• 華中科技大學(xué)同濟(jì)醫(yī)學(xué)院附屬同濟(jì)醫(yī)院膽胰外科（武漢430030）;

目的 探討聯(lián)合使用DNA甲基化酶抑制劑（DNA methyltransferase inhibitor, DNMTi）和組蛋白脫乙?；敢种苿╤istone deacetylase inhibitor, HDACi）干預(yù)膽管癌細(xì)胞后，對E-cadherin 基因的表達(dá)和細(xì)胞侵襲力的影響。
方法 根據(jù)給予膽管癌細(xì)胞不同的處理方法分為4組： 空白對照組、肼屈嗪組、丙戊酸組和肼屈嗪+丙戊酸組，用RT-PCR、Western blot檢測E-cadherin基因和蛋白的表達(dá)，用Transwell法檢測細(xì)胞體外侵襲、轉(zhuǎn)移力。
結(jié)果 空白對照組和丙戊酸組E-cadherin 基因和蛋白均無表達(dá)，肼屈嗪+丙戊酸組E-cadherin基因和蛋白表達(dá)量均明顯高于肼屈嗪組（ P ＜ 0.01）； 同時肼屈嗪+丙戊酸組細(xì)胞的侵襲、轉(zhuǎn)移力較空白對照組、丙戊酸組和肼屈嗪組明顯下降（ P ＜ 0.01）。
結(jié)論 DNMTi與HDACi協(xié)同恢復(fù)E-cadherin基因的表達(dá)，降低細(xì)胞侵襲、轉(zhuǎn)移力，對于膽管癌的治療有著重要的作用

引用本文： 李宏,舒藝,陳勇軍,鄒聲泉. DNMTi與HDACi對膽管癌細(xì)胞 E-cadherin表達(dá)和細(xì)胞侵襲力的影響. 中國普外基礎(chǔ)與臨床雜志, 2009, 16(1): 44-47. doi: 復(fù)制

1. 8 de la Cruz-Hernández E, Pérez-Cárdenas E, Contreras-Paredes A, et al . The effects of DNA methylation and histone deacetylase inhibitors on human papillomavirus early gene expression in cervical cancer, an in vitro and clinical study [Ｊ] . Virol J, 2007; 4： 18 9 Herman JG, Graff JR, Myhnen S, et al . Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands [Ｊ] . Proc Natl Acad Sci USA, 1996; 93(18)： 9821.
2. Berx G, Cleton-Jansen AM, Nollet F, et al . E-cadherin is a tumour/invasion suppressor gene mutated in human lobular breast cancers [Ｊ] . EMBO J, 1995; 14(24)： 6107.
3. 李強， 王劍明， 劉聰， 等. aPKC-ι和E-cadherin 在膽管癌組織中的表達(dá)及意義 [Ｊ] . 癌癥， 2007； 26(7)： 715.
4. Yang B, House MG, Guo M, et al . Promoter methylation profiles of tumor suppressor genes in intrahepatic and extrahepatic cholangiocarcinoma [Ｊ] . Mod Pathol, 2005; 18(3)： 412.
5. Santini V, Kantarjian HM, Issa JP. Changes in DNA methylation in neoplasia: pathophysiology and therapeutic implications [Ｊ] . Ann Intern Med, 2001; 134(7)： 573.
6. Zhu WG, Otterson GA. The interaction of histone deacetylase inhibitors and DNA methyltransferase inhibitors in the treatment of human cancer cells [Ｊ] . Curr Med Chem Anticancer Agents, 2003; 3(3)： 187.
7. Segura-Pacheco B, Trejo-Becerril C, Perez-Cardenas E, et al . Reactivation of tumor suppressor genes by the cardiovascular drugs hydralazine and procainamide and their potential use in cancer therapy [Ｊ] . Clin Cancer Res, 2003; 9(5)： 1596.
8. Chavez-Blanco A, Perez-Plasencia C, Perez-Cardenas E, et al . Antineoplastic effects of the DNA methylation inhibitor hydralazine and the histone deacety lase inhibitor valproic acid in cancer cell lines [Ｊ] . Cancer Cell Int, 2006; 6： 2.
9. Vleminckx K, Vakaet L Jr, Mareel M, et al . Genetic manipulation of E-cadherin expression by epithelial tumor cells reveals an invasion suppressor role [Ｊ] . Cell, 1991; 66(1)： 107.
10. 車向明， 王曙逢， 樊林， 等. E-cadherin反義寡核苷酸對腫瘤細(xì)胞浸潤能力影響的研究 [Ｊ] . 中國普外基礎(chǔ)與臨床雜志， 2006； 13(2)： 191.
11. Hirohashi S. Inactivation of the E-cadherin-mediated cell adhesion system in human cancers [Ｊ] . Am J Pathol, 1998; 153 (2)： 333.
12. Mareel M, Bracke M, van Roy F. Cancer metastasis: negative regulation by an invasion-suppressor complex [Ｊ] . Cancer Detect Prev, 1995; 19(5)： 451.
13. 鄒聲泉. 膽管癌外科治療的現(xiàn)狀與展望 [Ｊ] . 中國普外基礎(chǔ)與臨床雜志， 2008； 15(2)： 77.
14. 李哲夫， 史光軍. 膽管癌的基因表達(dá)及其臨床意義 [Ｊ] . 中國普外基礎(chǔ)與臨床雜志， 2000； 7(2)： 131.
15. Mikami T, Saegusa M, Mitomi H, et al . Significant correlations of E-cadherin, catenin, and CD44 variant form expression with carcinoma cell differentiation and prognosis of extrahepatic bile duct carcinomas [Ｊ] . Am J Clin Pathol, 2001; 116(3)： 369.
16. Asayama Y, Taguchi Ki K, Aishima Si S, et al . The mode of tumour progression in combined hepatocellular carcinoma and cholangiocarcinoma: an immunohistochemical analysis of E-cadherin, alpha-catenin and beta-catenin [Ｊ] . Liver, 2002; 22 (1)： 43.
17. Sharma D, Blum J, Yang X, et al . Release of methyl CpG binding proteins and histone deacetylase 1 from the Estrogen receptor alpha (ER) promoter upon reactivation in ER-negative human breast cancer cells [Ｊ] . Mol Endocrinol, 2005; 19(7)： 1740.
18. El-Osta A, Kantharidis P, Zalcberg JR, et al . Precipitous release of methyl-CpG binding protein 2 and histone deacetylase 1 from the methylated human multidrug resistance gene (MDR1) on activation [Ｊ] . Mol Cell Biol, 2002; 22(6)： 1844.
19. Zhang Y, Fatima N, Dufau ML. Coordinated changes in DNA methylation and histone modifications regulate silencing/derepression of luteinizing hormone receptor gene transcription [Ｊ] . Mol Cell Biol, 2005; 25(18)： 7929.
  1. 1. 8 de la Cruz-Hernández E, Pérez-Cárdenas E, Contreras-Paredes A, et al . The effects of DNA methylation and histone deacetylase inhibitors on human papillomavirus early gene expression in cervical cancer, an in vitro and clinical study [Ｊ] . Virol J, 2007; 4： 18 9 Herman JG, Graff JR, Myhnen S, et al . Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands [Ｊ] . Proc Natl Acad Sci USA, 1996; 93(18)： 9821.
  2. 2. Berx G, Cleton-Jansen AM, Nollet F, et al . E-cadherin is a tumour/invasion suppressor gene mutated in human lobular breast cancers [Ｊ] . EMBO J, 1995; 14(24)： 6107.
  3. 3. 李強， 王劍明， 劉聰， 等. aPKC-ι和E-cadherin 在膽管癌組織中的表達(dá)及意義 [Ｊ] . 癌癥， 2007； 26(7)： 715.
  4. 4. Yang B, House MG, Guo M, et al . Promoter methylation profiles of tumor suppressor genes in intrahepatic and extrahepatic cholangiocarcinoma [Ｊ] . Mod Pathol, 2005; 18(3)： 412.
  5. 5. Santini V, Kantarjian HM, Issa JP. Changes in DNA methylation in neoplasia: pathophysiology and therapeutic implications [Ｊ] . Ann Intern Med, 2001; 134(7)： 573.
  6. 6. Zhu WG, Otterson GA. The interaction of histone deacetylase inhibitors and DNA methyltransferase inhibitors in the treatment of human cancer cells [Ｊ] . Curr Med Chem Anticancer Agents, 2003; 3(3)： 187.
  7. 7. Segura-Pacheco B, Trejo-Becerril C, Perez-Cardenas E, et al . Reactivation of tumor suppressor genes by the cardiovascular drugs hydralazine and procainamide and their potential use in cancer therapy [Ｊ] . Clin Cancer Res, 2003; 9(5)： 1596.
  8. 8. Chavez-Blanco A, Perez-Plasencia C, Perez-Cardenas E, et al . Antineoplastic effects of the DNA methylation inhibitor hydralazine and the histone deacety lase inhibitor valproic acid in cancer cell lines [Ｊ] . Cancer Cell Int, 2006; 6： 2.
  9. 9. Vleminckx K, Vakaet L Jr, Mareel M, et al . Genetic manipulation of E-cadherin expression by epithelial tumor cells reveals an invasion suppressor role [Ｊ] . Cell, 1991; 66(1)： 107.
  10. 10. 車向明， 王曙逢， 樊林， 等. E-cadherin反義寡核苷酸對腫瘤細(xì)胞浸潤能力影響的研究 [Ｊ] . 中國普外基礎(chǔ)與臨床雜志， 2006； 13(2)： 191.
  11. 11. Hirohashi S. Inactivation of the E-cadherin-mediated cell adhesion system in human cancers [Ｊ] . Am J Pathol, 1998; 153 (2)： 333.
  12. 12. Mareel M, Bracke M, van Roy F. Cancer metastasis: negative regulation by an invasion-suppressor complex [Ｊ] . Cancer Detect Prev, 1995; 19(5)： 451.
  13. 13. 鄒聲泉. 膽管癌外科治療的現(xiàn)狀與展望 [Ｊ] . 中國普外基礎(chǔ)與臨床雜志， 2008； 15(2)： 77.
  14. 14. 李哲夫， 史光軍. 膽管癌的基因表達(dá)及其臨床意義 [Ｊ] . 中國普外基礎(chǔ)與臨床雜志， 2000； 7(2)： 131.
  15. 15. Mikami T, Saegusa M, Mitomi H, et al . Significant correlations of E-cadherin, catenin, and CD44 variant form expression with carcinoma cell differentiation and prognosis of extrahepatic bile duct carcinomas [Ｊ] . Am J Clin Pathol, 2001; 116(3)： 369.
  16. 16. Asayama Y, Taguchi Ki K, Aishima Si S, et al . The mode of tumour progression in combined hepatocellular carcinoma and cholangiocarcinoma: an immunohistochemical analysis of E-cadherin, alpha-catenin and beta-catenin [Ｊ] . Liver, 2002; 22 (1)： 43.
  17. 17. Sharma D, Blum J, Yang X, et al . Release of methyl CpG binding proteins and histone deacetylase 1 from the Estrogen receptor alpha (ER) promoter upon reactivation in ER-negative human breast cancer cells [Ｊ] . Mol Endocrinol, 2005; 19(7)： 1740.
  18. 18. El-Osta A, Kantharidis P, Zalcberg JR, et al . Precipitous release of methyl-CpG binding protein 2 and histone deacetylase 1 from the methylated human multidrug resistance gene (MDR1) on activation [Ｊ] . Mol Cell Biol, 2002; 22(6)： 1844.
  19. 19. Zhang Y, Fatima N, Dufau ML. Coordinated changes in DNA methylation and histone modifications regulate silencing/derepression of luteinizing hormone receptor gene transcription [Ｊ] . Mol Cell Biol, 2005; 25(18)： 7929.