P53基因突变和RARβ基因甲基化对肺癌发病的影响
摘要
目的研究P53基因突变、RARβ基因甲基化与肺癌临床病理类型的关系,探讨肺癌发病过程中P53突变与RARβ甲基化的相互关系。方法采用单纯病例研究方法,收集198例原发性肺癌患者术中切除的新鲜癌组织标本,并应用PCR产物直接测序及甲基化特异性PCR法分别检测其P53基因第5～9外显子突变及RARβ基因启动子CpG岛甲基化状况,结合患者问卷资料进行χ2检验及多因素logistic回归分析。结果P53突变及RARβ甲基化检出率分别为36.4%和58.1%。吸烟患者P53突变及RARβ甲基化的危险性增加,OR值分别为2.41及2.26；有肺癌家族史的病例P53突变的危险性减小,OR值为0.26,均有统计学意义(P<0.05)。吸烟、P53突变且吸烟使患鳞癌的危险性增加,OR值分别是3.01和4.29；RARβ甲基化使患周围型肺癌危险性增加,OR值为1.95；RARβ甲基化、RARβ甲基化且P53突变使患Ⅱ期及以上肺癌危险性增加,OR值分别是2.13和3.06(P值均<0.05)。RARβ甲基化癌组织P53G:C→T:A突变率及突变构成比均高于RARβ非甲基化癌组织,差异有统计学意义(P值均<0.05)。P53G:C→T:A型突变使检出RARβ甲基化的危险性增加,OR值为3.22；在吸烟和肺鳞癌患者中,该危险性分别增加至3.65及4.71倍(P值均<0.05)。结论P53突变、RARβ甲基化及吸烟与肺癌临床病理类型密切相关；肺癌发病过程中RARβ甲基化与P53G:C→T:A型突变有关。
Objective To investigate the relationship between P53mutation, RARβmethylation and the clinical and pathological type of lung cancer, and to explore the relationship between P53mutation and RARβ methylation in lung carcinogenisis. Methods Using case-only study, collected samples of fresh cancer tissue from198primary lung cancer patients during the resection surgery, detected their mutation status of exons5through9in P53gene and methylation status of CpG islands in the promoter of RARβ gene by direct sequencing of PCR products and methylation-specific PCR respectively, and analyzed the result with questionnaire data by chi-square test and logistic regression analysis. Results P53mutation and RARβ methylation were detected in36.4%and58.1%tumors respectively. Patients with smoking history had an increased risk of both P53mutation and RARβ methylation with OR of2.41and2.26and cases with family history of lung cancer had a decreased risk of P53mutation with OR of0.26(all P<0.05). Both Smoking and P53mutation with smoking history increased the risk of squamous cell carcinoma, OR values were3.01and4.29, respectively; RARβ methylation increased the risk of peripheral lung cancer with OR of1.95; Both RARβ methylation and RARβ methylation with P53mutation increased the risk of advanced lung cancer, OR values were2.13and3.06respectively (all P<0.05). Compared with tumors with unmethylated RARβ, P53G:C→T:A mutation rate and mutation proportions were higher in tumors with RARβ methylation with statistically significant (all P
Objective To investigate the relationship between P53mutation, RARβmethylation and the clinical and pathological type of lung cancer, and to explore the relationship between P53mutation and RARβ methylation in lung carcinogenisis. Methods Using case-only study, collected samples of fresh cancer tissue from198primary lung cancer patients during the resection surgery, detected their mutation status of exons5through9in P53gene and methylation status of CpG islands in the promoter of RARβ gene by direct sequencing of PCR products and methylation-specific PCR respectively, and analyzed the result with questionnaire data by chi-square test and logistic regression analysis. Results P53mutation and RARβ methylation were detected in36.4%and58.1%tumors respectively. Patients with smoking history had an increased risk of both P53mutation and RARβ methylation with OR of2.41and2.26and cases with family history of lung cancer had a decreased risk of P53mutation with OR of0.26(all P<0.05). Both Smoking and P53mutation with smoking history increased the risk of squamous cell carcinoma, OR values were3.01and4.29, respectively; RARβ methylation increased the risk of peripheral lung cancer with OR of1.95; Both RARβ methylation and RARβ methylation with P53mutation increased the risk of advanced lung cancer, OR values were2.13and3.06respectively (all P<0.05). Compared with tumors with unmethylated RARβ, P53G:C→T:A mutation rate and mutation proportions were higher in tumors with RARβ methylation with statistically significant (all P
引文
[1]Jemal A, Bray F, Center M M, et al. Global cancer statistics. CA Cancer J Clin, 2011,61(2):69-90.
[2]Alberg A J, Ford J G, Samet J M. Epidemiology of lung cancer:ACCP evidence-based clinical practice guidelines (2nd edition). Chest,2007,132(3 Suppl): 29S-55S.
[3]Molina J R, Yang P, Cassivi S D, et al. Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc,2008,83(5):584-594.
[4]Lantuejoul S, Salameire D, Salon C, et al. Pulmonary preneoplasia--equential molecular carcinogenetic events. Histopathology,2009,54(1):43-54.
[5]Paez J G, Janne P A, Lee J C, et al. EGFR mutations in lung cancer:correlation with clinical response to gefitinib therapy. Science,2004,304(5676):1497-1500.
[6]Broermann 0, Junker K, Brandt B H, et al. Trimodality treatment in Stage III nonsmall cell lung carcinoma:prrognostic impact of K-ras mutations after neoadjuvant therapy. Cancer,2002,94(7):2055-2062.
[7]Robles A I, Linke S P, Harris C C. The p53 network in lung carcinogenesis. Oncogene,2002,21(45):6898-6907.
|8] Mogi A, Kuwano II. TP53 mutations in nonsmall cell lung cancer. J Biomed Biotechnol,2011,2011:583929.
[9]Bird A. Perceptions of epigenetics. Nature,2007,447(7143):396-398.
[10]Sharma S, Kelly T K, Jones P A. Epigenetics in cancer. Carcinogenesis,2010, 31(1):27-36.
[11]Suzuki M, Shigematsu H, Iizasa T, et al. Exclusive mutation in epidermal growth factor receptor gene, HER-2, and KRAS, and synchronous methylation of nonsmall cell lung cancer. Cancer,2006,106(10):2200-2207.
[12]Zochbauer-Muller S, Fong K M, Virmani A K, et al. Aberrant promoter methylation of multiple genes in non-small cell lung cancers. Cancer Res,2001,61(1): 249-255.
[13]Bogos K, Renyi-Vamos F, Kovacs G, et al. Role of retinoic receptors in lung carcinogenesis. J Exp Clin Cancer Res,2008,27:18.
[14]Youssef E M, Lotan D, Issa J P, et al. Hypermethylation of the retinoic acid receptor-beta(2) gene in head and neck carcinogenesis. Clin Cancer Res,2004,10(5): 1733-1742.
[15]Wu J Y, Wang J, Lai J C, et al. Association of 06-methylguanine-DNA methyltransferase (MGMT) promoter methylation with p53 mutation occurrence in non-small cell lung cancer with different histology, gender, and smoking status. Ann Surg Oncol,2008,15(11):3272-3277.
[16]Lai J C, Cheng Y W, Goan Y G, et al. Promoter methylation of O(6)-methylguanine-DNA-methyltransferase in lung cancer is regulated by p53. DNA Repair (Amst),2008,7(8):1352-1363.
[17]Liu Y, Gao W, Siegfried J M, et al. Promoter methylation of RASSF1A and DAPK and mutations of K-ras, p53, and EGFR in lung tumors from smokers and never-smokers. BMC Cancer,2007,7:74.
[18]Kaur J, Chakravarti N, Mathur M, et al. Alterations in expression of retinoid receptor beta and p53 in oral submucous fibrosis. Oral Dis,2004,10(4):201-206.
[19]Oue N, Motoshita J, Yokozaki H, et al. Distinct promoter hypermethylation of p16INK4a, CDH1, and RAR-beta in intestinal, diffuse-adherent, and diffuse-scattered type gastric carcinomas. J Pathol,2002,198(1):55-59.
[20]Le Calvez F, Mukeria A, Hunt J D, et al. TP53 and KRAS mutation load and types in lung cancers in relation to tobacco smoke:distinct patterns in never, former, and current smokers. Cancer Res,2005,65(12):5076-5083.
[21]Marrogi A J, Mechanic L E, Welsh J A, et al. TP53 mutation spectrum in lung cancer is not different in women and men. Cancer Epidemiol Biomarkers Prev,2005, 14(4):1031-1033.
[22]Nelson H H, Wilkojmen M, Marsit C J, et al. TP53 mutation, allelism and survival in non-small cell lung cancer. Carcinogenesis,2005,26(10):1770-1773.
[23]Lind H, Ekstrom P O, Ryberg D, et al. Frequency of TP53 mutations in relation to Arg72Pro genotypes in non small cell lung cancer. Cancer Epidemiol Biomarkers Prev, 2007,16(10):2077-2081.
[24]Bumroongkit K, Rannala B, Traisathit P, et al. TP53 gene mutations of lung cancer patients in upper northern Thailand and environmental risk factors. Cancer Genet Cytogenet,2008,185(1):20-27.
[25]Gao W M, Mady H H, Yu G Y, et al. Comparison of p53 mutations between adenocarcinoma and squamous cell carcinoma of the lung:unique spectra involving G to A transitions and G to T transversions in both histologic types. Lung Cancer,2003, 40(2):141-150.
[26]Matter B, Wang G, Jones R, et al. Formation of diastereomeric benzo[a]pyrene diol epoxide-guanine adducts in p53 gene-derived DNA sequences. Chem Res Toxicol,2004, 17(6):731-741.
[27]Shimmyo T, Okada A, Hashimoto T, et al. Etiologic value of p53 mutation spectra and differences with histology in lung cancers. Cancer Sci,2008,99(2):287-295.
[28]Pfeifer G P, Besaratinia A. Mutational spectra of human cancer. Hum Genet,2009, 125(5-6):493-506.
[29]Chan E C, Lam S Y, Tsang K W, et al. Aberrant promoter methylation in Chinese patients with non-small cell lung cancer: patterns in primary tumors and potential diagnostic application in bronchoalevolar lavage. Clin Cancer Res,2002,8(12): 3741-3746.
[30]Liu Z, Zhao J, Chen X F, et al. CpG island methylator phenotype involving tumor suppressor genes located on chromosome 3p in non-small cell lung cancer. Lung Cancer, 2008,62(1):15-22.
[31]Ahrendt S A, Chow J T, Yang S C, et al. Alcohol consumption and cigarette smoking increase the frequency of p53 mutations in non-small cell lung cancer. Cancer Res,2000,60(12):3155-3159.
[32]Ng D P, Tan K W, Zhao B, et al. CYP1A1 polymorphisms and risk of lung cancer in non-smoking Chinese women:influence of environmental tobacco smoke exposure and GSTM1/T1 genetic variation. Cancer Causes Control,2005,16(4):399-405.
[33]Ohshima S, Xu Y. p53 gene mutations, and CYP1A1 and GSTM1 genotypes in pulmonary squamous cell carcinomas. Mol Pathol,1997,50(2):108-110.
[34]Tomizawa Y, Iijima H, Nomoto T, et al. Clinicopathological significance of aberrant methylation of RARbeta2 at 3p24, RASSF1A at 3p21.3, and FHIT at 3p14.2 in patients with non-small cell lung cancer. Lung Cancer,2004,46(3):305-312.
[35]Lin R K, Hsieh Y S, Lin P, et al. The tobacco-specific carcinogen NNK induces DNA methyltransferase 1 accumulation and tumor suppressor gene hypermethylation in mice and lung cancer patients. J Clin Invest,2010,120(2):521-532.
[36]Ye F, Xu X C. Benzo[a]pyrene diol epoxide suppresses retinoic acid receptor-beta2 expression by recruiting DNA (cytosine-5-)-methyltransferase 3A. Mol Cancer,2010,9: 93.
[37]Kenfield S A, Wei E K, Stampfer M J, et al. Comparison of aspects of smoking among the four histological types of lung cancer. Tob Control,2008,17(3):198-204
[38]Khuder S A. Effect of cigarette smoking on major histological types of lung cancer: a meta-analysis. Lung Cancer,2001,31(2-3):139-148.
[39]李志忠,王乐强,庄洪洁.吸烟与肺癌类型关系的探讨.中华流行病学杂志,2002,(5)：46.
[40]孙海基TP53. KRAS和EGFR基因在非小细胞肺癌顺铂辅助化疗中肿瘤标记物的研究：[博士学位论文].山东,山东师范大学,2009,1-119.
[41]齐文娟.Ki-67和p53蛋白在肺癌组织中的诊断阈值及预后意义研究：[硕士学位论文].广州,南方医科大学,2010,1-73.
[42]Divine K K, Pulling L C, Marron-Terada P G, et al. Multiplicity of abnormal promoter methylation in lung adenocarcinomas from smokers and never smokers. Int J Cancer,2005,114(3):400-405.
[43]Gerde P, Muggenburg B A, Stephens T, et al. A relevant dose of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone is extensively metabolized and rapidly absorbed in the canine tracheal mucosa. Cancer Res,1998,58(7):1417-1422.
[44]Gerde P, Muggenburg B A, Thornton-Manning J R, et al. Benzo[a]pyrene at an environmentally relevant dose is slowly absorbed by, and extensively metabolized in, tracheal epithelium. Carcinogenesis,1997,18(9):1825-1832.
[45]Vuillemenot B R, Pulling L C, Palmisano W A, et al. Carcinogen exposure differentially modulates RAR-beta promoter hypermethylation, an early and frequent event in mouse lung carcinogenesis. Carcinogenesis,2004,25(4):623-629.
[46]Maruyama R, Sugio K, Yoshino I, et al. Hypermethylation of FHIT as a prognostic marker in nonsmall cell lung carcinoma. Cancer,2004,100(7):1472-1477.
[47]Khuri F R, Lotan R, Kemp B L, et al. Retinoic acid receptor-beta as a prognostic indicator in stage I non-small-cell lung cancer. J Clin Oncol,2000,18(15):2798-2804.
[48]Peterson E J, Bogler O, Taylor S M. p53-mediated repression of DNA methyltransferase 1 expression by specific DNA binding. Cancer Res,2003,63(20): 6579-6582.
[49]Lin R K, Wu C Y, Chang J W, et al. Dysregulation of p53/Sp1 control leads to DNA methyltransferase-1 overexpression in lung cancer. Cancer Res,2010,70(14): 5807-5817.
[50]Zhang W, Rashid A, Wu H, et al. Differential expression of retinoic acid receptors and p53 protein in normal, premalignant, and malignant esophageal tissues. J Cancer Res Clin Oncol,2001,127(4):237-242.
[51]Brtko J, Dvorak Z. Role of retinoids, rexinoids and thyroid hormone in the expression of cytochrome p450 enzymes. Curr Drug Metab,2011,12(2):71-88.
[52]Fallone F, Villard P H, Seree E, et al. Retinoids repress Ah receptor CYP1A1 induction pathway through the SMRT corepressor. Biochem Biophys Res Commun, 2004,322(2):551-556.
[53]Genta V M, Kaufman D G, Harris C C, et al. Vitamin A deficiency enhances binding of benzo(a)pyrene to tracheal epithelial DNA. Nature,1974,247(5435):48-49.
[54]宋元宗.8-羟基鸟嘌呤及其检测.癌变.畸变.突变,1998,(2)：57-60.
[55]Shiota G. Role of retinoic acid receptor in steatohepatitis-related tumor formation. J Gastroenterol Hepatol,2007,22 Suppl 1:S101-S107.
[56]Lorenzo Y, Azqueta A, Luna L, et al. The carotenoid beta-cryptoxanthin stimulates the repair of DNA oxidation damage in addition to acting as an antioxidant in human cells. Carcinogenesis,2009,30(2):308-314.
[57]Kurie J M, Lotan R, Lee J J, et al. Treatment of former smokers with 9-cis-retinoic acid reverses loss of retinoic acid receptor-beta expression in the bronchial epithelium: results from a randomized placebo-controlled trial. J Natl Cancer Inst,2003,95(3): 206-214.
[58]Li Y, Tollefsbol T O. Impact on DNA methylation in cancer prevention and therapy by bioactive dietary components. Curr Med Chem,2010,17(20):2141-2151.
[1]Sharpless N E, Alson S, Chan S, et al. pl6(INK4a) and p53 deficiency cooperate in tumorigenesis. Cancer Res,2002,62(10):2761-2765.
[2]Bird A. Perceptions of epigenetics. Nature,2007,447(7143):396-398.
[3]Raveh T, Droguett G, Horwitz M S, et al. DAP kinase activates a p19ARF/p53-mediated apoptotic checkpoint to suppress oncogenic transformation. Nat Cell Biol,2001,3(1):1-7.
[4]李大虎,张令强,贺福初.突变体p53研究进展.遗传,2008,(6)：697-703.
[5]Bode A M, Dong Z. Post-translational modification of p53 in tumorigenesis. Nat Rev Cancer,2004,4(10):793-805.
[6]Sharma S, Kelly T K, Jones P A. Epigenetics in cancer. Carcinogenesis,2010,31(1): 27-36.
[7]Karsai S, Abel U, Roesch-Ely M, et al. Comparison of pl6(INK4a) expression with p53 alterations in head and neck cancer by tissue microarray analysis. J Pathol,2007, 211(3):314-322.
[8]Taghavi N, Biramijamal F, Sotoudeh M, et al. p16INK4a hypermethylation and p53, p16 and MDM2 protein expression in esophageal squamous cell carcinoma. BMC Cancer,2010,10:138.
[9]Havrilesky L J, Alvarez A A, Whitaker R S, et al. Loss of expression of the p16 tumor suppressor gene is more frequent in advanced ovarian cancers lacking p53 mutations. Gynecol Oncol,2001,83(3):491-500.
[10]Vonlanthen S, Heighway J, Tschan M P, et al. Expression of p16INK4a/p16alpha and p19ARF/pl6beta is frequently altered in non-small cell lung cancer and correlates with p53 overexpression. Oncogene,1998,17(21):2779-2785.
[11]Kinoshita I, Dosaka-Akita H, Mishina T, et al. Altered p161NK4 and retinoblastoma protein status in non-small cell lung cancer:potential synergistic effect with altered p53 protein on proliferative activity. Cancer Res,1996,56(24):5557-5562.
[12]Geradts J, Fong K M, Zimmerman P V, et al. Correlation of abnormal RB, pl6ink4a, and p53 expression with 3p loss of heterozygosity, other genetic abnormalities, and clinical features in 103 primary non-small cell lung cancers. Clin Cancer Res,1999,5(4):791-800.
[13]Jarmalaite S, Kannio A, Anttila S, et al. Aberrant p16 promoter methylation in smokers and former smokers with nonsmall cell lung cancer. Int J Cancer,2003,106(6): 913-918.
[14]Kim D H, Nelson H H, Wiencke J K, et al. pl6(INK4a) and histology-specific methylation of CpG islands by exposure to tobacco smoke in non-small cell lung cancer. Cancer Res,2001,61(8):3419-3424.
[15]Widschwendter M, Berger J, Hermann M, et al. Methylation and silencing of the retinoic acid receptor-beta2 gene in breast cancer. J Natl Cancer Inst,2000,92(10): 826-832.
[16]Oue N, Motoshita J, Yokozaki H, et al. Distinct promoter hypermethylation of p16INK4a, CDH1, and RAR-beta in intestinal, diffuse-adherent, and diffuse-scattered type gastric carcinomas. J Pathol,2002,198(1):55-59.
[17]Kaur J, Chakravarti N, Mathur M, et al. Alterations in expression of retinoid receptor beta and p53 in oral submucous fibrosis. Oral Dis,2004,10(4):201-206.
[18]Youssef E M, Lotan D, Issa J P, et al. Hypermethylation of the retinoic acid receptor-beta(2) gene in head and neck carcinogenesis. Clin Cancer Res,2004,10(5): 1733-1742.
[19]闵卫利,王西京,薛锋杰,等.乳腺癌组织DAPK和p53及Bcl-2表达及其相互关系的研究.中华肿瘤防治杂志,2008,(19)：1473-1476.
[20]Liu Y, Gao W, Siegfried J M, et al. Promoter methylation of RASSF1A and DAPK and mutations of K-ras, p53, and EGFR in lung tumors from smokers and never-smokers. BMC Cancer,2007,7:74.
[21]Tomizawa Y, Kohno T, Kondo H, et al. Clinicopathological significance of epigenetic inactivation of RASSF1A at 3p21.3 in stage I lung adenocarcinoma. Clin Cancer Res,2002,8(7):2362-2368.
[22]Wu J Y, Wang J, Lai J C, et al. Association of O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation with p53 mutation occurrence in non-small cell lung cancer with different histology, gender, and smoking status. Ann Surg Oncol,2008,15(11):3272-3277.
[23]Lai J C, Cheng Y W, Goan Y G, et al. Promoter methylation of O(6)-methylguanine-DNA-Methyltransferase in lung cancer is regulated by p53. DNA Repair (Amst),2008,7(8):1352-1363.
[24]Lin R K, Wu C Y, Chang J W, et al. Dysregulation of p53/Spl control leads to DNA methyltransferase-1 overexpression in lung cancer. Cancer Res,2010,70(14): 5807-5817.
[25]Peterson E J, Bogler O, Taylor S M. p53-mediated repression of DNA methyltransferase 1 expression by specific DNA binding. Cancer Res,2003,63(20): 6579-6582.
[26]沈金花.组蛋白密码与表观标志.国外医学(分子生物学分册),2002,(6)：337-340.
[27]李保华,张卫林.组蛋白乙酰化/去乙酰化与基因表达调控研究进展.安徽农业科学,2007,(18)：5364-5365.
[28]Seligson D B, Horvath S, Mcbrian M A, et al. Global levels of histone modifications predict prognosis in different cancers. Am J Pathol,2009,174(5): 1619-1628.
[29]Ebrahimi A, Schittenhelm J, Honegger J, et al. Histone acetylation patterns of typical and atypical pituitary adenomas indicate epigenetic shift of these tumours. J Neuroendocrinol,2011,23(6):525-530.
[30]Allison S J, Milner J. Loss of p53 has site-specific effects on histone H3 modification, including serine 10 phosphorylation important for maintenance of ploidy. Cancer Res,2003,63(20):6674-6679.
[31]Sankala H, Vaughan C, Wang J, et al. Upregulation of the mitochondrial transport protein, Tim50, by mutant p53 contributes to cell growth and chemoresistance. Arch Biochem Biophys,2011,512(1):52-60.
[32]Allison S J, Milner J. Remodelling chromatin on a global scale:a novel protective function of p53. Carcinogenesis,2004,25(9):1551-1557.
[33]Vrba L, Junk D J, Novak P, et al. p53 induces distinct epigenetic states at its direct target promoters. BMC Genomics,2008,9:486.
[34]Murphy M, Ahn J, Walker K K, et al. Transcriptional repression by wild-type p53 utilizes histone deacetylases, mediated by interaction with mSin3a. Genes Dev,1999, 13(19):2490-2501.
[35]Fan H, Harrell J R, Dipp S, et al. A novel pathological role of p53 in kidney development revealed by gene-environment interactions. Am J Physiol Renal Physiol, 2005,288(1):F98-F107.
[36]Li L, Qin X, Shi M, et al. Regulation of histone acetylation by NDRG2 in glioma cells. J Neurooncol,2011, [Epub ahead of print]
[37]Hermeking H. p53 enters the microRNA world. Cancer Cell,2007,12(5):414-418.
[38]Ji Q, Hao X, Meng Y, et al. Restoration of tumor suppressor miR-34 inhibits human p53-mutant gastric cancer tumorspheres. BMC Cancer,2008,8:266.
[39]Chen H C, Chen G H, Chen Y H, et al. MicroRNA deregulation and pathway alterations in nasopharyngeal carcinoma. Br J Cancer,2009,100(6):1002-1011.
[40]Rokhlin O W, Scheinker V S, Taghiyev A F, et al. MicroRNA-34 mediates AR-dependent p53-induced apoptosis in prostate cancer. Cancer Biol Ther,2008,7(8): 1288-1296.
[41]Ji Q, Hao X, Zhang M, et al. MicroRNA miR-34 inhibits human pancreatic cancer tumor-initiating cells. PLoS One,2009,4(8):e6816.
[42]Dalgard C L, Gonzalez M, Deniro J E, et al. Differential microRNA-34a expression and tumor suppressor function in retinoblastoma cells. Invest Ophthalmol Vis Sci,2009,50(10):4542-4551.
[43]Iorio M V, Ferracin M, Liu C G, et al. MicroRNA gene expression deregulation in human breast cancer. Cancer Res,2005,65(16):7065-7070.
[44]Raver-Shapira N, Marciano E, Meiri E, et al. Transcriptional activation of miR-34a contributes to p53-mediated apoptosis. Mol Cell,2007,26(5):731-743.
[45]Chang T C, Wentzel E A, Kent O A, et al. Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis. Mol Cell,2007,26(5): 745-752.
[46]Tarasov V, Jung P, Verdoodt B, et al. Differential regulation of microRNAs by p53 revealed by massively parallel sequencing:miR-34a is a p53 target that induces apoptosis and Gl-arrest. Cell Cycle,2007,6(13):1586-1593.
[47]He L, He X, Lim L P, et al. A microRNA component of the p53 tumour suppressor network. Nature,2007,447(7148):1130-1134.
[48]Yamakuchi M, Lowcnstcin C J. MiR-34, SIRT1 and p53:the feedback loop. Cell Cycle,2009,8(5):712-715.
[49]Yamakuchi M, Ferlito M, Lowenstein C J. miR-34a repression of SIRT1 regulates apoptosis. Proc Natl Acad Sci U S A,2008,105(36):13421-13426.
[50]Tazawa H, Tsuchiya N, Izumiya M, et al. Tumor-suppressive miR-34a induces senescence-like growth arrest through modulation of the E2F pathway in human colon cancer cells. Proc Natl Acad Sci U S A,2007,104(39):15472-15477.
[51]Wang X, Wang H K, Mccoy J P, et al. Oncogenic HPV infection interrupts the expression of tumor-suppressive miR-34a through viral oncoprotein E6. RNA,2009, 15(4):637-647.
[2]Alberg A J, Ford J G, Samet J M. Epidemiology of lung cancer:ACCP evidence-based clinical practice guidelines (2nd edition). Chest,2007,132(3 Suppl): 29S-55S.
[3]Molina J R, Yang P, Cassivi S D, et al. Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc,2008,83(5):584-594.
[4]Lantuejoul S, Salameire D, Salon C, et al. Pulmonary preneoplasia--equential molecular carcinogenetic events. Histopathology,2009,54(1):43-54.
[5]Paez J G, Janne P A, Lee J C, et al. EGFR mutations in lung cancer:correlation with clinical response to gefitinib therapy. Science,2004,304(5676):1497-1500.
[6]Broermann 0, Junker K, Brandt B H, et al. Trimodality treatment in Stage III nonsmall cell lung carcinoma:prrognostic impact of K-ras mutations after neoadjuvant therapy. Cancer,2002,94(7):2055-2062.
[7]Robles A I, Linke S P, Harris C C. The p53 network in lung carcinogenesis. Oncogene,2002,21(45):6898-6907.
|8] Mogi A, Kuwano II. TP53 mutations in nonsmall cell lung cancer. J Biomed Biotechnol,2011,2011:583929.
[9]Bird A. Perceptions of epigenetics. Nature,2007,447(7143):396-398.
[10]Sharma S, Kelly T K, Jones P A. Epigenetics in cancer. Carcinogenesis,2010, 31(1):27-36.
[11]Suzuki M, Shigematsu H, Iizasa T, et al. Exclusive mutation in epidermal growth factor receptor gene, HER-2, and KRAS, and synchronous methylation of nonsmall cell lung cancer. Cancer,2006,106(10):2200-2207.
[12]Zochbauer-Muller S, Fong K M, Virmani A K, et al. Aberrant promoter methylation of multiple genes in non-small cell lung cancers. Cancer Res,2001,61(1): 249-255.
[13]Bogos K, Renyi-Vamos F, Kovacs G, et al. Role of retinoic receptors in lung carcinogenesis. J Exp Clin Cancer Res,2008,27:18.
[14]Youssef E M, Lotan D, Issa J P, et al. Hypermethylation of the retinoic acid receptor-beta(2) gene in head and neck carcinogenesis. Clin Cancer Res,2004,10(5): 1733-1742.
[15]Wu J Y, Wang J, Lai J C, et al. Association of 06-methylguanine-DNA methyltransferase (MGMT) promoter methylation with p53 mutation occurrence in non-small cell lung cancer with different histology, gender, and smoking status. Ann Surg Oncol,2008,15(11):3272-3277.
[16]Lai J C, Cheng Y W, Goan Y G, et al. Promoter methylation of O(6)-methylguanine-DNA-methyltransferase in lung cancer is regulated by p53. DNA Repair (Amst),2008,7(8):1352-1363.
[17]Liu Y, Gao W, Siegfried J M, et al. Promoter methylation of RASSF1A and DAPK and mutations of K-ras, p53, and EGFR in lung tumors from smokers and never-smokers. BMC Cancer,2007,7:74.
[18]Kaur J, Chakravarti N, Mathur M, et al. Alterations in expression of retinoid receptor beta and p53 in oral submucous fibrosis. Oral Dis,2004,10(4):201-206.
[19]Oue N, Motoshita J, Yokozaki H, et al. Distinct promoter hypermethylation of p16INK4a, CDH1, and RAR-beta in intestinal, diffuse-adherent, and diffuse-scattered type gastric carcinomas. J Pathol,2002,198(1):55-59.
[20]Le Calvez F, Mukeria A, Hunt J D, et al. TP53 and KRAS mutation load and types in lung cancers in relation to tobacco smoke:distinct patterns in never, former, and current smokers. Cancer Res,2005,65(12):5076-5083.
[21]Marrogi A J, Mechanic L E, Welsh J A, et al. TP53 mutation spectrum in lung cancer is not different in women and men. Cancer Epidemiol Biomarkers Prev,2005, 14(4):1031-1033.
[22]Nelson H H, Wilkojmen M, Marsit C J, et al. TP53 mutation, allelism and survival in non-small cell lung cancer. Carcinogenesis,2005,26(10):1770-1773.
[23]Lind H, Ekstrom P O, Ryberg D, et al. Frequency of TP53 mutations in relation to Arg72Pro genotypes in non small cell lung cancer. Cancer Epidemiol Biomarkers Prev, 2007,16(10):2077-2081.
[24]Bumroongkit K, Rannala B, Traisathit P, et al. TP53 gene mutations of lung cancer patients in upper northern Thailand and environmental risk factors. Cancer Genet Cytogenet,2008,185(1):20-27.
[25]Gao W M, Mady H H, Yu G Y, et al. Comparison of p53 mutations between adenocarcinoma and squamous cell carcinoma of the lung:unique spectra involving G to A transitions and G to T transversions in both histologic types. Lung Cancer,2003, 40(2):141-150.
[26]Matter B, Wang G, Jones R, et al. Formation of diastereomeric benzo[a]pyrene diol epoxide-guanine adducts in p53 gene-derived DNA sequences. Chem Res Toxicol,2004, 17(6):731-741.
[27]Shimmyo T, Okada A, Hashimoto T, et al. Etiologic value of p53 mutation spectra and differences with histology in lung cancers. Cancer Sci,2008,99(2):287-295.
[28]Pfeifer G P, Besaratinia A. Mutational spectra of human cancer. Hum Genet,2009, 125(5-6):493-506.
[29]Chan E C, Lam S Y, Tsang K W, et al. Aberrant promoter methylation in Chinese patients with non-small cell lung cancer: patterns in primary tumors and potential diagnostic application in bronchoalevolar lavage. Clin Cancer Res,2002,8(12): 3741-3746.
[30]Liu Z, Zhao J, Chen X F, et al. CpG island methylator phenotype involving tumor suppressor genes located on chromosome 3p in non-small cell lung cancer. Lung Cancer, 2008,62(1):15-22.
[31]Ahrendt S A, Chow J T, Yang S C, et al. Alcohol consumption and cigarette smoking increase the frequency of p53 mutations in non-small cell lung cancer. Cancer Res,2000,60(12):3155-3159.
[32]Ng D P, Tan K W, Zhao B, et al. CYP1A1 polymorphisms and risk of lung cancer in non-smoking Chinese women:influence of environmental tobacco smoke exposure and GSTM1/T1 genetic variation. Cancer Causes Control,2005,16(4):399-405.
[33]Ohshima S, Xu Y. p53 gene mutations, and CYP1A1 and GSTM1 genotypes in pulmonary squamous cell carcinomas. Mol Pathol,1997,50(2):108-110.
[34]Tomizawa Y, Iijima H, Nomoto T, et al. Clinicopathological significance of aberrant methylation of RARbeta2 at 3p24, RASSF1A at 3p21.3, and FHIT at 3p14.2 in patients with non-small cell lung cancer. Lung Cancer,2004,46(3):305-312.
[35]Lin R K, Hsieh Y S, Lin P, et al. The tobacco-specific carcinogen NNK induces DNA methyltransferase 1 accumulation and tumor suppressor gene hypermethylation in mice and lung cancer patients. J Clin Invest,2010,120(2):521-532.
[36]Ye F, Xu X C. Benzo[a]pyrene diol epoxide suppresses retinoic acid receptor-beta2 expression by recruiting DNA (cytosine-5-)-methyltransferase 3A. Mol Cancer,2010,9: 93.
[37]Kenfield S A, Wei E K, Stampfer M J, et al. Comparison of aspects of smoking among the four histological types of lung cancer. Tob Control,2008,17(3):198-204
[38]Khuder S A. Effect of cigarette smoking on major histological types of lung cancer: a meta-analysis. Lung Cancer,2001,31(2-3):139-148.
[39]李志忠,王乐强,庄洪洁.吸烟与肺癌类型关系的探讨.中华流行病学杂志,2002,(5)：46.
[40]孙海基TP53. KRAS和EGFR基因在非小细胞肺癌顺铂辅助化疗中肿瘤标记物的研究：[博士学位论文].山东,山东师范大学,2009,1-119.
[41]齐文娟.Ki-67和p53蛋白在肺癌组织中的诊断阈值及预后意义研究：[硕士学位论文].广州,南方医科大学,2010,1-73.
[42]Divine K K, Pulling L C, Marron-Terada P G, et al. Multiplicity of abnormal promoter methylation in lung adenocarcinomas from smokers and never smokers. Int J Cancer,2005,114(3):400-405.
[43]Gerde P, Muggenburg B A, Stephens T, et al. A relevant dose of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone is extensively metabolized and rapidly absorbed in the canine tracheal mucosa. Cancer Res,1998,58(7):1417-1422.
[44]Gerde P, Muggenburg B A, Thornton-Manning J R, et al. Benzo[a]pyrene at an environmentally relevant dose is slowly absorbed by, and extensively metabolized in, tracheal epithelium. Carcinogenesis,1997,18(9):1825-1832.
[45]Vuillemenot B R, Pulling L C, Palmisano W A, et al. Carcinogen exposure differentially modulates RAR-beta promoter hypermethylation, an early and frequent event in mouse lung carcinogenesis. Carcinogenesis,2004,25(4):623-629.
[46]Maruyama R, Sugio K, Yoshino I, et al. Hypermethylation of FHIT as a prognostic marker in nonsmall cell lung carcinoma. Cancer,2004,100(7):1472-1477.
[47]Khuri F R, Lotan R, Kemp B L, et al. Retinoic acid receptor-beta as a prognostic indicator in stage I non-small-cell lung cancer. J Clin Oncol,2000,18(15):2798-2804.
[48]Peterson E J, Bogler O, Taylor S M. p53-mediated repression of DNA methyltransferase 1 expression by specific DNA binding. Cancer Res,2003,63(20): 6579-6582.
[49]Lin R K, Wu C Y, Chang J W, et al. Dysregulation of p53/Sp1 control leads to DNA methyltransferase-1 overexpression in lung cancer. Cancer Res,2010,70(14): 5807-5817.
[50]Zhang W, Rashid A, Wu H, et al. Differential expression of retinoic acid receptors and p53 protein in normal, premalignant, and malignant esophageal tissues. J Cancer Res Clin Oncol,2001,127(4):237-242.
[51]Brtko J, Dvorak Z. Role of retinoids, rexinoids and thyroid hormone in the expression of cytochrome p450 enzymes. Curr Drug Metab,2011,12(2):71-88.
[52]Fallone F, Villard P H, Seree E, et al. Retinoids repress Ah receptor CYP1A1 induction pathway through the SMRT corepressor. Biochem Biophys Res Commun, 2004,322(2):551-556.
[53]Genta V M, Kaufman D G, Harris C C, et al. Vitamin A deficiency enhances binding of benzo(a)pyrene to tracheal epithelial DNA. Nature,1974,247(5435):48-49.
[54]宋元宗.8-羟基鸟嘌呤及其检测.癌变.畸变.突变,1998,(2)：57-60.
[55]Shiota G. Role of retinoic acid receptor in steatohepatitis-related tumor formation. J Gastroenterol Hepatol,2007,22 Suppl 1:S101-S107.
[56]Lorenzo Y, Azqueta A, Luna L, et al. The carotenoid beta-cryptoxanthin stimulates the repair of DNA oxidation damage in addition to acting as an antioxidant in human cells. Carcinogenesis,2009,30(2):308-314.
[57]Kurie J M, Lotan R, Lee J J, et al. Treatment of former smokers with 9-cis-retinoic acid reverses loss of retinoic acid receptor-beta expression in the bronchial epithelium: results from a randomized placebo-controlled trial. J Natl Cancer Inst,2003,95(3): 206-214.
[58]Li Y, Tollefsbol T O. Impact on DNA methylation in cancer prevention and therapy by bioactive dietary components. Curr Med Chem,2010,17(20):2141-2151.
[1]Sharpless N E, Alson S, Chan S, et al. pl6(INK4a) and p53 deficiency cooperate in tumorigenesis. Cancer Res,2002,62(10):2761-2765.
[2]Bird A. Perceptions of epigenetics. Nature,2007,447(7143):396-398.
[3]Raveh T, Droguett G, Horwitz M S, et al. DAP kinase activates a p19ARF/p53-mediated apoptotic checkpoint to suppress oncogenic transformation. Nat Cell Biol,2001,3(1):1-7.
[4]李大虎,张令强,贺福初.突变体p53研究进展.遗传,2008,(6)：697-703.
[5]Bode A M, Dong Z. Post-translational modification of p53 in tumorigenesis. Nat Rev Cancer,2004,4(10):793-805.
[6]Sharma S, Kelly T K, Jones P A. Epigenetics in cancer. Carcinogenesis,2010,31(1): 27-36.
[7]Karsai S, Abel U, Roesch-Ely M, et al. Comparison of pl6(INK4a) expression with p53 alterations in head and neck cancer by tissue microarray analysis. J Pathol,2007, 211(3):314-322.
[8]Taghavi N, Biramijamal F, Sotoudeh M, et al. p16INK4a hypermethylation and p53, p16 and MDM2 protein expression in esophageal squamous cell carcinoma. BMC Cancer,2010,10:138.
[9]Havrilesky L J, Alvarez A A, Whitaker R S, et al. Loss of expression of the p16 tumor suppressor gene is more frequent in advanced ovarian cancers lacking p53 mutations. Gynecol Oncol,2001,83(3):491-500.
[10]Vonlanthen S, Heighway J, Tschan M P, et al. Expression of p16INK4a/p16alpha and p19ARF/pl6beta is frequently altered in non-small cell lung cancer and correlates with p53 overexpression. Oncogene,1998,17(21):2779-2785.
[11]Kinoshita I, Dosaka-Akita H, Mishina T, et al. Altered p161NK4 and retinoblastoma protein status in non-small cell lung cancer:potential synergistic effect with altered p53 protein on proliferative activity. Cancer Res,1996,56(24):5557-5562.
[12]Geradts J, Fong K M, Zimmerman P V, et al. Correlation of abnormal RB, pl6ink4a, and p53 expression with 3p loss of heterozygosity, other genetic abnormalities, and clinical features in 103 primary non-small cell lung cancers. Clin Cancer Res,1999,5(4):791-800.
[13]Jarmalaite S, Kannio A, Anttila S, et al. Aberrant p16 promoter methylation in smokers and former smokers with nonsmall cell lung cancer. Int J Cancer,2003,106(6): 913-918.
[14]Kim D H, Nelson H H, Wiencke J K, et al. pl6(INK4a) and histology-specific methylation of CpG islands by exposure to tobacco smoke in non-small cell lung cancer. Cancer Res,2001,61(8):3419-3424.
[15]Widschwendter M, Berger J, Hermann M, et al. Methylation and silencing of the retinoic acid receptor-beta2 gene in breast cancer. J Natl Cancer Inst,2000,92(10): 826-832.
[16]Oue N, Motoshita J, Yokozaki H, et al. Distinct promoter hypermethylation of p16INK4a, CDH1, and RAR-beta in intestinal, diffuse-adherent, and diffuse-scattered type gastric carcinomas. J Pathol,2002,198(1):55-59.
[17]Kaur J, Chakravarti N, Mathur M, et al. Alterations in expression of retinoid receptor beta and p53 in oral submucous fibrosis. Oral Dis,2004,10(4):201-206.
[18]Youssef E M, Lotan D, Issa J P, et al. Hypermethylation of the retinoic acid receptor-beta(2) gene in head and neck carcinogenesis. Clin Cancer Res,2004,10(5): 1733-1742.
[19]闵卫利,王西京,薛锋杰,等.乳腺癌组织DAPK和p53及Bcl-2表达及其相互关系的研究.中华肿瘤防治杂志,2008,(19)：1473-1476.
[20]Liu Y, Gao W, Siegfried J M, et al. Promoter methylation of RASSF1A and DAPK and mutations of K-ras, p53, and EGFR in lung tumors from smokers and never-smokers. BMC Cancer,2007,7:74.
[21]Tomizawa Y, Kohno T, Kondo H, et al. Clinicopathological significance of epigenetic inactivation of RASSF1A at 3p21.3 in stage I lung adenocarcinoma. Clin Cancer Res,2002,8(7):2362-2368.
[22]Wu J Y, Wang J, Lai J C, et al. Association of O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation with p53 mutation occurrence in non-small cell lung cancer with different histology, gender, and smoking status. Ann Surg Oncol,2008,15(11):3272-3277.
[23]Lai J C, Cheng Y W, Goan Y G, et al. Promoter methylation of O(6)-methylguanine-DNA-Methyltransferase in lung cancer is regulated by p53. DNA Repair (Amst),2008,7(8):1352-1363.
[24]Lin R K, Wu C Y, Chang J W, et al. Dysregulation of p53/Spl control leads to DNA methyltransferase-1 overexpression in lung cancer. Cancer Res,2010,70(14): 5807-5817.
[25]Peterson E J, Bogler O, Taylor S M. p53-mediated repression of DNA methyltransferase 1 expression by specific DNA binding. Cancer Res,2003,63(20): 6579-6582.
[26]沈金花.组蛋白密码与表观标志.国外医学(分子生物学分册),2002,(6)：337-340.
[27]李保华,张卫林.组蛋白乙酰化/去乙酰化与基因表达调控研究进展.安徽农业科学,2007,(18)：5364-5365.
[28]Seligson D B, Horvath S, Mcbrian M A, et al. Global levels of histone modifications predict prognosis in different cancers. Am J Pathol,2009,174(5): 1619-1628.
[29]Ebrahimi A, Schittenhelm J, Honegger J, et al. Histone acetylation patterns of typical and atypical pituitary adenomas indicate epigenetic shift of these tumours. J Neuroendocrinol,2011,23(6):525-530.
[30]Allison S J, Milner J. Loss of p53 has site-specific effects on histone H3 modification, including serine 10 phosphorylation important for maintenance of ploidy. Cancer Res,2003,63(20):6674-6679.
[31]Sankala H, Vaughan C, Wang J, et al. Upregulation of the mitochondrial transport protein, Tim50, by mutant p53 contributes to cell growth and chemoresistance. Arch Biochem Biophys,2011,512(1):52-60.
[32]Allison S J, Milner J. Remodelling chromatin on a global scale:a novel protective function of p53. Carcinogenesis,2004,25(9):1551-1557.
[33]Vrba L, Junk D J, Novak P, et al. p53 induces distinct epigenetic states at its direct target promoters. BMC Genomics,2008,9:486.
[34]Murphy M, Ahn J, Walker K K, et al. Transcriptional repression by wild-type p53 utilizes histone deacetylases, mediated by interaction with mSin3a. Genes Dev,1999, 13(19):2490-2501.
[35]Fan H, Harrell J R, Dipp S, et al. A novel pathological role of p53 in kidney development revealed by gene-environment interactions. Am J Physiol Renal Physiol, 2005,288(1):F98-F107.
[36]Li L, Qin X, Shi M, et al. Regulation of histone acetylation by NDRG2 in glioma cells. J Neurooncol,2011, [Epub ahead of print]
[37]Hermeking H. p53 enters the microRNA world. Cancer Cell,2007,12(5):414-418.
[38]Ji Q, Hao X, Meng Y, et al. Restoration of tumor suppressor miR-34 inhibits human p53-mutant gastric cancer tumorspheres. BMC Cancer,2008,8:266.
[39]Chen H C, Chen G H, Chen Y H, et al. MicroRNA deregulation and pathway alterations in nasopharyngeal carcinoma. Br J Cancer,2009,100(6):1002-1011.
[40]Rokhlin O W, Scheinker V S, Taghiyev A F, et al. MicroRNA-34 mediates AR-dependent p53-induced apoptosis in prostate cancer. Cancer Biol Ther,2008,7(8): 1288-1296.
[41]Ji Q, Hao X, Zhang M, et al. MicroRNA miR-34 inhibits human pancreatic cancer tumor-initiating cells. PLoS One,2009,4(8):e6816.
[42]Dalgard C L, Gonzalez M, Deniro J E, et al. Differential microRNA-34a expression and tumor suppressor function in retinoblastoma cells. Invest Ophthalmol Vis Sci,2009,50(10):4542-4551.
[43]Iorio M V, Ferracin M, Liu C G, et al. MicroRNA gene expression deregulation in human breast cancer. Cancer Res,2005,65(16):7065-7070.
[44]Raver-Shapira N, Marciano E, Meiri E, et al. Transcriptional activation of miR-34a contributes to p53-mediated apoptosis. Mol Cell,2007,26(5):731-743.
[45]Chang T C, Wentzel E A, Kent O A, et al. Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis. Mol Cell,2007,26(5): 745-752.
[46]Tarasov V, Jung P, Verdoodt B, et al. Differential regulation of microRNAs by p53 revealed by massively parallel sequencing:miR-34a is a p53 target that induces apoptosis and Gl-arrest. Cell Cycle,2007,6(13):1586-1593.
[47]He L, He X, Lim L P, et al. A microRNA component of the p53 tumour suppressor network. Nature,2007,447(7148):1130-1134.
[48]Yamakuchi M, Lowcnstcin C J. MiR-34, SIRT1 and p53:the feedback loop. Cell Cycle,2009,8(5):712-715.
[49]Yamakuchi M, Ferlito M, Lowenstein C J. miR-34a repression of SIRT1 regulates apoptosis. Proc Natl Acad Sci U S A,2008,105(36):13421-13426.
[50]Tazawa H, Tsuchiya N, Izumiya M, et al. Tumor-suppressive miR-34a induces senescence-like growth arrest through modulation of the E2F pathway in human colon cancer cells. Proc Natl Acad Sci U S A,2007,104(39):15472-15477.
[51]Wang X, Wang H K, Mccoy J P, et al. Oncogenic HPV infection interrupts the expression of tumor-suppressive miR-34a through viral oncoprotein E6. RNA,2009, 15(4):637-647.