P值为0.030(双侧)。
结论:
(1)FHIT蛋白和p16蛋白在OSF伴发口腔癌组织中表达下调和缺失,可能是OSF癌变过程中的早期表现。
(2)FHIT蛋白和p16蛋白在OSF及其伴发口腔癌组织中的表达呈显著正相关,表明两者可能有协同作用,共同参与OSF癌变的过程。
Objective:
To investigate the expression of FHIT and p16 protein in oral submucous fibrosis(OSF)and oral submucous fibrosis concomitant with oral squamous cell carcinoma(OSCC),and to evaluate their possible roles in carcinogenesis of OSF.
Methods:
Immunohistochemical staining by SP methods was utilized to detect the expression of FHIT,p16 in 44 cases of OSF,15 cases of oral submucous fibrosis concomitant with OSCC and 8 cases of normal control oral mucosa tissue.
Results:
(1)The positive rates of FHIT in normal tissues,OSF and OSF concomitant with OSCC are 87.5%,70.4%40.0%respectively. The differences which in expression between normal tissues group and carcinogenesis of OSF group,between OSF group and OSF concomitant with OSCC group are statistically significant (P＜0.05).
(2)The positive rates of p16 in normal tissues,OSF and OSF concomitant with OSCC are 100.0%,72.7%,40.0%respectively. The differences which in expression between normal tissues group and carcinogenesis of OSF group,between OSF group and OSF concomitant with OSCC group are statistically significant (P＜0.05).
(3)The expressions of FHIT are corresponding higher than the expression of p16 among the five groups,the differences are statistically significant(P＜0.05).There are positive correlation between the expression of FHIT and p16 in OSF and OSF concomitant with OSCC group(r=0.970,P＜0.05).
Conclusions:
(1)The loss of FHIT or p16 is likely to be an early occurrence in the carcinogenesis of OSF.
(2)The positive correlation between the expression of FHIT and P16 demonstrats that they may act together promoting the carcinogenesis of OSF.
检测抑癌基因脆性组氨酸三联体(FHIT)、p16蛋白在口腔黏膜下纤维性病变(Oral Submucous Fibrosis,OSF)及其伴发口腔癌组织中的表达与分布情况,初步探讨FHIT、p16在OSF癌变发生,发展过程中的作用。
方法:
采用免疫组化SP法,用鼠抗人FHIT、p16单克隆抗体检测44例OSF组织、15例OSF伴发的口腔癌组织及8例正常对照者的口腔粘膜组织中FHIT、p16蛋白的表达及分布。
结果:
(1)FHIT蛋白阳性表达定位于细胞质,少数可见细胞核黄染。FHIT蛋白在正常口腔粘膜组织高表达率为87.5%,OSF组织中的高表达率为70.4%,两者之间没有显著性差异(P＞0.05);FHIT蛋白在正常口腔粘膜组织与OSF伴发口腔癌组织中的高表达率(40.0%)有显著性差异(P＜0.05);FHIT蛋白在OSF组织与OSF伴发口腔癌组织中的表达有显著性差异(P＜0.05)。
(2)p16蛋白在细胞核和细胞质均有表达,其在正常口腔粘膜组织高表达率为100.0%,在OSF组织中的高表达率72.7%,两者之间没有显著性差异(P＞0.05);p16蛋白在正常口腔粘膜组织与OSF伴发口腔癌组织中的高表达率(40.0%)有显著性差异(P＜0.05);p16蛋白在OSF组织与OSF伴发口腔癌组织中的表达有显著性差异(P＜0.05)。
(3)p16蛋白在各组病变组织中表达的平均灰度值均分别小于FHIT蛋白在各其病变组织中表达的平均灰度值,差别有统计学意义(P＜0.05)。FHIT蛋白和p16蛋白在不同病变组织中的表达显示二者正相关,其Person相关系数为0.970,P值为0.030(双侧)。
结论:
(1)FHIT蛋白和p16蛋白在OSF伴发口腔癌组织中表达下调和缺失,可能是OSF癌变过程中的早期表现。
(2)FHIT蛋白和p16蛋白在OSF及其伴发口腔癌组织中的表达呈显著正相关,表明两者可能有协同作用,共同参与OSF癌变的过程。
Objective:
To investigate the expression of FHIT and p16 protein in oral submucous fibrosis(OSF)and oral submucous fibrosis concomitant with oral squamous cell carcinoma(OSCC),and to evaluate their possible roles in carcinogenesis of OSF.
Methods:
Immunohistochemical staining by SP methods was utilized to detect the expression of FHIT,p16 in 44 cases of OSF,15 cases of oral submucous fibrosis concomitant with OSCC and 8 cases of normal control oral mucosa tissue.
Results:
(1)The positive rates of FHIT in normal tissues,OSF and OSF concomitant with OSCC are 87.5%,70.4%40.0%respectively. The differences which in expression between normal tissues group and carcinogenesis of OSF group,between OSF group and OSF concomitant with OSCC group are statistically significant (P＜0.05).
(2)The positive rates of p16 in normal tissues,OSF and OSF concomitant with OSCC are 100.0%,72.7%,40.0%respectively. The differences which in expression between normal tissues group and carcinogenesis of OSF group,between OSF group and OSF concomitant with OSCC group are statistically significant (P＜0.05).
(3)The expressions of FHIT are corresponding higher than the expression of p16 among the five groups,the differences are statistically significant(P＜0.05).There are positive correlation between the expression of FHIT and p16 in OSF and OSF concomitant with OSCC group(r=0.970,P＜0.05).
Conclusions:
(1)The loss of FHIT or p16 is likely to be an early occurrence in the carcinogenesis of OSF.
(2)The positive correlation between the expression of FHIT and P16 demonstrats that they may act together promoting the carcinogenesis of OSF.
引文
[1]Rajalalitha P,ValiS.Molecular pathogenesis of oral submucous fibrosis acollagen metabolic disorder.J Oral Pathol Med,2005,34(6):321-8.
[2]Reichart PA.Oral precancerous conditions-an overview.Mund Kiefer Gesichtschir,2003;7(4):201-207.
[3]Ho PS,Ko YC,Yang YH,The incidience of oropharyneal cancer in Twaiwan:an endemic betel quid chewing area.Oral Pathol Med,2002,31(4):213-21
[4]Yang YH,Chen CH,Chang JSF et al.Incidence rates of oral cancer and oral precancercous lesion in a 6-year follow-up study of a Taiwanese aboriginal community.J Oral Pathol Med,2005,34:596-601.
[5]高义军,凌天牖,尹晓敏,等.口腔黏膜下纤维性变癌变的回顾性研究.临床口腔医学杂志,2005:21(2):119-120.
[6]Jeng JH,Hahn LJ,Lin BR,et al.Effects of areca nut,inflorescence piper betle extracts and arecoline on cytotoxicity,total and unscheduled DNA synthesis in cultured gingival keratinocytes.J Oral Pathol Med.1999;28(2):64-71.
[7]Chang YC,Tai KW,Cheng MH,et al.Cytotoxic and non-genotoxic effects of arecoline on human buccal fibroblasts in vitro.J Oral Pathol Med.1998;27(2):68-71.
[8]Lee PH,Chang MC,Chang WH,etal.Prolonged exposure to arecoline arrested human KB epithelial cell growth:Regulatory mechanisms of cell cycle and apoptosis.Toxicology.2006;Jan 11.
[9]Jeng JH,Chang MC,Hahn LJ.Role of areca nut in betel quid-associated chemical carcinogenesis:current awareness and future perspectives.Oral Oncol.2001;37(6):477-492.
[10]Ohta M,Inoue,Cotticelli MG,et al.The FHIT gene,spanning the chromosome 3p14.2 fragile site and renal carcinoma-associated t(3; 8)breakpoint,is abnormal in digestive tractcancers.Cell,1996,84(4):587-597.
[11]Sozzi G,Pastorino U,Moiraghi L,et al.Loss of FHIT function in lung cancer and preinvasive bronchial lesions.Cancer Res,1998,58(22):5032-5037.
[12]Tomizawa Y,Nakajima T,Kohno T,et al.Clinicopathological significance of FHIT protein expression in stage Ⅰ non_small cell lung carcinoma.Cancer Res,1998,58(23):5478-5483.
[13]Zhao P,Liu W,Lu YL,et al.Clinicopathological significance of FHIT protein expression in gastric adenocarcinoma patients World J Gastroenterol,2005,11(36):5735-5738.
[14]Arun B,Kilic G,Yen C.Loss of FHIT expression in breast cancer is correlated with poor prognostic markers.Cancer Epidemiol Biomarkers Prev,2005,14(7):1681-1685.
[15]王萍,张庆,王祖义,等.非小细胞肺癌组织中FHIT和p16基因表达的研究.癌变畸变突变.2007,19(3):0242-0245.
[16]IshiiH,Dumon K R,Vecchione A,et a.1 Effect of adenoviral transduction of the fragile histidine triad gene into esophageal cancer cells.CancerRes,2001,61(4):1578-1584.
[17]谷建琦,张英怀,杨威.脆性组氨酸三聚体蛋白在口腔鳞状细胞癌中的表达及意义.北京口腔医学,2006,14(4):241-243.
[18]Kamb A,Gruis NA,Weaver FJ,et al.A cell cycle regulator potentially involved in genesis of many tumor types.Science,1994,264(5157):436.
[19]Nobori T,Miura K,Wu DJ,et al.Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers.Nature,1994,368(6473):753.
[20]Marx J.New tumor suppressor may rival p53.Science,1994,264(5157):344-5.
[21]Klaes R,Friedrich T,Spitkovsky D,et al.Overexpression of p16INK4aas a specific marker for dysplastic and neoplastic epithelial cellsofthe cercixuteri.Int J Cancer,2001,92(2):276-284
[22]Serrano M,Harmon GJ,Beach D.A new regulatory motif in cell cycle control causing specific inhibition of cyclin D/CDK4.Nature,1993,366(16):704-707.
[23]Kamb A,Gruis NA,Feldhaus JW,et al.A cell cycle regular potentially involved in genesis of many tumao types.Science,1994,264(15):436-440.
[24]刘宏伟,胡碧琼,曹采芳,等.p16和p53蛋白在口腔白斑和鳞状细胞癌中表达的比较研究.现代口腔医学杂志,2005,19(6):607-11.
[25]Toledo G,Sola JJ,hozano MD,et al.Loss of FHIT protein expression is related to high proliferation,low apoptosis and worse prognosis in non-small-cell-lung cancer.Mod Pathol,2004,17(4):440-448.
[26]AskariM D,Vo-Dinh T.Implication ofmitochondrial involvement in apoptotic activity of fragile histidine triad gene:application of synchronous luminescence spectroscopy.Biopolymers,2004,73(4):510-523.
[27]Salehi Z,Geffers L,Vilena C,et a.1 A nuclear protein in Schizosaccharomyces probe with homology to the human tumor supressor Fhit has decapping activity.Molecular Microbiology,2002,46(1):49-6.
[28]Barnes L D,Garrison P N,Siprashrili Z,eta.1 Fhit a putative tumorsuppressor in humans,is a dinucleside 5,5″-p,1 p3-triphosphate hydrolase.Biochemistry,1996,35(36):11529-11535.
[29]SevignaniC,Calin G A,CesafiR,eta.1 Restoration of fragile histidine trim(FHIT)expression induces apoptesis and supresses turnof-genicity inbreastCallcer cellines.CancerRes,2003,63(6):1183-1187.
[30]ChaudhuriA R,Khan IA,Prasad V,et a.1 The tumor suppressor protein Fhit.A novel interaction with tubulin.J Biol Chem,1999,274(34):24378-24382.
[31] Laurav, Michele S, Susanne M, et al. FHIT gene alterations in head and neck squamous cell carcinomas . Proc Natl Acad Sci USA, 1996, 93(18): 9770-9775.
[32] Gonzez MV, Pellomf, Ablanedo P, et al. Chromosome 3p loss of heterozygosity and mutation analysis of the FHIT and beta-cat genes in squamous cell carcinoma of the head and neck . J Clin Pathol, 1998, 51 (7): 520-524
[33] Mao L. Molecular changes in early carcinogenesis of the lung. Lung Cancer, 2000, 29(Suppl2):40-58.
[34] Ramesh R, Saeki T, Templeton NS,et al. Successful treatment of primary and disseminated human lung cancer by systemic delivery of tumor suppressor genes using an improved liposome vector. Mol Ther, 2001, 3 (3): 337-350.
[35] Chang KW, Kao S Y, Tzeng R J, et al. Multiple molecular alterations of FHIT in betel-associated oral carcinoma. J Pathol, 2002, 196 (3): 300-306.
[36] Uzawan, Akanuma D, Negishi A, et al. Homozygous deletions on the short arm of chromosome 3 in human oral squamous cell carcinomas. Oral Oncol, 2001, 37 (4): 351-356.
[37] Kannan K, Munirajan A K, Bhuvarahamurthy V, et al. FHIT gene mutations and single nucleotide polymorphism in Indian oral and cervical squamous cell carcinomas. Oral Oncol, 2000, 36 (2):189-193.
[38] Pateromichelakis S, Lee G, Langdon J D, et al. The FHITgene in oral squamous cell carcinoma: allelic imbalance is frequent but cDNA aberrations are uncommon. Oral Oncol, 2000, 36 (2):180-188.
[39] Partridgem, Emiliong, Pateromichelakis S, et al. Location of candidate tumour suppressorgene loci at chromosomes 3p, 8p and 9p for oral squamous cell carcinomas. Int J Cancer, 1999, 83 (3):318-325.
[40] Vanheerden WF, Swart TJ, Vanheerdenmb, et al. FHITprotein expression in oral epithelium: immunohistochemical evaluation of three antisera.Anticancer Res,2001,21(4A):2419-2423.
[41]Tanimoto K,Hayashi S,Tsuchiya E,et al.Abnormalities of the FHIT gene in human oral carcinogenesis.Br J Cancer,2000,82(4):838-843
[42]王萍,张庆,王祖义,等.非小细胞肺癌组织中FHIT和p16基因表达的研究.癌变畸变突变,2007,19(3)0242-0245.
[43]SanoT,Oyama T,Kshiwabara K,et al.Expression status of p16protein is associatedwith human papillomavirus oncogenic potenial in cervical and genital lesions.Am J Patho,1 1998,153(6):1741-1748
[44]Kato A,Shimizu K,Shimoichi Y et al.Aberrant DNA methylation of E-cadherin and p16genesinratlung adeno-carcinomas induced by N-nitrosobis(2-hydroxypropyl)a-mine.Molecular Carcinogenesis,2006,45(2):106
[45]Wu MF,Cheng YW,Lai JC et al.Frequent p16INK4a promoter hypermethylation in human papillomavirus-infected female lung cancer in Taiwan.International Journal of Cancer,2005,113(3):440
[46]Lin SY,Yeh KT,Chen WTL et al.Promoter CpG methylation of tumor suppressor genes in colorectal cancer and its relationship to clinical features.Oncology Reports,2004,11(2):341
[47]于卫芳,张立伟,孟霞,等.食管鳞状上皮癌变过程中p16与Fhit的表达及其意义.中国综合临床.2006,22(1):13-15
[1]OhtaM,InoueH,CotticelliM G,et a.l The FHIT gene,span ning the chromosome 3p14.2 fragile site and renal carcinoma-as-sociated t(3.8)breakpoint is abnormal in digestive tract cancers.Cel,1 1996,84(4):587-597.
[2]Barnes L D,Garrison P N,Siprashrili Z,et a.l Fhit a putative tumorsuppressor in humans,is a dinucleside 5,5″-p,1 p3-triphosphate hydrolase.Biochemistry,1996,35(36):11529-11535.
[3]AskariM D,Vo-Dinh T.Implication ofmitochondrial involvement in apoptotic activity of fragile histidine triad gene:application of synchronous luminescence spectroscopy.Biopolymers,2004,73(4):510-523.
[4]SevignaniC,Calin G A,CesafiR,eta.1 Restoration of fragile histidine trim(FHIT)expression induces apoptesis and supresses turn of genicity inbreastCallcer cellines.CancerRes,2003,63(6):1183-1187.
[5]ChaudhuriA R,Khan IA,Prasad V,et a.l The tumor suppress or protein Fhit.A novel interaction with tubulin.J Biol Chem,1999,274(34):24378-24382.
[6]Druck T,Hadaczek P,Fu TB,et al.Structure and expression of the human FHIT gene in normal and tumor cell.Cancer Res,1997,57:5045
[7]Mao L.Molecular changes in early carcinogenesis of the lung.Lung Cancer,2000,29(Supp12):40-58.
[8]Ramesh R,Saeki T,Templeton NS,et al.Successful treatment of primary and disseminated human lung cancer by systemic delivery of tumor suppressor genes using an improved liposome vector.Mol Zher,2001,3(3):337-350.
[9]王萍,张庆,王祖义,等.非小细胞肺癌组织中FHIT和p16基因表达的研究.癌变畸变突变,2007,19(3)0242-0245.
[10]Denison SR,Wang F,Becker NA,et al.Alterations in the common fragile site gene Parkin in overian and other cancers.Oncogene,2003,22(51):8307-8378.
[11]Buttitta F,Marchetti A,Radi O,et al.Evaluation of FHIT gene alter-atins in ovarian cancer.Br J Cancer,1998,77(7):1048-1054.
[12]Manderson EN,Presneau N,Provencher D,et al.Comparative analysis of loss of heterozygosity of specific chromosome 3,13,17,and X loci and Tp53 mutations in human Epithelial ovarian cancer.Mol Carcinog,2002,34(2):78-90.
[13]Mandai M,Konishi I,Kuroda H,et al.Expression of abnormal transcrips of the FHIT(fragile histidine triad)gene in ovarian carcinoma.Eur J Cancer,1998,34(5):745-749.
[14]Ozaki K,Enomoto T,Yoshino K,et al.Impaired Fhit expression characterizes serous ovarian carcinoma.Br J Cancer,2001,85(2):247-254.
[15]Wistuba II,Montellano FD,Milchgrub S,et al.Deletions of chromosome 3p are frequent and early events in the pathogenesis of uterine cervical carcinoma.Cancer Res,1997,57:3154-3158.
[16]Butler D,Collins C,Mabruk M,et al.Deletion of the FHIT gene in neoplastic and invasive cervical lesions is related ti high risk HPV infection but is independent of histopathological features.J Pathol,2000,192:502-510.
[17]Nakagawa S,Yoshikawa H,Kimura M,et al.A possible in volvement of the uterine cervix.Br J Cancer, 1999, 79:589-594.
[18] Ji L, Fang B, Yen N, et al. Induction of apoptosis and inhibition of tumor igenicity and tumor growth by adenovirus vector-mediated fragile histidine triad(FHIT) gene overexpression. Cancer Res ,1999,59:3333-3339.
[19] Van Heerden WF, Swart TJ, Robson B, et al. FHIT RNA and protein expression in oral squamous cell carcinoma. Anticancer Res, 2001, 21 (4): 2425-2428.
[20] Chang K W, Kao S Y, Tzeng R J, et al. Multiple molecular alterations of FHIT in betel-associated oral carcinoma. J Pathol, 2002, 196(3) :300-306.
[21] Uzawa N, Akanum D, Negishi A, et al. Homozygous deletions on the short arm of chromosome 3 in human oral squamous cell carcinomas. Oral Oncol, 2001,37 (4): 351-356.
[22] Kannan K, Munirajan A K, Bhuvarahamurthy V, et al. FHIT gene mutations and single nucleotide polymorphism in Indian oral and cervical squamous cell carcinomas. Oral Oncol, 2000, 36 (2): 189 - 193.
[23] Pateromichelakis S, Lee G, Langdon J D, et al. The FHIT gene in oral squamous cell carcinoma: allelic imbalance is frequent but cDNA aberrations are uncommon. Oral Oncol, 2000, 36 (2):180- 188.
[24] Partridge M, Emilion G, Pateromichelakis S, et al. Location of candidate tumour suppressor gene loci at chromosomes 3p, 8p and 9p for oral squamous cell carcinomas. Int J Cancer, 1999, 83 (3) :318 - 325.
[25] Van Heerden WF, Swart TJ, Van Heerden MB, et al. FHIT protein expression in oral epithelium: immunohistochemical evaluation of three antisera. Anticancer Res, 2001,21:2419-2423.
[26] Tanimoto K, Hayashi S, Tsuchiya E, et al. Abnormalities of the FHIT gene in human oral carcinogenesis. Br J Cancer, 2000, 82 (4): 838- 843.
[27]PichiorriF,Trapasso F,PalumboT,et a.l Preclinical assessment of FHIT gene replacement therapy in human leukemia using a chimeric adenovirus,Ad5/F35.Clin Cancer Res,2006,12(11 Pt1):3494-3501.
[28]IshiiH,VecchioneA,FongLY,et a.l Cancer prevention and therapy in a preclinicalmousemode:1 impact of FHIT viruses.Curr Gene Ther,2004,4(1):53-63.
[29]AndrianiF,Perego P,CareniniN,et a.l Increased sensitivity to cisplatin in non-small cell lung cancer cell lines after FHIT gene transfer.Neoplasia,2006,8(1):9-17.
[30]SurranoM,Hannon GJ,Beach D.Anewregulatorymotifin cell-cycle control cousing specific inhibition of cyclin D/CDK4.Nature,1993,336(6456):704-707
[31]MarxJA.challengetopl6 geneasa major tumor suppressor.Science,1994,264(5167):1846.
[32]陆哲明.P16抑癌基因的发现与研究.国外医学:肿瘤学分册,1995,22(6):321-323.
[33]Kamb,GruisN,Weaver-FeldausJ.etal.A cell cycle regulator potentially in Volve dingenesis of many tumor types,suence,1994,264(5157):436-440
[34]Plass C.Cancer epigenomics[J].HumMol Genet,2002.11(20):2749-2488.
[35]Kato A,Shimizu K,Shimoichi Y et al.Aberrant DNA methylation of E-cadherin and p16genesinratlung adeno-carcinomas induced by N-nitrosobis(2-hydroxypropyl)a-mine.Molecular Carcinogenesis,2006,45(2):106
[36]Wu MF,Cheng YW,Lai JC et al.Frequent p16INK4a promoter hypermethylation in human papillomavirus-infected female lung cancer in Taiwan.International Journal of Cancer,2005,113(3):440
[37]Cirincione R,Lintas C,Conte D et al.Methylation profile in tumor and sputum samples of lung cancer patients detected by spiral computed tomography:A nested case-control study.International Journal of Cancer,2006,118(5):124
[38]Chang KW,Kao S Y,Tzeng R J,et al.Multiple molecular alterations of FHIT in betel-associated oral carcinoma.J Pathol,2002,196(3):300-306.
[39]Kim NR,Lin ZH,Kim KR et al.Epstein-Barr virus and p16(INK4a)methylation in squamous cell carcinoma and precancerous lesions of the cervix uteri.Journal of Korean Medical Science,2005,20(4):63
[40]Ishikawa M,Fujii T,Saito M et al.Overexpression of p16(INK4a)as an indicator for human papillomavirus oncogenic activity in cervical squamous neoplasia.International Journal of Gynecological Cancer,2006,16(1):347
[41]黄勇,唐艳.CIN和宫颈浸润癌组织中p16~(INK4a)蛋白表达检测的意义.四川医学,2008,29(1):40-42.
[42]Ichidaw a Y,Yo shidas US,Koyam a Y,et al.Inac2ti2 vation of p16 CDK2 and clinical stages of primary o2 varian tumors.Int J Cancer,1996,69(6):466-470.
[43]LinSC,Chang KW,Chang CS,et al.Alterations of P16/MTS1 gene in oral squamous cell carcinomas from Taiwanese.J Oral Pathol Med,2000,29(4):159-166.
[44]NakaharaY,ShintaniS,MiharaM,etal.High frequency of homozygous deletion andmethylation ofp16(INK4A)gene in oral squamous cell carcinomas.Cancer Lett,2001,163(2):221
[45]米贤军,杨接辉,李政,等.乳腺癌组织蛋白酶D、c-erbB-2、P53、nm23蛋白表达与淋巴结转移的关系.实用医学杂志,2007,23(14):2150-52.
[46]Lin SY,Yeh KT,Chen WTL et al.Promoter CpG methylation of tumor suppressor genes in colorectal cancer and its relationship to clinical features.Oncology Reports,2004,11(2):341
[47]于卫芳,张立伟,孟霞,等.食管鳞状上皮癌变过程中p16与Fhit的表达及其意义.中国综合临床,2006,22(1):13-15
[2]Reichart PA.Oral precancerous conditions-an overview.Mund Kiefer Gesichtschir,2003;7(4):201-207.
[3]Ho PS,Ko YC,Yang YH,The incidience of oropharyneal cancer in Twaiwan:an endemic betel quid chewing area.Oral Pathol Med,2002,31(4):213-21
[4]Yang YH,Chen CH,Chang JSF et al.Incidence rates of oral cancer and oral precancercous lesion in a 6-year follow-up study of a Taiwanese aboriginal community.J Oral Pathol Med,2005,34:596-601.
[5]高义军,凌天牖,尹晓敏,等.口腔黏膜下纤维性变癌变的回顾性研究.临床口腔医学杂志,2005:21(2):119-120.
[6]Jeng JH,Hahn LJ,Lin BR,et al.Effects of areca nut,inflorescence piper betle extracts and arecoline on cytotoxicity,total and unscheduled DNA synthesis in cultured gingival keratinocytes.J Oral Pathol Med.1999;28(2):64-71.
[7]Chang YC,Tai KW,Cheng MH,et al.Cytotoxic and non-genotoxic effects of arecoline on human buccal fibroblasts in vitro.J Oral Pathol Med.1998;27(2):68-71.
[8]Lee PH,Chang MC,Chang WH,etal.Prolonged exposure to arecoline arrested human KB epithelial cell growth:Regulatory mechanisms of cell cycle and apoptosis.Toxicology.2006;Jan 11.
[9]Jeng JH,Chang MC,Hahn LJ.Role of areca nut in betel quid-associated chemical carcinogenesis:current awareness and future perspectives.Oral Oncol.2001;37(6):477-492.
[10]Ohta M,Inoue,Cotticelli MG,et al.The FHIT gene,spanning the chromosome 3p14.2 fragile site and renal carcinoma-associated t(3; 8)breakpoint,is abnormal in digestive tractcancers.Cell,1996,84(4):587-597.
[11]Sozzi G,Pastorino U,Moiraghi L,et al.Loss of FHIT function in lung cancer and preinvasive bronchial lesions.Cancer Res,1998,58(22):5032-5037.
[12]Tomizawa Y,Nakajima T,Kohno T,et al.Clinicopathological significance of FHIT protein expression in stage Ⅰ non_small cell lung carcinoma.Cancer Res,1998,58(23):5478-5483.
[13]Zhao P,Liu W,Lu YL,et al.Clinicopathological significance of FHIT protein expression in gastric adenocarcinoma patients World J Gastroenterol,2005,11(36):5735-5738.
[14]Arun B,Kilic G,Yen C.Loss of FHIT expression in breast cancer is correlated with poor prognostic markers.Cancer Epidemiol Biomarkers Prev,2005,14(7):1681-1685.
[15]王萍,张庆,王祖义,等.非小细胞肺癌组织中FHIT和p16基因表达的研究.癌变畸变突变.2007,19(3):0242-0245.
[16]IshiiH,Dumon K R,Vecchione A,et a.1 Effect of adenoviral transduction of the fragile histidine triad gene into esophageal cancer cells.CancerRes,2001,61(4):1578-1584.
[17]谷建琦,张英怀,杨威.脆性组氨酸三聚体蛋白在口腔鳞状细胞癌中的表达及意义.北京口腔医学,2006,14(4):241-243.
[18]Kamb A,Gruis NA,Weaver FJ,et al.A cell cycle regulator potentially involved in genesis of many tumor types.Science,1994,264(5157):436.
[19]Nobori T,Miura K,Wu DJ,et al.Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers.Nature,1994,368(6473):753.
[20]Marx J.New tumor suppressor may rival p53.Science,1994,264(5157):344-5.
[21]Klaes R,Friedrich T,Spitkovsky D,et al.Overexpression of p16INK4aas a specific marker for dysplastic and neoplastic epithelial cellsofthe cercixuteri.Int J Cancer,2001,92(2):276-284
[22]Serrano M,Harmon GJ,Beach D.A new regulatory motif in cell cycle control causing specific inhibition of cyclin D/CDK4.Nature,1993,366(16):704-707.
[23]Kamb A,Gruis NA,Feldhaus JW,et al.A cell cycle regular potentially involved in genesis of many tumao types.Science,1994,264(15):436-440.
[24]刘宏伟,胡碧琼,曹采芳,等.p16和p53蛋白在口腔白斑和鳞状细胞癌中表达的比较研究.现代口腔医学杂志,2005,19(6):607-11.
[25]Toledo G,Sola JJ,hozano MD,et al.Loss of FHIT protein expression is related to high proliferation,low apoptosis and worse prognosis in non-small-cell-lung cancer.Mod Pathol,2004,17(4):440-448.
[26]AskariM D,Vo-Dinh T.Implication ofmitochondrial involvement in apoptotic activity of fragile histidine triad gene:application of synchronous luminescence spectroscopy.Biopolymers,2004,73(4):510-523.
[27]Salehi Z,Geffers L,Vilena C,et a.1 A nuclear protein in Schizosaccharomyces probe with homology to the human tumor supressor Fhit has decapping activity.Molecular Microbiology,2002,46(1):49-6.
[28]Barnes L D,Garrison P N,Siprashrili Z,eta.1 Fhit a putative tumorsuppressor in humans,is a dinucleside 5,5″-p,1 p3-triphosphate hydrolase.Biochemistry,1996,35(36):11529-11535.
[29]SevignaniC,Calin G A,CesafiR,eta.1 Restoration of fragile histidine trim(FHIT)expression induces apoptesis and supresses turnof-genicity inbreastCallcer cellines.CancerRes,2003,63(6):1183-1187.
[30]ChaudhuriA R,Khan IA,Prasad V,et a.1 The tumor suppressor protein Fhit.A novel interaction with tubulin.J Biol Chem,1999,274(34):24378-24382.
[31] Laurav, Michele S, Susanne M, et al. FHIT gene alterations in head and neck squamous cell carcinomas . Proc Natl Acad Sci USA, 1996, 93(18): 9770-9775.
[32] Gonzez MV, Pellomf, Ablanedo P, et al. Chromosome 3p loss of heterozygosity and mutation analysis of the FHIT and beta-cat genes in squamous cell carcinoma of the head and neck . J Clin Pathol, 1998, 51 (7): 520-524
[33] Mao L. Molecular changes in early carcinogenesis of the lung. Lung Cancer, 2000, 29(Suppl2):40-58.
[34] Ramesh R, Saeki T, Templeton NS,et al. Successful treatment of primary and disseminated human lung cancer by systemic delivery of tumor suppressor genes using an improved liposome vector. Mol Ther, 2001, 3 (3): 337-350.
[35] Chang KW, Kao S Y, Tzeng R J, et al. Multiple molecular alterations of FHIT in betel-associated oral carcinoma. J Pathol, 2002, 196 (3): 300-306.
[36] Uzawan, Akanuma D, Negishi A, et al. Homozygous deletions on the short arm of chromosome 3 in human oral squamous cell carcinomas. Oral Oncol, 2001, 37 (4): 351-356.
[37] Kannan K, Munirajan A K, Bhuvarahamurthy V, et al. FHIT gene mutations and single nucleotide polymorphism in Indian oral and cervical squamous cell carcinomas. Oral Oncol, 2000, 36 (2):189-193.
[38] Pateromichelakis S, Lee G, Langdon J D, et al. The FHITgene in oral squamous cell carcinoma: allelic imbalance is frequent but cDNA aberrations are uncommon. Oral Oncol, 2000, 36 (2):180-188.
[39] Partridgem, Emiliong, Pateromichelakis S, et al. Location of candidate tumour suppressorgene loci at chromosomes 3p, 8p and 9p for oral squamous cell carcinomas. Int J Cancer, 1999, 83 (3):318-325.
[40] Vanheerden WF, Swart TJ, Vanheerdenmb, et al. FHITprotein expression in oral epithelium: immunohistochemical evaluation of three antisera.Anticancer Res,2001,21(4A):2419-2423.
[41]Tanimoto K,Hayashi S,Tsuchiya E,et al.Abnormalities of the FHIT gene in human oral carcinogenesis.Br J Cancer,2000,82(4):838-843
[42]王萍,张庆,王祖义,等.非小细胞肺癌组织中FHIT和p16基因表达的研究.癌变畸变突变,2007,19(3)0242-0245.
[43]SanoT,Oyama T,Kshiwabara K,et al.Expression status of p16protein is associatedwith human papillomavirus oncogenic potenial in cervical and genital lesions.Am J Patho,1 1998,153(6):1741-1748
[44]Kato A,Shimizu K,Shimoichi Y et al.Aberrant DNA methylation of E-cadherin and p16genesinratlung adeno-carcinomas induced by N-nitrosobis(2-hydroxypropyl)a-mine.Molecular Carcinogenesis,2006,45(2):106
[45]Wu MF,Cheng YW,Lai JC et al.Frequent p16INK4a promoter hypermethylation in human papillomavirus-infected female lung cancer in Taiwan.International Journal of Cancer,2005,113(3):440
[46]Lin SY,Yeh KT,Chen WTL et al.Promoter CpG methylation of tumor suppressor genes in colorectal cancer and its relationship to clinical features.Oncology Reports,2004,11(2):341
[47]于卫芳,张立伟,孟霞,等.食管鳞状上皮癌变过程中p16与Fhit的表达及其意义.中国综合临床.2006,22(1):13-15
[1]OhtaM,InoueH,CotticelliM G,et a.l The FHIT gene,span ning the chromosome 3p14.2 fragile site and renal carcinoma-as-sociated t(3.8)breakpoint is abnormal in digestive tract cancers.Cel,1 1996,84(4):587-597.
[2]Barnes L D,Garrison P N,Siprashrili Z,et a.l Fhit a putative tumorsuppressor in humans,is a dinucleside 5,5″-p,1 p3-triphosphate hydrolase.Biochemistry,1996,35(36):11529-11535.
[3]AskariM D,Vo-Dinh T.Implication ofmitochondrial involvement in apoptotic activity of fragile histidine triad gene:application of synchronous luminescence spectroscopy.Biopolymers,2004,73(4):510-523.
[4]SevignaniC,Calin G A,CesafiR,eta.1 Restoration of fragile histidine trim(FHIT)expression induces apoptesis and supresses turn of genicity inbreastCallcer cellines.CancerRes,2003,63(6):1183-1187.
[5]ChaudhuriA R,Khan IA,Prasad V,et a.l The tumor suppress or protein Fhit.A novel interaction with tubulin.J Biol Chem,1999,274(34):24378-24382.
[6]Druck T,Hadaczek P,Fu TB,et al.Structure and expression of the human FHIT gene in normal and tumor cell.Cancer Res,1997,57:5045
[7]Mao L.Molecular changes in early carcinogenesis of the lung.Lung Cancer,2000,29(Supp12):40-58.
[8]Ramesh R,Saeki T,Templeton NS,et al.Successful treatment of primary and disseminated human lung cancer by systemic delivery of tumor suppressor genes using an improved liposome vector.Mol Zher,2001,3(3):337-350.
[9]王萍,张庆,王祖义,等.非小细胞肺癌组织中FHIT和p16基因表达的研究.癌变畸变突变,2007,19(3)0242-0245.
[10]Denison SR,Wang F,Becker NA,et al.Alterations in the common fragile site gene Parkin in overian and other cancers.Oncogene,2003,22(51):8307-8378.
[11]Buttitta F,Marchetti A,Radi O,et al.Evaluation of FHIT gene alter-atins in ovarian cancer.Br J Cancer,1998,77(7):1048-1054.
[12]Manderson EN,Presneau N,Provencher D,et al.Comparative analysis of loss of heterozygosity of specific chromosome 3,13,17,and X loci and Tp53 mutations in human Epithelial ovarian cancer.Mol Carcinog,2002,34(2):78-90.
[13]Mandai M,Konishi I,Kuroda H,et al.Expression of abnormal transcrips of the FHIT(fragile histidine triad)gene in ovarian carcinoma.Eur J Cancer,1998,34(5):745-749.
[14]Ozaki K,Enomoto T,Yoshino K,et al.Impaired Fhit expression characterizes serous ovarian carcinoma.Br J Cancer,2001,85(2):247-254.
[15]Wistuba II,Montellano FD,Milchgrub S,et al.Deletions of chromosome 3p are frequent and early events in the pathogenesis of uterine cervical carcinoma.Cancer Res,1997,57:3154-3158.
[16]Butler D,Collins C,Mabruk M,et al.Deletion of the FHIT gene in neoplastic and invasive cervical lesions is related ti high risk HPV infection but is independent of histopathological features.J Pathol,2000,192:502-510.
[17]Nakagawa S,Yoshikawa H,Kimura M,et al.A possible in volvement of the uterine cervix.Br J Cancer, 1999, 79:589-594.
[18] Ji L, Fang B, Yen N, et al. Induction of apoptosis and inhibition of tumor igenicity and tumor growth by adenovirus vector-mediated fragile histidine triad(FHIT) gene overexpression. Cancer Res ,1999,59:3333-3339.
[19] Van Heerden WF, Swart TJ, Robson B, et al. FHIT RNA and protein expression in oral squamous cell carcinoma. Anticancer Res, 2001, 21 (4): 2425-2428.
[20] Chang K W, Kao S Y, Tzeng R J, et al. Multiple molecular alterations of FHIT in betel-associated oral carcinoma. J Pathol, 2002, 196(3) :300-306.
[21] Uzawa N, Akanum D, Negishi A, et al. Homozygous deletions on the short arm of chromosome 3 in human oral squamous cell carcinomas. Oral Oncol, 2001,37 (4): 351-356.
[22] Kannan K, Munirajan A K, Bhuvarahamurthy V, et al. FHIT gene mutations and single nucleotide polymorphism in Indian oral and cervical squamous cell carcinomas. Oral Oncol, 2000, 36 (2): 189 - 193.
[23] Pateromichelakis S, Lee G, Langdon J D, et al. The FHIT gene in oral squamous cell carcinoma: allelic imbalance is frequent but cDNA aberrations are uncommon. Oral Oncol, 2000, 36 (2):180- 188.
[24] Partridge M, Emilion G, Pateromichelakis S, et al. Location of candidate tumour suppressor gene loci at chromosomes 3p, 8p and 9p for oral squamous cell carcinomas. Int J Cancer, 1999, 83 (3) :318 - 325.
[25] Van Heerden WF, Swart TJ, Van Heerden MB, et al. FHIT protein expression in oral epithelium: immunohistochemical evaluation of three antisera. Anticancer Res, 2001,21:2419-2423.
[26] Tanimoto K, Hayashi S, Tsuchiya E, et al. Abnormalities of the FHIT gene in human oral carcinogenesis. Br J Cancer, 2000, 82 (4): 838- 843.
[27]PichiorriF,Trapasso F,PalumboT,et a.l Preclinical assessment of FHIT gene replacement therapy in human leukemia using a chimeric adenovirus,Ad5/F35.Clin Cancer Res,2006,12(11 Pt1):3494-3501.
[28]IshiiH,VecchioneA,FongLY,et a.l Cancer prevention and therapy in a preclinicalmousemode:1 impact of FHIT viruses.Curr Gene Ther,2004,4(1):53-63.
[29]AndrianiF,Perego P,CareniniN,et a.l Increased sensitivity to cisplatin in non-small cell lung cancer cell lines after FHIT gene transfer.Neoplasia,2006,8(1):9-17.
[30]SurranoM,Hannon GJ,Beach D.Anewregulatorymotifin cell-cycle control cousing specific inhibition of cyclin D/CDK4.Nature,1993,336(6456):704-707
[31]MarxJA.challengetopl6 geneasa major tumor suppressor.Science,1994,264(5167):1846.
[32]陆哲明.P16抑癌基因的发现与研究.国外医学:肿瘤学分册,1995,22(6):321-323.
[33]Kamb,GruisN,Weaver-FeldausJ.etal.A cell cycle regulator potentially in Volve dingenesis of many tumor types,suence,1994,264(5157):436-440
[34]Plass C.Cancer epigenomics[J].HumMol Genet,2002.11(20):2749-2488.
[35]Kato A,Shimizu K,Shimoichi Y et al.Aberrant DNA methylation of E-cadherin and p16genesinratlung adeno-carcinomas induced by N-nitrosobis(2-hydroxypropyl)a-mine.Molecular Carcinogenesis,2006,45(2):106
[36]Wu MF,Cheng YW,Lai JC et al.Frequent p16INK4a promoter hypermethylation in human papillomavirus-infected female lung cancer in Taiwan.International Journal of Cancer,2005,113(3):440
[37]Cirincione R,Lintas C,Conte D et al.Methylation profile in tumor and sputum samples of lung cancer patients detected by spiral computed tomography:A nested case-control study.International Journal of Cancer,2006,118(5):124
[38]Chang KW,Kao S Y,Tzeng R J,et al.Multiple molecular alterations of FHIT in betel-associated oral carcinoma.J Pathol,2002,196(3):300-306.
[39]Kim NR,Lin ZH,Kim KR et al.Epstein-Barr virus and p16(INK4a)methylation in squamous cell carcinoma and precancerous lesions of the cervix uteri.Journal of Korean Medical Science,2005,20(4):63
[40]Ishikawa M,Fujii T,Saito M et al.Overexpression of p16(INK4a)as an indicator for human papillomavirus oncogenic activity in cervical squamous neoplasia.International Journal of Gynecological Cancer,2006,16(1):347
[41]黄勇,唐艳.CIN和宫颈浸润癌组织中p16~(INK4a)蛋白表达检测的意义.四川医学,2008,29(1):40-42.
[42]Ichidaw a Y,Yo shidas US,Koyam a Y,et al.Inac2ti2 vation of p16 CDK2 and clinical stages of primary o2 varian tumors.Int J Cancer,1996,69(6):466-470.
[43]LinSC,Chang KW,Chang CS,et al.Alterations of P16/MTS1 gene in oral squamous cell carcinomas from Taiwanese.J Oral Pathol Med,2000,29(4):159-166.
[44]NakaharaY,ShintaniS,MiharaM,etal.High frequency of homozygous deletion andmethylation ofp16(INK4A)gene in oral squamous cell carcinomas.Cancer Lett,2001,163(2):221
[45]米贤军,杨接辉,李政,等.乳腺癌组织蛋白酶D、c-erbB-2、P53、nm23蛋白表达与淋巴结转移的关系.实用医学杂志,2007,23(14):2150-52.
[46]Lin SY,Yeh KT,Chen WTL et al.Promoter CpG methylation of tumor suppressor genes in colorectal cancer and its relationship to clinical features.Oncology Reports,2004,11(2):341
[47]于卫芳,张立伟,孟霞,等.食管鳞状上皮癌变过程中p16与Fhit的表达及其意义.中国综合临床,2006,22(1):13-15