新疆维吾尔族妇女宫颈上皮内瘤变及宫颈癌中FHIT、p16~（INK4a）、RARB蛋白表达及意义
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摘要
目的探讨脆性组氨酸三联体(fragile histidine triad ,FHIT)、p16~(INK4a)与视黄酸受体β(retinoic acid receptor-beta,RARB)蛋白在新疆维吾尔族妇女宫颈上皮内瘤变(cervical intra-epithelial neoplasia,CIN)及宫颈癌中的表达及其意义。方法采用免疫组化链酶卵白素-辣根过氧化物酶(SP)法检测20例慢性宫颈炎、30例CIN(CINⅠ10例、CINⅡ10例、CINⅢ10例)以及40例浸润性宫颈鳞癌组织标本中FHIT、p16~(INK4a)及RARB蛋白的表达。结果(1)FHIT蛋白阳性表达率依次为慢性宫颈炎(90.00%)>CIN(66.67%)>浸润性宫颈鳞癌(27.50%),差异具有统计学意义(P=0.000);p16~(INK4a)蛋白阳性表达率依次为浸润性宫颈鳞癌(82.50%)>CIN(46.67%)>慢性宫颈炎(0.00%),差异都具有统计学意义(P=0.000);RARB蛋白阳性表达率依次为浸润性宫颈鳞癌(90.00%)>CIN(53.33%)>慢性宫颈炎(10.00%),差异都具有统计学意义(P=0.000)。(2)在宫颈各组织中,FHIT蛋白与p16~(INK4a)蛋白表达呈负相关(r =-0.384,P=0.000);FHIT蛋白与RARB蛋白表达呈负相关(r =-0.291,P=0.006);p16~(INK4a)蛋白与RARB蛋白表达呈正相关(r = 0.445,P =0.000)。结论抑癌基因FHIT表达缺失与p16~(INK4a)和RARB过度表达与宫颈癌的发生发展密切相关,并且FHIT、p16~(INK4a)、RARB具有协同作用。FHIT蛋白与p16~(INK4a)蛋白和RARB蛋白的联合检测可作为宫颈癌早期诊断和宫颈癌进展的分子指标。
Objective To stdudy expression and clinical significance of the fragile histidine triad (fragile histidine triad, FHIT), p16~(INK4a) and retinoic acid receptorβ(retinoic acid receptor-beta, RARB) protein in the Xinjiang Uygur women cervical intraepithelial neoplasia (cervical intra-epithelial neoplasia , CIN) and cervical cancer. Methods Using immunohistochemical streptomycin avidin-peroxidase link (SP) method to detect expression of FHIT, p16~(INK4a) and RARB protein of 20 cases of chronic cervicitis, 30 cases of CIN (CINⅠ10, CINⅡ10, CINⅢ10) and 40 cases of invasive cervical squamous cell carcinoma specimens. Results (1) FHIT protein expression was followed by chronic cervicitis (90.00%) > CIN (66.67%) > invasive cervical squamous cell carcinoma (27.50%) and the difference was statistically significant (P = 0.000);Expression of p16~(INK4a) and RARB protein was followed by invasive cervical squamous cell carcinoma (82.50%; 90.00%) > CIN (46.67%; 53.33%) > chronic cervicitis (0.00%; 10.00%) and the difference is statistically significant (P = 0.000; P = 0.000). (2) In Various cervix uteritissue, the expression of FHIT and p16~(INK4a) protein was negatively correlated (r = -0.384, P = 0.000); The expression of FHIT and RARB was negatively correlated (r = -0.291, P = 0.006); The expression of p16~(INK4a) and RARB protein was positively correlated (r = 0.445, P = 0.000). Conclusion Expression and deletion of tumor suppressor gene - FHIT and overexpression p16~(INK4a) and RARB is closely related to the genesis and development of cervical cancer. The protein of FHIT, p16~(INK4a) and RARB have a synergistic effect in cervical cancer. The detection FHIT, p16~(INK4a) and RARB protein can be considered as a early detection index of cervical cancer and progress of cervical cancer.
Objective To stdudy expression and clinical significance of the fragile histidine triad (fragile histidine triad, FHIT), p16~(INK4a) and retinoic acid receptorβ(retinoic acid receptor-beta, RARB) protein in the Xinjiang Uygur women cervical intraepithelial neoplasia (cervical intra-epithelial neoplasia , CIN) and cervical cancer. Methods Using immunohistochemical streptomycin avidin-peroxidase link (SP) method to detect expression of FHIT, p16~(INK4a) and RARB protein of 20 cases of chronic cervicitis, 30 cases of CIN (CINⅠ10, CINⅡ10, CINⅢ10) and 40 cases of invasive cervical squamous cell carcinoma specimens. Results (1) FHIT protein expression was followed by chronic cervicitis (90.00%) > CIN (66.67%) > invasive cervical squamous cell carcinoma (27.50%) and the difference was statistically significant (P = 0.000);Expression of p16~(INK4a) and RARB protein was followed by invasive cervical squamous cell carcinoma (82.50%; 90.00%) > CIN (46.67%; 53.33%) > chronic cervicitis (0.00%; 10.00%) and the difference is statistically significant (P = 0.000; P = 0.000). (2) In Various cervix uteritissue, the expression of FHIT and p16~(INK4a) protein was negatively correlated (r = -0.384, P = 0.000); The expression of FHIT and RARB was negatively correlated (r = -0.291, P = 0.006); The expression of p16~(INK4a) and RARB protein was positively correlated (r = 0.445, P = 0.000). Conclusion Expression and deletion of tumor suppressor gene - FHIT and overexpression p16~(INK4a) and RARB is closely related to the genesis and development of cervical cancer. The protein of FHIT, p16~(INK4a) and RARB have a synergistic effect in cervical cancer. The detection FHIT, p16~(INK4a) and RARB protein can be considered as a early detection index of cervical cancer and progress of cervical cancer.
引文
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[1] Cornelison TL. Human papillomavirus genotype 16 vaccines forcervical cancer prophylaxis and treatment[ J ]. Current Opinion Oncol,2000,12: 466-473.
[2] Ferlay J, Bray F, Pisani P, et al. Cancer Incidence,Mortality and Prevalence Worldwide[ J ]. Annals of Oncology,2005,16(3):481-488.
[3] Bull Worl Health Organ . Bulletin of the World Health Organization, 2008,vol.86 no.6.Pint Issn 0042-9686.
[4] Bosch FX, Lorincz A, Munoz N, et al. The causal relation between human papillomavirus and cervical cancer [ J ]. Clin Pathol, 2002,55:244–65.
[5] Xavier Castellsagué. Natural history and epidemiology of HPV infection and cervical cancer[ J ]. Gynecologic Oncolog,2008,110(3 Suppl 2):S4-7.
[6] Roz L ,Andriani F ,Ferreira CG,et al. The apoptotic pathway triggered by the FHIT protein in lung cancer cell lines is not affected by bcl-X(L) overexpression[ J ] . Oncogene,2004,23(56):9102- 9110.
[7] Murphy GA ,Halliday D ,McLennan AG. The Fhit tumor suppres-sor protein regulates the intracellular concerntration of diadenosine triphophate but not diadenosine tetraphosphate[ J ].Cancer Res,2000,60 (9):2342-2344.
[8] Noguchi T , Takeno S , Kimura Y, et al. FHIT expression and hypermethylation in esophageal squamous cell carcinoma .Int J Mol Med,2003,11:441.
[9] Kuroki T , Trapasso F , Yendamuri S , et al. Allele loss and promoter hypermethylation of VHL , RARObeta , RASSF1A ,and FHIT tumor suppressor genes on chromosome 3p in esophageal squamous cell carcinoma[ J ].Cancer Res,2003,63:3724.
[10] Roz L ,Gramegna M ,Ishii H ,et al . Restoration of Fragile His-tidine Triad ( FHIT) Expression Induces Apoptosis Andsup-presses Tumorigenicity in Lung ang Ceuvical Cancer Cell lines[J ].Prox Natl Acad Sci USA,2002,99:3615-3620.
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[13] Holschneider CH, Baldwin RL, Tumber K, et al. The fragilehistidinetriad gene: amoleculer link between cigarette smoking and cervical cancer [ J ].Clin Cancer Res,2005,11(16):5756– 63.
[14] Bahnassy AA , Zekri AR , Madbouly MS ,et al. The correlation Between FHIT,P53 and MMR gene in human papillomavirus-associatted cervical carcinoma [ J ]. Egypt Natl Canc Inst,2006,18(3):191-202.
[15] Butler D, Collins C, Mabruk M ,et al. Loss of Fhit Expression as a potential marker of malignant progression in preinvasive squamous cervical cancer[ J ].Gynecol Oncol,2002,86(2);144-9.
[16] Longatto-Fiho A, Etlinger D, Pereira SM, et al.The association of p16(INK4A) and fragile histidine triad gene expression and cervical lesions[ J ].Low Genit Tract Dis, 2007 ,11(3):151-7.
[17] Takizawa S, Nakagawa S, Nakagawe K, et al. Abnormal Fhit expression is an Independent poor prognostic factor for cervical cancer [ J ].Br Cancer,2003, 88(8):1213-6.
[18] Yoon So. Abnormal fragile histidine triad(Fhit) expression in invasive cervical adenocarcinoma: association with tumor aggressiveness[ J ].Hum Pathol,2007, 38(2):326-31.
[19] Virmani AK, Muller C, Rathi A, et al. Aberrant methylation during cervical carcinogenesis [ J ].Clin Cancer Res,2001,7(3):584-589.
[20] Wu Y, Meng L, Wang H, et al. Regulation of DNA methytation on the expression of the FHIT gene contributes to cervical carcinoma cell tumorigenesis[ J ] .Oncol Rep, 2006,16(3):625-9.
[21] Ren CC, Miao XH, Yang B,et al. Methylation status of FHIT in plasma and expression of FHIT gene in cancer tissue of cervical cancer patients [ J ] . Zhonghua Yi Xue Yi Chuan Xue Za Zhi, 2006,23(5):565-7.
[22] Ren CC, Miao XH, Yang B, et al. Methylation status of the fregile histidine triad and E-cadherin genes in plasma of cervical cancer patients[ J ].Int Gynecol Cancer, 2006,16(5):1862-7.
[23] Neyaz MK, Kumar RS, Hussain S, et al. Effect of aberrant promoter methylation of FHIT and RASSF1A genes on susceptibility to cervical cancer in a north Indian population [ J ].Biomarkers,2008,23:1-10.
[24] Butler D, Collins C, Mabruk M, et al. Deletion of the FHIT gene in neoplastic and invastive cervical lesions is related to high-risk HPV infection but is independent of histopathological features[ J ].Pathol,2000,192(4):502-10.
[25] Zhang WM, Shuai CX, Zheng FY, et al. Expression of FHIT genes in CIN and cervical carcinoma and the relationship between FHIT gene and p53 and HPV16/18 [ J ].Zhonghua Zhong Liu Za Zhi,2006 ,28(6):452-5.
[26] Kamb A ,Gruis NA ,Waever-Frldhaus J ,et a1.A cell cycle regulator Potentially involved in genesis of many tumor types [J ].Science,1994 ,264 (5157) :436– 440.
[27] Hirama T, Koeffler HP. Role of the cyclin-dependent kinase inhibitors in the development of cancer [ J ].Blood,1995,88 (3):841～854.
[28]梁艳芳,胡新荣. HPV和P16INK4a与宫颈癌的关系研究进展[ J ].西南军医,2009,11 (4):731-733.
[29] Sano T ,Oyama T , Kshiwabara K,et a1. Explession status of p16 protein is associated with human papillomavirus oncogenic potential in cervical and genital lesion[J ].Am Pathol ,1998 ,153 (6) :1741 - 1 748.
[30] Milde Langosch K,Riethdorf S , Kraus Poppinghaus A ,et al. Expression of cyclin- dependent kinase inhibitors p16 MTS1 ,p21WAF1 ,and p27 KIPl in HPV-positive and HPV-negative cervical adenocarcinomas [ J ] .Virchows Arch ,2001,439(1):55 -61.
[31] Nakao Y, Yang X , Yokoyama M , et al. Induction of p16 during immortalization by HPV l6 and 18 and nor during malignant transfornation[J ].Br Cancer,1997,75 (3):1410-12.
[32] Braganca JF, Sarian LO, Pitta DR, et al.Expression of p16 and cervical infection with high-risk human papillomavires are not related to p53 activity in cervical intraepithelia neoplasia [ J ]. Int Gynecol Cancer, 2008, 18 (5) : 1060-1064.
[33] Alfsen GC, ReedW, Sandstad B, et al. The prognostic impact of cyclin dependent kinase inhibitors p21WAF1, P27Kip1 and p16 INK4 /MTS1 in adenocarcinomas of the uterine cervix: an immunohistochemical evaluation of expression patterns in population-based material from142 patients with international federation of gynecology and obstetricsstageⅠandⅡadenocarcinoma [J]. Cancer, 2003, 98 (9):1880 - 1889.
[34] Kim NR, L IN Z, Kim KR, et al. Epstein-Barr virus and p16 INK4A methylation in squamous cell carcinoma and precancerous lesions of the cervix uteri [ J ].Korean Med Sci,2005,20 (4):636～642.
[35] Guo M ,Hu L ,Baliga M ,et al. The predictive value of p16 INK4a and hybrid capture human papillomavirus testing for high -grade cervical intraepithelial neoplasia [ J ] . Am Clin Pathol ,2004 ,122 (6) :894 - 901.
[36] Riethdorf L , Riethdorf S , Lee KR , et al. Human papillomavinuses ,expression ofp16INK4a ,and early endocervical glandular neoplasia[J ] .Hum Pathal ,2002 ,33 (9) :899 - 904.
[37] Wirtanen L, Seguin C. Cloning of cDNAs encoding retinoic acid receptors RARγ1 , RARγ2 , and a new splicing variant, RARγ3, from Ambystoma mexicanum and characterization of their expression duringearly development [ J ]. Biochim Biophys Acta, 2000, 1492:81-93.
[38] LeidM, Kastner P, Durand H, et al. Retinoic acid signal transduction pathways [ J ]. Ann N Y Acad Sci, 1993, 684: 19-34.
[39] LeidM, Kastner P and Chambon P. Multiplicity generates diversity in the retinoic acid sinalling pathways [ J ].Trends Biochem Sci,1992,17: 427-433.
[40] Zhang X K, PfahlM. Regulation of retinoid and thyroid hormone action through homodimeric and heterodimeric receptors [ J ]. Trends Endocrinol Metab, 1993, (4) : 156-162.
[41] Toulouse A, LoubeauM,Morin J , et al. RARbeta involvement in enhancement of lung tumor cell immunogenicity revealed by array analysis [ J ]. FASEB, 2000, 14: 1224-1232.
[42] De-Castro Arce J , Gockel-Krzikalla E, Rosl F. Retinoic acid recep tor beta silences human papillomavirus18 oncogene expression by induction of denovo methylation and heterochromatinization of the viral control region[ J ].Biol Chem, 2007, 282: 28520-28529.
[43] Geisen C,Denk C, Küpper JH, et al. Growth inhibition of cervical cancer cells by the human retinoic acid receptor beta gene [ J ]. Int Cancer, 2000, 85: 289-295.
[44] Gao YP, Li M, Zhang YY et al.Relationship between RAR-beta gene expression defect and its methylation .Zhonghua Fu Chan Ke Za Zhi. 2007 Jul;42(7):472-6.
[45] Ivanova T, Petrenko A, Gritsko T et al. Methylation and silencing of the retinoic acid receptor-beta2 gene in cervical cancer[ J ].BMC Cancer. 2002 Mar 21;2:4.
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[26] Kamb A ,Gruis NA ,Waever-Frldhaus J ,et a1.A cell cycle regulator Potentially involved in genesis of many tumor types [J ].Science,1994 ,264 (5157) :436– 440.
[27] Hirama T, Koeffler HP. Role of the cyclin-dependent kinase inhibitors in the development of cancer [ J ].Blood,1995,88 (3):841～854.
[28]梁艳芳,胡新荣. HPV和P16INK4a与宫颈癌的关系研究进展[ J ].西南军医,2009,11 (4):731-733.
[29] Sano T ,Oyama T , Kshiwabara K,et a1. Explession status of p16 protein is associated with human papillomavirus oncogenic potential in cervical and genital lesion[J ].Am Pathol ,1998 ,153 (6) :1741 - 1 748.
[30] Milde Langosch K,Riethdorf S , Kraus Poppinghaus A ,et al. Expression of cyclin- dependent kinase inhibitors p16 MTS1 ,p21WAF1 ,and p27 KIPl in HPV-positive and HPV-negative cervical adenocarcinomas [ J ] .Virchows Arch ,2001,439(1):55 -61.
[31] Nakao Y, Yang X , Yokoyama M , et al. Induction of p16 during immortalization by HPV l6 and 18 and nor during malignant transfornation[J ].Br Cancer,1997,75 (3):1410-12.
[32] Braganca JF, Sarian LO, Pitta DR, et al.Expression of p16 and cervical infection with high-risk human papillomavires are not related to p53 activity in cervical intraepithelia neoplasia [ J ]. Int Gynecol Cancer, 2008, 18 (5) : 1060-1064.
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[34] Kim NR, L IN Z, Kim KR, et al. Epstein-Barr virus and p16 INK4A methylation in squamous cell carcinoma and precancerous lesions of the cervix uteri [ J ].Korean Med Sci,2005,20 (4):636～642.
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[39] LeidM, Kastner P and Chambon P. Multiplicity generates diversity in the retinoic acid sinalling pathways [ J ].Trends Biochem Sci,1992,17: 427-433.
[40] Zhang X K, PfahlM. Regulation of retinoid and thyroid hormone action through homodimeric and heterodimeric receptors [ J ]. Trends Endocrinol Metab, 1993, (4) : 156-162.
[41] Toulouse A, LoubeauM,Morin J , et al. RARbeta involvement in enhancement of lung tumor cell immunogenicity revealed by array analysis [ J ]. FASEB, 2000, 14: 1224-1232.
[42] De-Castro Arce J , Gockel-Krzikalla E, Rosl F. Retinoic acid recep tor beta silences human papillomavirus18 oncogene expression by induction of denovo methylation and heterochromatinization of the viral control region[ J ].Biol Chem, 2007, 282: 28520-28529.
[43] Geisen C,Denk C, Küpper JH, et al. Growth inhibition of cervical cancer cells by the human retinoic acid receptor beta gene [ J ]. Int Cancer, 2000, 85: 289-295.
[44] Gao YP, Li M, Zhang YY et al.Relationship between RAR-beta gene expression defect and its methylation .Zhonghua Fu Chan Ke Za Zhi. 2007 Jul;42(7):472-6.
[45] Ivanova T, Petrenko A, Gritsko T et al. Methylation and silencing of the retinoic acid receptor-beta2 gene in cervical cancer[ J ].BMC Cancer. 2002 Mar 21;2:4.
[46] Zhang Z, Joh K, Yatsuki H et al. Retinoic acid receptor beta2 is epigenetically silenced either by DNA methylation or repressive histone modifications at the promoter in cervical cancer cells[ J ].Cancer Lett.2007 Mar 18;247(2):318-27.
[47] Narayan G, Arias- Pulido H, Koul S, et al.Frequent promoter methylation of CDH1, DAPK, RARB, and HIC1 genes in carcinoma of cervix uteri: its relationship to clinical outcome [ J] . Molec Cancer,2003, 2( 5) :24- 36.
[48] Feng Q, Balasubramanian A, Hawes SE, et al. Detection of hypermethylated genes in women with and without cervical neoplasia [ J]. Natl Cancer Inst, 2005,97(10) :273- 282.
[49] Terra AP, Murta EF, Maluf PJ, et al.Aberrant promoter methylation can be useful as a marker of recurrent disease in patients with cervical intraepithelial neoplasia grade III. [ J ]Tumori,2007 Nov-Dec;93(6):572-9.
[50] Xavier Castellsagué. Natural history and epidemiology of HPV infection and cervical cancer[ J ].Gynecologic Oncolog, 2008, 110(3 Suppl 2):S4-7.
[51] Castellsague X, Bosch FX, Munoz N. The male role in cervical cancer[ J ] .Salud publica Mex,2003,45(Suppl 3):S345–53.
[52] Woodman CB, Collins S,Winter H, et al. Natural history of cervical human papillomavirus infection in young women: a longitudinal cohort study [ J ] .Lancet, 2001,357(9271):1831–6.
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[59] Doorbar J, Griffin H. Intrabody strategies for the treatment of human papillomavirus-associated disease [ J ] . Expert Opin Biol Ther,2007,7(5): 677-89.
[60] Vinokurous S, Wentzensen N. Type-dependent integration frequency of human papillomavirus genemes in cervical lesions[ J ].Cancer Res,2008, 68(1):307-13.
[61] Lie AK, Kristensen G. Human papillomavirus E6/E7mRNA testing as a predictive marker for cervical carcinoma[ J ].Expert Rev Mol Diagn, 2008,8(4):405-15.