荷卵巢癌裸鼠E-钙粘素启动子去甲基化的研究
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摘要
目的：
观察DNA甲基化转移酶(DNA methyltransferase,DNMT)抑制剂5-氮杂-2'-脱氧胞苷(5-Aza-2'-deoxycytidine,5-Aza-CdR)联合组蛋白去乙酰化酶(histone deacetylase,HDAC)抑制剂苯丁酸钠(Sodium 4-Phenylbutyrate,SPB)对荷卵巢癌细胞系SKOV3裸鼠的抗肿瘤增殖作用及其与上皮性钙黏素(epithelial cadherin,E-cad)表达变化的关系。
方法：
1.用人卵巢浆液性乳头状囊腺癌细胞系SKOV3建立卵巢癌裸鼠腹腔移植瘤模型,成瘤后随机分为4组：对照组、5-Aza-CdR组、SPB组和5-Aza-CdR+SPB组。
2.观察5-Aza-CdR,SPB以及5-Aza-CdR+SPB对裸鼠腹腔移植瘤的抑制作用及对裸鼠的副作用。
3.免疫组化法检测腹腔移植瘤中DNMT1、HDAC1以及E-cad的表达变化情况。
4.应用甲基化特异性PCR(methylation specific polymerase chain reaction,MSP)检测各组移植瘤E-cad基因启动子区5'CpG岛甲基化状况,以凝胶成像系统对结果进行分析。
5.RT-PCR法检测各组移植瘤E-cad mRNA的表达变化情况。
6. Western印迹方法检测各组移植瘤E-cad蛋白的表达变化情况。
结果：
1.比较4组裸鼠在治疗前后的体重变化,发现对照组裸鼠体重有所减轻,与治疗组相比无统计学差异(P>0.05)；各组裸鼠体重在治疗前后均无统计学差异(P>0.05)。
2.与对照组相比,治疗组中裸鼠腹围增长量较小,腹水量较少,差异显著(P<0.05),而与单用药组相比,联合组裸鼠腹围增长量较小,腹水量较少,差异显著(P<0.05),两组单用药组之间腹水量无统计学差异(P>0.05)。
3.与对照组相比,治疗组裸鼠瘤重明显减轻,差异显著(P<0.05),与单用药组相比,联合组瘤重明显较轻,差异显著,(P<0.05)；而单用药组间瘤重无统计学差异(P>0.05)。联合组比单用药组裸鼠腹腔移植瘤抑瘤率高,差异显著(P<0.05)。
4.与对照组相比,各治疗组腹腔肿瘤负荷分级要低,差异显著(P<0.05),而联合组与单用药组相比,联合组腹腔肿瘤负荷分级要低,差异显著(P<0.05),两单用药组之间无统计学差异(P>0.05)。
5.与对照组相比,治疗组中肝转移减少,差异显著(P<0.05),而各给药组问肝转移无统计学差异(P>0.05),肺、肾、胰、脾转移情况各组间无统计学差异(P>0.05)
6.在移植瘤组织中,DNMT1和HDAC1呈高表达,5-Aza-CdR能抑制DNMT1的表达,SPB能抑制HDAC1的表达,与对照组相比,差异显著(P<0.05),联合应用5-Aza-CdR和SPS对DNMT1和HDAC1的抑制未见协同作用。
7.MSP检测发现对照组、SPB组移植瘤中E-cad基因高甲基化,5-Aza-CdR能够诱导甲基化的E-cad基因去甲基化,联合应用5-Aza-CdR和SPB可更大程度上诱导甲基化的E-cad基因去甲基化。
8.RT-PCR检测发现对照组、SPB组移植瘤中甲基化的E-cad基因表达缺失或者下调,而经过5-Aza-CdR治疗后,mRNA恢复表达或者表达增强。联合应用5-Aza-CdR和SPS可更大程度上恢复mRNA的表达。
9.免疫组化和Western-blotting检测发现对照组、SPB组移植瘤中甲基化的E-cad蛋白表达缺失或者下调,而经过5-Aza-CdR治疗后,E-cad蛋白恢复表达或者表达增强。联合应用5-Aza-CdR和SPB可更大程度上恢复E-cad蛋白的表达。
结论：
1.5-Aza-CdR和SPB对荷卵巢癌细胞系SKOV3裸鼠都有抑制增殖和诱导凋亡作用,而联合用药组抑制增殖和诱导凋亡作用明显增强；联合用药组比单用药组裸鼠腹腔移植瘤抑瘤率高。
2.5-Aza-CdR和SPB都无明显的毒副作用,联合用药组也未发现明显的毒副作用
3.5-Aza-CdR能够降低E-cad基因启动子区的甲基化,可恢复其表达；联合应用5-Aza-CdR和SPB可产生协同效应,显著增强甲基化的E-cad基因的表达,降低细胞侵袭、转移力,对于卵巢癌的治疗有着重要的作用。
Objective:
To evaluate the effect of inhibiting growth of the tumor on nude mice models of SKOV3 after given 5-Aza-CdR and SPB and its relationship with the expression of epithelial cadherin.
Methods:
1.To establish the ascite implantation nude mice models of SKOV3.The tumor-bearing nude mice were randomly divided into four groups:control group,5-Aza-CdR group,SPB group,and 5-Aza-CdR plus SPB group.
2.Observe the effect of inhibiting carcinoma and adverse effects to the nude mice after given 5-Aza-CdR and SPB.
3.The DNMT1,HDAC and E-cad expression in xenograft tumors were analyzed by immunohistochemical staining.
4. The CpG island methylation status of E-cadherin promoter region in xenograft tumors were analyzed by MSP.
5.The mRNA expressions of E-cad was analyzed by RT-PCR.
6.The protein expressions of E-cad was analyzed by Western blotting.
Results:
1.Comparison the weight changes of four groups before and after treatment,the weight of control group was loss,compared to the treating-group,there is no significant difference in weight with the treating-group,and no significant difference in weight among four groups before and after treatment(P>0.05).
2.Compared to the control group, there is significant difference in increment of abdominal circumference and the volumn of ascites with the treating-group(P<0.05). Compared to the Single drug group, there is significant difference in increment of abdominal circumference and the volumn of ascites with the Combination group(P<0.05);Compared two groups of single-drug group, there is no significant difference in increment of abdominal circumference and the volumn of ascites(P>0.05).
3.Compared to the control group, there is significant difference in Tumor weight with the treating-group(P<0.05);Compared to the Single drug group,there is significant difference in Tumor weight with the Combination group(P<0.05); Compared two groups of single-drug group, there is no significant difference in Tumor weight(P>0.05).There is significant difference in the inhibiting tumor rate between single-drug group and Combination group(P<0.05).
4. Compared to the control group, there is significant difference in levels of tumor load with the treating-group(P<0.05);Compared to the Single drug group, there is significant difference in evels of tumor load with the Combination group(P<0.05); Compared two groups of single-drug group, there is no significant difference in evels of tumor load(P>0.05).There is significant difference in the inhibiting tumor rate between single-drug group and Combination group(P<0.05).
5.Compared to the control group,there is significant difference in the rate of liver tranplantation with the treating-group(P<0.05), and no significant difference in the rate of liver transplantation among the treating-groups.(P>0.05).There is no significant difference in the rate of Lung, kidney, pancreas and spleen transplantation among the four groups.
6.Immunohistochemistry detection:DNMT1 protein and HDACl protein was high expressed in xenograft tumors;5-Aza-CdR can inhibit the expression of DNMT1,SPB can inhibit the expression of HDAC1;Compared to the control group,there is significant difference in the the expression of DNMTl protein and HDAC1 protein with the treating-group(P<0.05);The combining 5-Aza-CdR with SPB have no obvious synergistic effect on the inhibition of DNMT1 and HDAC1.
7.MSP detection:E-cad gene was hypermethylated in xenograft tumors of control group and SPB group;5-Aza-CdR induced the demethylation of E-cad gene and the methylation of E-cad in xenograft tumors were reversed after 5-Aza-CdR treatment.The combination of 5-5-Aza-CdR and SPB dramatically enhance the effect of demethylation.
8.RT-PCR detection:E-cad mRNA was expressed in xenograft tumors after 5-Aza-CdR treatment,but it was undetectable or express weakly before the treatment.The combination of 5-Aza-CdR and SPB dramatically up-regulate expression of mRNA in xenograft tumors.
9.Immunohistochemistry and western-blotting detection:E-cad protein was expressed in xenograft tumors after 5-Aza-CdR treatment,but it was undetectable or express weakly before the treatment.The combination of 5-Aza-CdR and SPB dramatically up-regulate xpression of E-cad protein in xenograft tumors.
Conclusions:
1.Both 5-Aza-CdR and SPB can inhibit proliferation and induce apoptosis to the implantion tumor on nude mice models of SKOV3,Combined treatment group inhibited proliferation and induced apoptosis significantly increased;The Combination group is better than the Single drug group in the rate of inhibition.
2.5-Aza-CdR and SPB are no obvious side effects, the combination group also found no obvious side effects.
3.5-Aza-CdR can cut down the methylation of E-cadherin promoter region and recover the expression of E-cadherin;5-Aza-CdR and SPB can synergistically re-express E-cadherin gene and weaken the invasiveness of SKOV3 cell,which plays an important part in treatment of ovarian cancer.
观察DNA甲基化转移酶(DNA methyltransferase,DNMT)抑制剂5-氮杂-2'-脱氧胞苷(5-Aza-2'-deoxycytidine,5-Aza-CdR)联合组蛋白去乙酰化酶(histone deacetylase,HDAC)抑制剂苯丁酸钠(Sodium 4-Phenylbutyrate,SPB)对荷卵巢癌细胞系SKOV3裸鼠的抗肿瘤增殖作用及其与上皮性钙黏素(epithelial cadherin,E-cad)表达变化的关系。
方法：
1.用人卵巢浆液性乳头状囊腺癌细胞系SKOV3建立卵巢癌裸鼠腹腔移植瘤模型,成瘤后随机分为4组：对照组、5-Aza-CdR组、SPB组和5-Aza-CdR+SPB组。
2.观察5-Aza-CdR,SPB以及5-Aza-CdR+SPB对裸鼠腹腔移植瘤的抑制作用及对裸鼠的副作用。
3.免疫组化法检测腹腔移植瘤中DNMT1、HDAC1以及E-cad的表达变化情况。
4.应用甲基化特异性PCR(methylation specific polymerase chain reaction,MSP)检测各组移植瘤E-cad基因启动子区5'CpG岛甲基化状况,以凝胶成像系统对结果进行分析。
5.RT-PCR法检测各组移植瘤E-cad mRNA的表达变化情况。
6. Western印迹方法检测各组移植瘤E-cad蛋白的表达变化情况。
结果：
1.比较4组裸鼠在治疗前后的体重变化,发现对照组裸鼠体重有所减轻,与治疗组相比无统计学差异(P>0.05)；各组裸鼠体重在治疗前后均无统计学差异(P>0.05)。
2.与对照组相比,治疗组中裸鼠腹围增长量较小,腹水量较少,差异显著(P<0.05),而与单用药组相比,联合组裸鼠腹围增长量较小,腹水量较少,差异显著(P<0.05),两组单用药组之间腹水量无统计学差异(P>0.05)。
3.与对照组相比,治疗组裸鼠瘤重明显减轻,差异显著(P<0.05),与单用药组相比,联合组瘤重明显较轻,差异显著,(P<0.05)；而单用药组间瘤重无统计学差异(P>0.05)。联合组比单用药组裸鼠腹腔移植瘤抑瘤率高,差异显著(P<0.05)。
4.与对照组相比,各治疗组腹腔肿瘤负荷分级要低,差异显著(P<0.05),而联合组与单用药组相比,联合组腹腔肿瘤负荷分级要低,差异显著(P<0.05),两单用药组之间无统计学差异(P>0.05)。
5.与对照组相比,治疗组中肝转移减少,差异显著(P<0.05),而各给药组问肝转移无统计学差异(P>0.05),肺、肾、胰、脾转移情况各组间无统计学差异(P>0.05)
6.在移植瘤组织中,DNMT1和HDAC1呈高表达,5-Aza-CdR能抑制DNMT1的表达,SPB能抑制HDAC1的表达,与对照组相比,差异显著(P<0.05),联合应用5-Aza-CdR和SPS对DNMT1和HDAC1的抑制未见协同作用。
7.MSP检测发现对照组、SPB组移植瘤中E-cad基因高甲基化,5-Aza-CdR能够诱导甲基化的E-cad基因去甲基化,联合应用5-Aza-CdR和SPB可更大程度上诱导甲基化的E-cad基因去甲基化。
8.RT-PCR检测发现对照组、SPB组移植瘤中甲基化的E-cad基因表达缺失或者下调,而经过5-Aza-CdR治疗后,mRNA恢复表达或者表达增强。联合应用5-Aza-CdR和SPS可更大程度上恢复mRNA的表达。
9.免疫组化和Western-blotting检测发现对照组、SPB组移植瘤中甲基化的E-cad蛋白表达缺失或者下调,而经过5-Aza-CdR治疗后,E-cad蛋白恢复表达或者表达增强。联合应用5-Aza-CdR和SPB可更大程度上恢复E-cad蛋白的表达。
结论：
1.5-Aza-CdR和SPB对荷卵巢癌细胞系SKOV3裸鼠都有抑制增殖和诱导凋亡作用,而联合用药组抑制增殖和诱导凋亡作用明显增强；联合用药组比单用药组裸鼠腹腔移植瘤抑瘤率高。
2.5-Aza-CdR和SPB都无明显的毒副作用,联合用药组也未发现明显的毒副作用
3.5-Aza-CdR能够降低E-cad基因启动子区的甲基化,可恢复其表达；联合应用5-Aza-CdR和SPB可产生协同效应,显著增强甲基化的E-cad基因的表达,降低细胞侵袭、转移力,对于卵巢癌的治疗有着重要的作用。
Objective:
To evaluate the effect of inhibiting growth of the tumor on nude mice models of SKOV3 after given 5-Aza-CdR and SPB and its relationship with the expression of epithelial cadherin.
Methods:
1.To establish the ascite implantation nude mice models of SKOV3.The tumor-bearing nude mice were randomly divided into four groups:control group,5-Aza-CdR group,SPB group,and 5-Aza-CdR plus SPB group.
2.Observe the effect of inhibiting carcinoma and adverse effects to the nude mice after given 5-Aza-CdR and SPB.
3.The DNMT1,HDAC and E-cad expression in xenograft tumors were analyzed by immunohistochemical staining.
4. The CpG island methylation status of E-cadherin promoter region in xenograft tumors were analyzed by MSP.
5.The mRNA expressions of E-cad was analyzed by RT-PCR.
6.The protein expressions of E-cad was analyzed by Western blotting.
Results:
1.Comparison the weight changes of four groups before and after treatment,the weight of control group was loss,compared to the treating-group,there is no significant difference in weight with the treating-group,and no significant difference in weight among four groups before and after treatment(P>0.05).
2.Compared to the control group, there is significant difference in increment of abdominal circumference and the volumn of ascites with the treating-group(P<0.05). Compared to the Single drug group, there is significant difference in increment of abdominal circumference and the volumn of ascites with the Combination group(P<0.05);Compared two groups of single-drug group, there is no significant difference in increment of abdominal circumference and the volumn of ascites(P>0.05).
3.Compared to the control group, there is significant difference in Tumor weight with the treating-group(P<0.05);Compared to the Single drug group,there is significant difference in Tumor weight with the Combination group(P<0.05); Compared two groups of single-drug group, there is no significant difference in Tumor weight(P>0.05).There is significant difference in the inhibiting tumor rate between single-drug group and Combination group(P<0.05).
4. Compared to the control group, there is significant difference in levels of tumor load with the treating-group(P<0.05);Compared to the Single drug group, there is significant difference in evels of tumor load with the Combination group(P<0.05); Compared two groups of single-drug group, there is no significant difference in evels of tumor load(P>0.05).There is significant difference in the inhibiting tumor rate between single-drug group and Combination group(P<0.05).
5.Compared to the control group,there is significant difference in the rate of liver tranplantation with the treating-group(P<0.05), and no significant difference in the rate of liver transplantation among the treating-groups.(P>0.05).There is no significant difference in the rate of Lung, kidney, pancreas and spleen transplantation among the four groups.
6.Immunohistochemistry detection:DNMT1 protein and HDACl protein was high expressed in xenograft tumors;5-Aza-CdR can inhibit the expression of DNMT1,SPB can inhibit the expression of HDAC1;Compared to the control group,there is significant difference in the the expression of DNMTl protein and HDAC1 protein with the treating-group(P<0.05);The combining 5-Aza-CdR with SPB have no obvious synergistic effect on the inhibition of DNMT1 and HDAC1.
7.MSP detection:E-cad gene was hypermethylated in xenograft tumors of control group and SPB group;5-Aza-CdR induced the demethylation of E-cad gene and the methylation of E-cad in xenograft tumors were reversed after 5-Aza-CdR treatment.The combination of 5-5-Aza-CdR and SPB dramatically enhance the effect of demethylation.
8.RT-PCR detection:E-cad mRNA was expressed in xenograft tumors after 5-Aza-CdR treatment,but it was undetectable or express weakly before the treatment.The combination of 5-Aza-CdR and SPB dramatically up-regulate expression of mRNA in xenograft tumors.
9.Immunohistochemistry and western-blotting detection:E-cad protein was expressed in xenograft tumors after 5-Aza-CdR treatment,but it was undetectable or express weakly before the treatment.The combination of 5-Aza-CdR and SPB dramatically up-regulate xpression of E-cad protein in xenograft tumors.
Conclusions:
1.Both 5-Aza-CdR and SPB can inhibit proliferation and induce apoptosis to the implantion tumor on nude mice models of SKOV3,Combined treatment group inhibited proliferation and induced apoptosis significantly increased;The Combination group is better than the Single drug group in the rate of inhibition.
2.5-Aza-CdR and SPB are no obvious side effects, the combination group also found no obvious side effects.
3.5-Aza-CdR can cut down the methylation of E-cadherin promoter region and recover the expression of E-cadherin;5-Aza-CdR and SPB can synergistically re-express E-cadherin gene and weaken the invasiveness of SKOV3 cell,which plays an important part in treatment of ovarian cancer.
引文
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[43]Strait KA,Dabbas B,Hammond EH,et al.Cell cycle blockade and differentiation of ovarian cancer cells by the histone deacetylase inhibitor trichostatin A are associated with changes in p21,Rb,and Id proteins[J].Mol Cancer Ther,2002,1(13): 1181-1190.
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[45]Chobanian NH,Greenberg VL,Gass JM,et al.Histone deaeetylase inhibitors enhance paclitaxel-induced cell death in ovarian cancer cell lines independent of p53 status[J].Anticancer Res,2004,24(2B):539-545.
[46]Shaker S,Bernstein M,Momparler LF,et al.Preclinical evaluation of antineoplastic activity of inhibitors of DNA methylation (5-aza-2'-deoxycytidine) and histone deacetylation(trichostatin A,depsipeptide)in combination against myeloid leukemic cells[J].Leuk Res,2003,27(5):437-444.
[47]Zhu WG,Otterson GA. The interaction of histone deacetylase inhibitors and DNA methyltransferase inhibitors in the treatment of human cancer cells[J].Currr Med Chem Anticancer Agents,2003,3(3):187-199.
[48]Balch C,Huang TH,Brown R,et al.The epigenetics of ovarian cancer drug resistance and resensitization[J].Am J Obstet Gynecol,2004,191(5):1552-1572.
[49]Piura B,Rabinovich A,Aizenberg N,et al.Cadherins in malignancies of the female genital tract[J].Harefuah,2005,14(4):261-265.
[50]Daugherty RL,Gottardi CJ.Phospho-regulation of Beta-catenin adhesion and signaling functions[J].Physiology (Bethesda),2007,22:303.
[51]Negraes PD,Favaro FP,Camargo JL,et al.DNA methylation patterns in bladder cancer and washing cell sediments:a perspective for tumor recurence detection[J]. BMC Cancer,2008,8:238.
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[1]Patra SK,Patra A,Rizzi F,et al.Demethylation of (Cytosine-5-C-methyl) DNA and regulation of transcription in the epigenetic pathways of cancer development[J]. Cancer Metastasis Rev,2008,27(2):315-334.
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[8]Phalke S,Nickel O, Walluscheck D, et al.Retrotransposon silencing and telomere integrity in somatic cells of Drosophila depends on the cytosine-5 methyltransferase DNMT2[J].Nat Genet.2009 Jun;41(6):696-702.
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[10]Kalantari M, Lee D, Calleja-Macias IE, et al.Effects of cellular differentiation, chromosomal integration and 5-aza-2'-deoxycytidine treatment on human papillomavirus-16 DNA methylation in cultured cell lines[J].Virology.2008 May 10;374(2):292-303.
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[36]Senese S,Zaragoza K,Minardi S,et al.Role for histone deacetylase 1 in human tumor cell proliferation[J].Mol Cell Bid,2007,27(13):4784-4795.
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[46]Shaker S,Bernstein M,Momparler LF,et al.Preclinical evaluation of antineoplastic activity of inhibitors of DNA methylation (5-aza-2'-deoxycytidine) and histone deacetylation(trichostatin A,depsipeptide)in combination against myeloid leukemic cells[J].Leuk Res,2003,27(5):437-444.
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[50]Daugherty RL,Gottardi CJ.Phospho-regulation of Beta-catenin adhesion and signaling functions[J].Physiology (Bethesda),2007,22:303.
[51]Negraes PD,Favaro FP,Camargo JL,et al.DNA methylation patterns in bladder cancer and washing cell sediments:a perspective for tumor recurence detection[J]. BMC Cancer,2008,8:238.
[52]Zhang KL,Sun Y, Li Y,et al.Increased frequeney of CpG island methylator phenotype and CDH1 methylation in a gastric cancer highrisk region of china[J]. Transl Oncol,2008,1:28-35.
[53]Shieh YS,Shiah SQJeng HH,et al.DNA methyltransferase 1 expression and promoter methylation of E-cadherin in mucoepidermoid carcinoma[J].Cancer,2005, 104(5):1013-21.
[54]Zazula M,Ferreira AM,Czopek JP,et al.CDH1 gene promoter hypermethylation in gastric cancer:relationship to Goseki grading,microsatellite instability status,and EBV invasion[J].Diagn Mol Pathol,2006,15(1):24-9.
[55]Li LC,Zhao H,Nakajima K,et al.Methylation of the E-cadherin gene promoter correlates with progression of prostate cancer[J].J Urol,2001,166(2):705-9.
[56]Chan MW,Chan LW,Tang NL,et al.Hypermethylation of multiple genes in tumor tissues and voided urine in urinary bladder cancer patients[J].Clin Cancer Res, 2002,8(2):464-70.
[57]Cameron EE,Bachman KE,Myohanen S,et al.Synergy of demethylation and histone deacetylase inhibition in there:expression of genes silenced in cancer[J].Nat Genet,1999,21(1):103-107.
[58]李宏,舒艺,陈勇军,等.DNMTi与HDACi对胆管癌细胞E-cadherin表达和细胞侵袭力的影响[J].中国普外基础与临床杂志,2009,16(1)：44-51.
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[1]Patra SK,Patra A,Rizzi F,et al.Demethylation of (Cytosine-5-C-methyl) DNA and regulation of transcription in the epigenetic pathways of cancer development[J]. Cancer Metastasis Rev,2008,27(2):315-334.
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[3]Margot JB,Cardoso MC,Leonhardt H.Mammalian DNA methyltransferases show different subnuclear distributions[J].J Cell Biochem,2001,83(3):373-379.
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[5]Kumar S,Cheng X,Klimasauskas S,et al.The DNA(cytosine-5) methyltranferase [J].Nucleic Acids Res,1994,22(1):1-10.
[6]Kato Y, Kaneda M, Hata K,et al.Role of the Dnmt3 family in de novo methylation of imprinted and repetitive sequences during male germ cell development in the mouse[J].Hum Mol Genet.2007 Oct 1;16(19):2272-80.
[7]Schaefer M, Hagemann S,Hanna K, et al.Azacytidine inhibits RNA methylation at DNMT2 target sites in human cancer cell lines[J].Cancer Res.2009 Oct 15;69 (20):8127-32.
[8]Phalke S,Nickel O, Walluscheck D, et al.Retrotransposon silencing and telomere integrity in somatic cells of Drosophila depends on the cytosine-5 methyltransferase DNMT2[J].Nat Genet.2009 Jun;41(6):696-702.
[9]Fandy TE. Development of DNA methyltransferase inhibitors for the treatment of neoplastic diseases[J].Curr Med Chem.2009;16(17):2075-85.
[10]Kalantari M, Lee D, Calleja-Macias IE, et al.Effects of cellular differentiation, chromosomal integration and 5-aza-2'-deoxycytidine treatment on human papillomavirus-16 DNA methylation in cultured cell lines[J].Virology.2008 May 10;374(2):292-303.
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