邻苯二甲酸二乙基己酯对前列腺癌LNCaP细胞DNA甲基化的影响
详细信息 查看官网全文
摘要
[目的]研究医疗塑材中邻苯二甲酸二异辛酯(Di-2-Ethylhexyl Phthalate,DEHP)的主要毒性代谢产物邻苯二甲酸二乙基己酯(Mono-2-Ethyhexyl Phthalate,MEHP)对前列腺癌细胞系LNCaP细胞中全基因组5-mc、5-hmc以及抑癌基因PTCH甲基化的影响。[方法]对LNCaP细胞进行MEHP(1、5、10和25μmol/L)体外染毒72 h,利用ELISA法测定5-mc、5-hmc的含量,并通过焦磷酸测序法测定PTCH多个CpG位点的甲基化水平。[结果]与对照组相比,1、5、10和25μmol/L剂量组的MEHP可使LNCaP细胞中5-mc(%)显著性降低(P<0.01),且存在一定的剂量反应趋势;与对照组相比,经MEHP处理后,LNCaP细胞中5-hmc(%)、PTCH各CpG位点甲基化水平、PTCH总甲基化水平的改变均无统计学差异。[结论]塑化剂DEHP的医源性暴露普遍存在,其主要代谢产物MEHP可能通过降低全基因组5-mc含量,从而促进前列腺癌的恶化、转移。
引文
[1]Jemal A,Samuels A,Ghafoor A,et al.Cancer Statistics[J].CA Cancer J Clin.2003(53):5-26.
[2]SEER Stat Fact Sheets:Prostate Cancer,http://seer,cancer,gov/statfactshtmlprost.html[Z].
[3]Lamont K R,Tindall D J.Minireview:Alternative activation pathways for the androgen receptor in prostate cancer[J].Mol Endocrinol.2011,25(6):897-907.
[4]宋晓峰,魏光辉.医用塑料增塑剂DEHP安全性研究及对策[J].国外医学(卫生学分册).2005(06):38-41.
[5]Safety Assessment of Di(2-ethylhexyl)phthalate(DEHP)Released from PVC Medical Devices,http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM080457.pdf.
[6]Lee H R,Hwang K A,Choi K C.The estrogen receptor signaling pathway activated by phthalates is linked with transforming growth factor-beta in the progression of LNCaP prostate cancer models[J].Int J Oncol.2014,45(2):595-602.
[7]Ehrlich M.DNA hypomethylation in cancer cells[J].Epigenomics.2009,1(2):239-259.
[8]Jones PA,Baylin S B.The epigenomics of cancer[J].Cell.2007,128(4):683-692.
[9]Wolf I,Bose S,Desmond J C,et al.Unmasking of epigenetically silenced genes reveals DNA promoter methylation and reduced expression of PTCH in breast cancer[J].Breast Cancer Res Treat 2007,105(2):139-155.
[10]Du P,Ye H R,Gao J,et al.Methylation of PTCH1a gene in a subset of gastric cancers[J].World J Gastroenterol.2009,15(30):3799-3806.
[11]Lof-Ohlin Z M,Levanat S,Sabol M,et al.Promoter methylation in the PTCH gene in cervical epithelial cancer and ovarian cancer tissue as studied by eight novel Pyrosequencing(R)assays[J].Int J Oncol.2011,38(3):685-692.
[12]Rodriguez J,Frigola J,Vendrell E,et al.Chromosomal instability correlates with genome-wide DNA demethylation in human primary colorectal cancers[J].Cancer Res.2006,66(17):8462-9468.
[13]Wilson A S,Power B E,Molloy P L DNA hypomethylation and human diseases[J].Biochim Biophys Acta2007,1775(1):138-162.
[14]Cravo M,Pinto R,Fidalgo P,et al.Global DNA hypomethylation occurs in the early stages of intestinal type gastric carcinoma[J].Gut 1996,39(3):434-438.
[15]Soares J,Pinto A E,Cunha C V,et al.Global DNA hypomethylation in breast carcinoma:correlation with prognostic factors and tumor progression[J].Cancer.1999,85(1):112-118.
[16]Yegnasubramanian S,Haffner M C,Zhang Y,et al.DNA Hypomethylation Arises Later in Prostate Cancer Progression than CpG Island Hypermethylation and Contributes to Metastatic Tumor Heterogeneity[J].Cancer Research.2008,68(21):8954-8967.
[17.]Yang B,Sun H,Lin W,et al.Evaluation of global DNA hypomethylation in human prostate cancer and prostatic intraepithelial neoplasm tissues by immunohistochemistry[J].Urologic Oncology:Seminars and Original Investigations.2013,31(5):628-634.
[18]Brothman A R,Swanson G,Maxwell T M,et al.Global hypomethylation is common in prostate cancer cells:a quantitative predictor for clinical outcome?[J].Cancer Genet Cytogenet.2005,156(1):31-36.
[19]Bedford M T,van Helden P D.Hypomethylation of DNA in pathological conditions of the human prostate[J].Cancer Res.1987,47(20):5274-5276.
[20]Rusiecki J A,Baccarelli A,Bollati V,et al.Global DNA hypomethylation is associated with high serum-persistent organic pollutants in Greenlandic Inuit[J].Environ Health Perspect.2008,116(11):1547-1552.
[21]Kim K Y,Kim D S,Lee S K,et al.Association of low-dose exposure to persistent organic pollutants with global DNA hypomethylation in healthy Koreans[J].Environ Health PerspecL 2010,118(3):370-374.
[22]Nestor C E,Ottaviano R,Reddington J,et al.Tissue type is a major modifier of the 5-hydroxymethylcytosine content of human genes[J].Genome Res.2012,22(3):467-477.
[23]Li W,Liu M.Distribution of 5-hydroxymethylcytosine in different human tissues[J].J Nucleic Acids.2011,2011:870726.
[24]Yang H,Liu Y,Bai F,et al.Tumor development is associated with decrease of TET gene expression and 5-methylcytosine hydroxylation[J].Oncogene.2013,32(5):663-669.
[25]Chowdhury B,Cho I H,Hahn N,et al.Quantification of 5-methylcytosine,5-hydroxymethylcytosine and 5-carboxylcytosine from the blood of cancer patients by an enzyme-based immunoassay[J].Anal Chim Acta2014,852:212-217.
[26]Haffner M C,Chaux A,Meeker A K,et al.Global 5-hydroxymethylcytosine content is significantly reduced in tissue stem/progenitor cell compartments and in human cancers[J].Oncotarget 2011,2(8):627-637.
[27]Baylin S B.DNA methylation and gene silencing in cancer[J].Nat Clin Pract Oncol.2005,2 Suppl 1:S4-S11.
[28]Cohen M J.The hedgehog signaling network[J].Am J Med Genet A.2003,123A(1):5-28.
[29]Chen M,Tanner M,Levine AC,et al.Androgenic regulation of hedgehog signaling pathway components in prostate cancer cells[J].Cell Cycle.2009,8(1):149-157.
[30]Wolf I,Bose S,Desmond J C,et al.Unmasking of epigenetically silenced genes reveals DNA promoter methylation and reduced expression of PTCH in breast cancer[J].Breast Cancer Res Treat 2007,105(2):139-155.
[31]Li L C,Carroll P R,Dahiya R.Epigenetic changes in prostate cancer:implication for diagnosis and treatment[J].J Natl Cancer Inst 2005,97(2):103-115.
[2]SEER Stat Fact Sheets:Prostate Cancer,http://seer,cancer,gov/statfactshtmlprost.html[Z].
[3]Lamont K R,Tindall D J.Minireview:Alternative activation pathways for the androgen receptor in prostate cancer[J].Mol Endocrinol.2011,25(6):897-907.
[4]宋晓峰,魏光辉.医用塑料增塑剂DEHP安全性研究及对策[J].国外医学(卫生学分册).2005(06):38-41.
[5]Safety Assessment of Di(2-ethylhexyl)phthalate(DEHP)Released from PVC Medical Devices,http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM080457.pdf.
[6]Lee H R,Hwang K A,Choi K C.The estrogen receptor signaling pathway activated by phthalates is linked with transforming growth factor-beta in the progression of LNCaP prostate cancer models[J].Int J Oncol.2014,45(2):595-602.
[7]Ehrlich M.DNA hypomethylation in cancer cells[J].Epigenomics.2009,1(2):239-259.
[8]Jones PA,Baylin S B.The epigenomics of cancer[J].Cell.2007,128(4):683-692.
[9]Wolf I,Bose S,Desmond J C,et al.Unmasking of epigenetically silenced genes reveals DNA promoter methylation and reduced expression of PTCH in breast cancer[J].Breast Cancer Res Treat 2007,105(2):139-155.
[10]Du P,Ye H R,Gao J,et al.Methylation of PTCH1a gene in a subset of gastric cancers[J].World J Gastroenterol.2009,15(30):3799-3806.
[11]Lof-Ohlin Z M,Levanat S,Sabol M,et al.Promoter methylation in the PTCH gene in cervical epithelial cancer and ovarian cancer tissue as studied by eight novel Pyrosequencing(R)assays[J].Int J Oncol.2011,38(3):685-692.
[12]Rodriguez J,Frigola J,Vendrell E,et al.Chromosomal instability correlates with genome-wide DNA demethylation in human primary colorectal cancers[J].Cancer Res.2006,66(17):8462-9468.
[13]Wilson A S,Power B E,Molloy P L DNA hypomethylation and human diseases[J].Biochim Biophys Acta2007,1775(1):138-162.
[14]Cravo M,Pinto R,Fidalgo P,et al.Global DNA hypomethylation occurs in the early stages of intestinal type gastric carcinoma[J].Gut 1996,39(3):434-438.
[15]Soares J,Pinto A E,Cunha C V,et al.Global DNA hypomethylation in breast carcinoma:correlation with prognostic factors and tumor progression[J].Cancer.1999,85(1):112-118.
[16]Yegnasubramanian S,Haffner M C,Zhang Y,et al.DNA Hypomethylation Arises Later in Prostate Cancer Progression than CpG Island Hypermethylation and Contributes to Metastatic Tumor Heterogeneity[J].Cancer Research.2008,68(21):8954-8967.
[17.]Yang B,Sun H,Lin W,et al.Evaluation of global DNA hypomethylation in human prostate cancer and prostatic intraepithelial neoplasm tissues by immunohistochemistry[J].Urologic Oncology:Seminars and Original Investigations.2013,31(5):628-634.
[18]Brothman A R,Swanson G,Maxwell T M,et al.Global hypomethylation is common in prostate cancer cells:a quantitative predictor for clinical outcome?[J].Cancer Genet Cytogenet.2005,156(1):31-36.
[19]Bedford M T,van Helden P D.Hypomethylation of DNA in pathological conditions of the human prostate[J].Cancer Res.1987,47(20):5274-5276.
[20]Rusiecki J A,Baccarelli A,Bollati V,et al.Global DNA hypomethylation is associated with high serum-persistent organic pollutants in Greenlandic Inuit[J].Environ Health Perspect.2008,116(11):1547-1552.
[21]Kim K Y,Kim D S,Lee S K,et al.Association of low-dose exposure to persistent organic pollutants with global DNA hypomethylation in healthy Koreans[J].Environ Health PerspecL 2010,118(3):370-374.
[22]Nestor C E,Ottaviano R,Reddington J,et al.Tissue type is a major modifier of the 5-hydroxymethylcytosine content of human genes[J].Genome Res.2012,22(3):467-477.
[23]Li W,Liu M.Distribution of 5-hydroxymethylcytosine in different human tissues[J].J Nucleic Acids.2011,2011:870726.
[24]Yang H,Liu Y,Bai F,et al.Tumor development is associated with decrease of TET gene expression and 5-methylcytosine hydroxylation[J].Oncogene.2013,32(5):663-669.
[25]Chowdhury B,Cho I H,Hahn N,et al.Quantification of 5-methylcytosine,5-hydroxymethylcytosine and 5-carboxylcytosine from the blood of cancer patients by an enzyme-based immunoassay[J].Anal Chim Acta2014,852:212-217.
[26]Haffner M C,Chaux A,Meeker A K,et al.Global 5-hydroxymethylcytosine content is significantly reduced in tissue stem/progenitor cell compartments and in human cancers[J].Oncotarget 2011,2(8):627-637.
[27]Baylin S B.DNA methylation and gene silencing in cancer[J].Nat Clin Pract Oncol.2005,2 Suppl 1:S4-S11.
[28]Cohen M J.The hedgehog signaling network[J].Am J Med Genet A.2003,123A(1):5-28.
[29]Chen M,Tanner M,Levine AC,et al.Androgenic regulation of hedgehog signaling pathway components in prostate cancer cells[J].Cell Cycle.2009,8(1):149-157.
[30]Wolf I,Bose S,Desmond J C,et al.Unmasking of epigenetically silenced genes reveals DNA promoter methylation and reduced expression of PTCH in breast cancer[J].Breast Cancer Res Treat 2007,105(2):139-155.
[31]Li L C,Carroll P R,Dahiya R.Epigenetic changes in prostate cancer:implication for diagnosis and treatment[J].J Natl Cancer Inst 2005,97(2):103-115.