Dnmt1和Dnmt3b在唾液腺黏液表皮样癌中的表达及意义
|
摘要
目的:探讨DNA甲基转移酶(DNA methyltransferase,Dnmt)在唾液腺黏液表皮样癌(mucoepidermoid carcinoma,MEC)中的表达及意义。方法:选取2010年1月—2013年9月间中国医科大学附属盛京医院口腔颌面外科手术切除的唾液腺术后的标本43例,正常唾液腺组织17例,应用免疫组织化学和蛋白免疫印迹(Western blot)方法检测正常组织及MEC组织中Dnmt1和Dnmt3b的表达。采用SPSS22.0软件包对数据进行统计学分析。结果:Dnmt1在MEC组织中的阳性表达率为37.21%,与正常唾液腺组织的17.65%相比,差异无显著性(P>0.05);Dnmt3b在MEC组织中的阳性表达率为83.72%,显著高于正常唾液腺组织的11.76%(P<0.01);但两者的高表达与临床病理参数之间无显著相关性(P>0.05)。结论:Dnmt3b在唾液腺MEC的发生中可能发挥一定作用。
PURPOSE:To investigate the effects of DNA methyltransferase in mucoepidermoid carcinoma of human salivary glands tissues.METHODS:Forty-three samples from mucoepidermoid carcinoma of salivary glands and 17 normal salivary gland tissues were collected from January 2010 to September 2013.Immunohistochemistry and Western blot were used to detect the expression of Dnmt1 and Dnmt3 b in normal tissues and specimen of mucoepidermoid carcinoma of salivary glands.The data were analysed with SPSS 22.0 software package.RESULTS:The positive expression rate of Dnmt1 in mucoepidermoid carcinoma tissue was 37.21%,and that in normal salivary gland tissues was 17.65%,there was no significant difference between them;the positive expression rate of Dnmt3 b in mucoepidermoid carcinoma tissue was83.72%,which was significantly higher than that in normal salivary gland tissue(11.76%,P<0.01).However,there was no significant correlation between high expression of Dnmt1 and Dnmt3 b and clinicopathological parameters.CONCLUSIONS:Dnmt3 b may play a role in the tumorigenesis of mucoepidermoid carcinoma in salivary glands.
PURPOSE:To investigate the effects of DNA methyltransferase in mucoepidermoid carcinoma of human salivary glands tissues.METHODS:Forty-three samples from mucoepidermoid carcinoma of salivary glands and 17 normal salivary gland tissues were collected from January 2010 to September 2013.Immunohistochemistry and Western blot were used to detect the expression of Dnmt1 and Dnmt3 b in normal tissues and specimen of mucoepidermoid carcinoma of salivary glands.The data were analysed with SPSS 22.0 software package.RESULTS:The positive expression rate of Dnmt1 in mucoepidermoid carcinoma tissue was 37.21%,and that in normal salivary gland tissues was 17.65%,there was no significant difference between them;the positive expression rate of Dnmt3 b in mucoepidermoid carcinoma tissue was83.72%,which was significantly higher than that in normal salivary gland tissue(11.76%,P<0.01).However,there was no significant correlation between high expression of Dnmt1 and Dnmt3 b and clinicopathological parameters.CONCLUSIONS:Dnmt3 b may play a role in the tumorigenesis of mucoepidermoid carcinoma in salivary glands.
引文
[1]Guzzo M,Locati LD,Prott FJ,et al.Major and minor salivary gland tumors[J].Crit Rev Oncol Hematol,2010,74(2):134-148.
[2]Sultan I,Rodriguez-Galindo C,Al-Sharabati S,et al.Salivary gland carcinomas in children and adolescents:A populationbased study,with comparison to adult cases[J].Head Neck,2011,33(10):1476-1481.
[3]Wang YL,Zhu YX,Chen TZ,et al.Clinicopathologic study of1176 salivary gland tumors in a Chinese population:experience of one cancer center 1997-2007[J].Acta Otolaryngol,2012,132(8):879-886.
[4]Chiaravalli S,Guzzo M,Bisogno G,et al.Salivary gland carcinomas in children and adolescents:the Italian TREP project experience[J].Pediatr Blood Cancer,2014,61(11):1961-1968.
[5]Coca-Pelaz A,Rodrigo JP,Triantafyllou A,et al.Salivary mucoepidermoid carcinoma revisited[J].Eur Arch Otorhinolaryngol,2015,272(4):799-819.
[6]Trenkic Bozinovic M,Krasic D,Katic V,et al.A retrospective review of 139 major and minor salivary gland tumors[J].Med Glas(Zenica),2015,12(1):73-78.
[7]Jin B,Li Y,Robertson KD.DNA methylation:superior or subordinate in the epigenetic hierarchy?[J].Genes Cancer,2011,2(6):607-617.
[8]Manimaran A,Manoharan S,Neelakandan M.Emodin efficacy on the AKT,MAPK,ERK and DNMT expression pattern during DMBA-induced oral carcinoma in golden syrian hamsters[J].Afr J Tradit Complement Altern Med,2016,13(6):186-193.
[9]Estève PO,Zhang G,Ponnaluri VK,et al.Binding of 14-3-3reader proteins to phosphorylated DNMT1 facilitates aberrant DNA methylation and gene expression[J].Nucleic Acids Res,2016,44(4):1642-1656.
[10]Poole CJ,Zheng W,Lodh A,et al.DNMT3B overexpression contributes to aberrant DNA methylation and MYC-driven tumor maintenance in T-ALL and Burkitt's lymphoma[J].Oncotarget,2017,8(44):76898-76920.
[11]Siebenkas C,Chiappinelli KB,Guzzetta AA,et al.Inhibiting DNA methylation activates cancer testis antigens and expression of the antigen processing and presentation machinery in colon and ovarian cancer cells[J].PLo S One,2017,12(6):e0179501.
[12]Al-Khafaji BM,Nestok BR,Katz RL.Fine-needle aspiration of154 parotid masses with histologic correlation:ten-year experience at the University of Texas M.D.Anderson Cancer Center[J].Cancer,1998,84(3):153-159.
[13]Joseph TP,Joseph CP,Jayalakshmy PS,et al.Diagnostic challenges in cytology of mucoepidermoid carcinoma:report of 6 cases with histopathological correlation[J].J Cytol,2015,32(1):21-24.
[14]Bajaj J,Gimenez C,Slim F,et al.Fine-needle aspiration cytology of mammary analog secretory carcinoma masquerading as low-grade mucoepidermoid carcinoma:case report with a review of the literature[J].Acta Cytol,2014,58(5):501-510.
[15]Dyhdalo KS,Chen L.Endobronchial ultrasound-guided fineneedle aspiration cytology of bronchial low-grade mucoepidermoid carcinoma:Rapid on-site evaluation of cytopathologic findings[J].Diagn Cytopathol,2013,41(12):1096-1099.
[16]Vargas PA,Gerhard R,Araújo Filho VJ,et al.Salivary gland tumors in a Brazilian population:a retrospective study of 124cases[J].Rev Hosp Clin Fac Med Sao Paulo,2002,57(6):271-276.
[17]Majumder S,Kutay H,Datta J,et al.Epigenetic regulation of metallothionein-i gene expression:differential regulation of methylated and unmethylated promoters by DNA methyltransferases and methyl Cp G binding proteins[J].J Cell Biochem,2006,97(6):1300-1316.
[18]Ghoshal K,Li X,Datta J,et al.A folate-and methyl-deficient diet alters the expression of DNA methyltransferases and methyl Cp G binding proteins involved in epigenetic gene silencing in livers of F344 rats[J].J Nutr,2006,136(6):1522-1527.
[19]Oue N,Kuraoka K,Kuniyasu H,et al.DNA methylation status of h MLH1,p16(INK4a),and CDH1 is not associated with m RNA expression levels of DNA methyltransferase and DNA demethylase in gastric carcinomas[J].Oncol Rep,2001,8(5):1085-1089.
[20]Wu F,Liu J,Qiu YL,et al.Correlation of chromosome damage and promoter methylation status of the DNA repair genes MGMT and h MLH1 in Chinese vinyl chloride monomer(VCM)-exposed workers[J].Int J Occup Med Environ Health,2013,26(1):173-182.
[21]Momparler RL,CtéS,Momparler LF,et al.Inhibition of DNA and histone methylation by 5-Aza-2'-deoxycytidine(decitabine)and 3-deazaneplanocin-A on antineoplastic action and gene expression in myeloid leukemic cells[J].Front Oncol,2017,7:19.
[22]Esteller M.Cancer epigenetics for the 21st century:What's next?[J].Genes Cancer,2011,2(6):604-606.
[23]Daniel FI,Cherubini K,Yurgel LS,et al.The role of epigenetic transcription repression and DNA methyltransferases in cancer[J].Cancer,2011,117(4):677-687.
[24]Ding WJ,Fang JY,Chen XY,et al.The expression and clinical significance of DNA methyltransferase proteins in human gastric cancer[J].Dig Dis Sci,2008,53(8):2083-2089.
[25]Yang J,Zhu XB,He LX,et al.Clinical significance of epigenetic silencing and re-expression of O6-methylguanine-DNA methyltransferase using epigenetic agents in laryngeal carcinoma[J].Oncol Lett,2015,9(1):35-42.
[26]Arai E,Kanai Y,Ushijima S,et al.Regional DNA hypermethylation and DNA methyltransferase(DNMT)1 protein overexpression in both renal tumors and corresponding nontumorous renal tissues[J].Int J Cancer,2006,119(2):288-296.
[27]Peng DF,Kanai Y,Sawada M,et al.Increased DNA methyltransferase 1(DNMT1)protein expression in precancerous conditions and ductal carcinomas of the pancreas[J].Cancer Sci,2005,96(7):403-408.
[28]Peralta-Arrieta I,Hernández-Sotelo D,Castro-Coronel Y,et al.DNMT3B modulates the expression of cancer-related genes and downregulates the expression of the gene VAV3 via methylation[J].Am J Cancer Res,2017,7(1):77-87.
[29]Sawada M,Kanai Y,Arai E,et al.Increased expression of DNA methyltransferase 1(DNMT1)protein in uterine cervix squamous cell carcinoma and its precursor lesion[J].Cancer Lett,2007,251(2):211-219.
[30]Fu XR,Sun ZC,Chang Y.Expression and clinical significance of P53,O6-methylguanine-dna methyltransferase and epidermal growth factor receptor in glioma[J].J Biol Regul Homeost Agents,2015,29(4):853-858.
[31]Liu S,Song L,Yao H,et al.Mi R-375 is epigenetically downregulated by HPV-16 E6 mediated DNMT1 upregulation and modulates EMT of cervical cancer cells by suppressing lnc RNA MALAT1[J].PLo S One,2016,11(9):e0163460.
[32]Au Yeung CL,Tsang WP,Tsang TY,et al.HPV-16 E6upregulation of DNMT1 through repression of tumor suppressor p53[J].Oncol Rep,2010,24(6):1599-1604.
[33]Zagorac S,Alcala S,Fernandez Bayon G,et al.DNMT1inhibition reprograms pancreatic cancer stem cells via upregulation of the mi R-17-92 cluster[J].Cancer Res,2016,76(15):4546-4558.
[34]Delpu Y,Cordelier P,Cho WC,et al.DNA methylation and cancer diagnosis[J].Int J Mol Sci,2013,14(7):15029-15058.
[35]Skowronski K,Dubey S,Rodenhiser D,et al.Ischemia dysregulates DNA methyltransferases and p16INK4a methylation in human colorectal cancer cells[J].Epigenetics,2010,5(6):547-556.
[36]Gopalakrishnan S,Van Emburgh BO,Robertson KD.DNA methylation in development and human disease[J].Mutat Res,2008,647(1-2):30-38.
[37]De Souza RA,Islam SA,Mc Ewen LM,et al.DNA methylation profiling in human huntington's disease brain[J].Hum Mol Genet,2016,25(10):2013-2030.
[38]Li W,Wang Y,Fang X,et al.Differential expression and clinical significance of DNA methyltransferase 3B(DNMT3B),phosphatase and tensin homolog(PTEN)and Human Mut L Homologs 1(h MLH1)in endometrial carcinomas[J].Med Sci Monit,2017,23:938-947.
[39]Su X,Lv C,Qiao F,et al.Expression pattern and clinical significance of DNA methyltransferase 3B variants in gastric carcinoma[J].Oncol Rep,2010,23(3):819-826.
[40]王晓宁,姚建娜,王晓娟,等.DNMT3b基因在骨髓瘤RPMI8226细胞株中的表达及其生物学意义[J].中国实验血液学杂志,2017,25(5):1431-1435.
[41]Cavaliéri Gomes C,da Silveira e Oliveira C,Santos Pimenta LG,et al.Immunolocalization of DNMT1 and DNMT3a in salivary gland neoplasms[J].Pathobiology,2009,76(3):136-140.
[42]Walker BA,Wardell CP,Chiecchio L,et al.Aberrant global methylation patterns affect the molecular pathogenesis and prognosis of multiple myeloma[J].Blood,2011,117(2):553-562.
[43]Takayama K,Shimoda N,Takanaga S,et al.Expression patterns of dnmt3aa,dnmt3ab,and dnmt4 during development and fin regeneration in zebrafish[J].Gene Expr Patterns,2014,14(2):105-110.
[44]Zhang C,Li J,Huang T,et al.Meta-analysis of DNA methylation biomarkers in hepatocellular carcinoma[J].Oncotarget,2016,7(49):81255-81267.
[45]Hua D,Hu Y,Wu YY,et al.Quantitative methylation analysis of multiple genes using methylation-sensitive restriction enzymebased quantitative PCR for the detection of hepatocellular carcinoma[J].Exp Mol Pathol,2011,91(1):455-460.
[46]Fan H,Chen L,Zhang F,et al.MTSS1,a novel target of DNA methyltransferase 3B,functions as a tumor suppressor in hepatocellular carcinoma[J].Oncogene,2012,31(18):2298-2308.
[2]Sultan I,Rodriguez-Galindo C,Al-Sharabati S,et al.Salivary gland carcinomas in children and adolescents:A populationbased study,with comparison to adult cases[J].Head Neck,2011,33(10):1476-1481.
[3]Wang YL,Zhu YX,Chen TZ,et al.Clinicopathologic study of1176 salivary gland tumors in a Chinese population:experience of one cancer center 1997-2007[J].Acta Otolaryngol,2012,132(8):879-886.
[4]Chiaravalli S,Guzzo M,Bisogno G,et al.Salivary gland carcinomas in children and adolescents:the Italian TREP project experience[J].Pediatr Blood Cancer,2014,61(11):1961-1968.
[5]Coca-Pelaz A,Rodrigo JP,Triantafyllou A,et al.Salivary mucoepidermoid carcinoma revisited[J].Eur Arch Otorhinolaryngol,2015,272(4):799-819.
[6]Trenkic Bozinovic M,Krasic D,Katic V,et al.A retrospective review of 139 major and minor salivary gland tumors[J].Med Glas(Zenica),2015,12(1):73-78.
[7]Jin B,Li Y,Robertson KD.DNA methylation:superior or subordinate in the epigenetic hierarchy?[J].Genes Cancer,2011,2(6):607-617.
[8]Manimaran A,Manoharan S,Neelakandan M.Emodin efficacy on the AKT,MAPK,ERK and DNMT expression pattern during DMBA-induced oral carcinoma in golden syrian hamsters[J].Afr J Tradit Complement Altern Med,2016,13(6):186-193.
[9]Estève PO,Zhang G,Ponnaluri VK,et al.Binding of 14-3-3reader proteins to phosphorylated DNMT1 facilitates aberrant DNA methylation and gene expression[J].Nucleic Acids Res,2016,44(4):1642-1656.
[10]Poole CJ,Zheng W,Lodh A,et al.DNMT3B overexpression contributes to aberrant DNA methylation and MYC-driven tumor maintenance in T-ALL and Burkitt's lymphoma[J].Oncotarget,2017,8(44):76898-76920.
[11]Siebenkas C,Chiappinelli KB,Guzzetta AA,et al.Inhibiting DNA methylation activates cancer testis antigens and expression of the antigen processing and presentation machinery in colon and ovarian cancer cells[J].PLo S One,2017,12(6):e0179501.
[12]Al-Khafaji BM,Nestok BR,Katz RL.Fine-needle aspiration of154 parotid masses with histologic correlation:ten-year experience at the University of Texas M.D.Anderson Cancer Center[J].Cancer,1998,84(3):153-159.
[13]Joseph TP,Joseph CP,Jayalakshmy PS,et al.Diagnostic challenges in cytology of mucoepidermoid carcinoma:report of 6 cases with histopathological correlation[J].J Cytol,2015,32(1):21-24.
[14]Bajaj J,Gimenez C,Slim F,et al.Fine-needle aspiration cytology of mammary analog secretory carcinoma masquerading as low-grade mucoepidermoid carcinoma:case report with a review of the literature[J].Acta Cytol,2014,58(5):501-510.
[15]Dyhdalo KS,Chen L.Endobronchial ultrasound-guided fineneedle aspiration cytology of bronchial low-grade mucoepidermoid carcinoma:Rapid on-site evaluation of cytopathologic findings[J].Diagn Cytopathol,2013,41(12):1096-1099.
[16]Vargas PA,Gerhard R,Araújo Filho VJ,et al.Salivary gland tumors in a Brazilian population:a retrospective study of 124cases[J].Rev Hosp Clin Fac Med Sao Paulo,2002,57(6):271-276.
[17]Majumder S,Kutay H,Datta J,et al.Epigenetic regulation of metallothionein-i gene expression:differential regulation of methylated and unmethylated promoters by DNA methyltransferases and methyl Cp G binding proteins[J].J Cell Biochem,2006,97(6):1300-1316.
[18]Ghoshal K,Li X,Datta J,et al.A folate-and methyl-deficient diet alters the expression of DNA methyltransferases and methyl Cp G binding proteins involved in epigenetic gene silencing in livers of F344 rats[J].J Nutr,2006,136(6):1522-1527.
[19]Oue N,Kuraoka K,Kuniyasu H,et al.DNA methylation status of h MLH1,p16(INK4a),and CDH1 is not associated with m RNA expression levels of DNA methyltransferase and DNA demethylase in gastric carcinomas[J].Oncol Rep,2001,8(5):1085-1089.
[20]Wu F,Liu J,Qiu YL,et al.Correlation of chromosome damage and promoter methylation status of the DNA repair genes MGMT and h MLH1 in Chinese vinyl chloride monomer(VCM)-exposed workers[J].Int J Occup Med Environ Health,2013,26(1):173-182.
[21]Momparler RL,CtéS,Momparler LF,et al.Inhibition of DNA and histone methylation by 5-Aza-2'-deoxycytidine(decitabine)and 3-deazaneplanocin-A on antineoplastic action and gene expression in myeloid leukemic cells[J].Front Oncol,2017,7:19.
[22]Esteller M.Cancer epigenetics for the 21st century:What's next?[J].Genes Cancer,2011,2(6):604-606.
[23]Daniel FI,Cherubini K,Yurgel LS,et al.The role of epigenetic transcription repression and DNA methyltransferases in cancer[J].Cancer,2011,117(4):677-687.
[24]Ding WJ,Fang JY,Chen XY,et al.The expression and clinical significance of DNA methyltransferase proteins in human gastric cancer[J].Dig Dis Sci,2008,53(8):2083-2089.
[25]Yang J,Zhu XB,He LX,et al.Clinical significance of epigenetic silencing and re-expression of O6-methylguanine-DNA methyltransferase using epigenetic agents in laryngeal carcinoma[J].Oncol Lett,2015,9(1):35-42.
[26]Arai E,Kanai Y,Ushijima S,et al.Regional DNA hypermethylation and DNA methyltransferase(DNMT)1 protein overexpression in both renal tumors and corresponding nontumorous renal tissues[J].Int J Cancer,2006,119(2):288-296.
[27]Peng DF,Kanai Y,Sawada M,et al.Increased DNA methyltransferase 1(DNMT1)protein expression in precancerous conditions and ductal carcinomas of the pancreas[J].Cancer Sci,2005,96(7):403-408.
[28]Peralta-Arrieta I,Hernández-Sotelo D,Castro-Coronel Y,et al.DNMT3B modulates the expression of cancer-related genes and downregulates the expression of the gene VAV3 via methylation[J].Am J Cancer Res,2017,7(1):77-87.
[29]Sawada M,Kanai Y,Arai E,et al.Increased expression of DNA methyltransferase 1(DNMT1)protein in uterine cervix squamous cell carcinoma and its precursor lesion[J].Cancer Lett,2007,251(2):211-219.
[30]Fu XR,Sun ZC,Chang Y.Expression and clinical significance of P53,O6-methylguanine-dna methyltransferase and epidermal growth factor receptor in glioma[J].J Biol Regul Homeost Agents,2015,29(4):853-858.
[31]Liu S,Song L,Yao H,et al.Mi R-375 is epigenetically downregulated by HPV-16 E6 mediated DNMT1 upregulation and modulates EMT of cervical cancer cells by suppressing lnc RNA MALAT1[J].PLo S One,2016,11(9):e0163460.
[32]Au Yeung CL,Tsang WP,Tsang TY,et al.HPV-16 E6upregulation of DNMT1 through repression of tumor suppressor p53[J].Oncol Rep,2010,24(6):1599-1604.
[33]Zagorac S,Alcala S,Fernandez Bayon G,et al.DNMT1inhibition reprograms pancreatic cancer stem cells via upregulation of the mi R-17-92 cluster[J].Cancer Res,2016,76(15):4546-4558.
[34]Delpu Y,Cordelier P,Cho WC,et al.DNA methylation and cancer diagnosis[J].Int J Mol Sci,2013,14(7):15029-15058.
[35]Skowronski K,Dubey S,Rodenhiser D,et al.Ischemia dysregulates DNA methyltransferases and p16INK4a methylation in human colorectal cancer cells[J].Epigenetics,2010,5(6):547-556.
[36]Gopalakrishnan S,Van Emburgh BO,Robertson KD.DNA methylation in development and human disease[J].Mutat Res,2008,647(1-2):30-38.
[37]De Souza RA,Islam SA,Mc Ewen LM,et al.DNA methylation profiling in human huntington's disease brain[J].Hum Mol Genet,2016,25(10):2013-2030.
[38]Li W,Wang Y,Fang X,et al.Differential expression and clinical significance of DNA methyltransferase 3B(DNMT3B),phosphatase and tensin homolog(PTEN)and Human Mut L Homologs 1(h MLH1)in endometrial carcinomas[J].Med Sci Monit,2017,23:938-947.
[39]Su X,Lv C,Qiao F,et al.Expression pattern and clinical significance of DNA methyltransferase 3B variants in gastric carcinoma[J].Oncol Rep,2010,23(3):819-826.
[40]王晓宁,姚建娜,王晓娟,等.DNMT3b基因在骨髓瘤RPMI8226细胞株中的表达及其生物学意义[J].中国实验血液学杂志,2017,25(5):1431-1435.
[41]Cavaliéri Gomes C,da Silveira e Oliveira C,Santos Pimenta LG,et al.Immunolocalization of DNMT1 and DNMT3a in salivary gland neoplasms[J].Pathobiology,2009,76(3):136-140.
[42]Walker BA,Wardell CP,Chiecchio L,et al.Aberrant global methylation patterns affect the molecular pathogenesis and prognosis of multiple myeloma[J].Blood,2011,117(2):553-562.
[43]Takayama K,Shimoda N,Takanaga S,et al.Expression patterns of dnmt3aa,dnmt3ab,and dnmt4 during development and fin regeneration in zebrafish[J].Gene Expr Patterns,2014,14(2):105-110.
[44]Zhang C,Li J,Huang T,et al.Meta-analysis of DNA methylation biomarkers in hepatocellular carcinoma[J].Oncotarget,2016,7(49):81255-81267.
[45]Hua D,Hu Y,Wu YY,et al.Quantitative methylation analysis of multiple genes using methylation-sensitive restriction enzymebased quantitative PCR for the detection of hepatocellular carcinoma[J].Exp Mol Pathol,2011,91(1):455-460.
[46]Fan H,Chen L,Zhang F,et al.MTSS1,a novel target of DNA methyltransferase 3B,functions as a tumor suppressor in hepatocellular carcinoma[J].Oncogene,2012,31(18):2298-2308.