DACT1在人乳腺癌中的表观遗传学调控及其抑制乳腺癌细胞生长和转移的机制研究
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摘要
根据2011年全球癌症统计（Global cancer statistics，2011）报道，乳腺癌（Breast cancer, BRCA）的发病率和死亡率在女性人群中位居第一。尽管目前在乳腺癌的综合治疗方面已经取得了很大的进展，但是晚期乳腺癌的治疗效果依然不佳，其无病生存（Disease free survival,DSF）和总生存（Overall survival, OS）时间远低于早期乳腺癌患者。因此，积极有效地提高乳腺癌的早期诊断率对于乳腺癌的治疗及预后有着非常重要作用。表观遗传学是当今医学基础研究的热点，深入其机制的探讨有利于了解乳腺癌的发生和发展。其中，抑癌基因（Tumorsuppressor gene, TSG）启动子甲基化的研究为乳腺癌的早期诊断及预后评估提供了潜在的可能。
DACT1(dapper, antagonist of beta-catenin, homolog1Xenopuslaevis)，又名HDPR1，属于DAPPER家族，文献提示它在肝癌、肺癌、胃结肠癌中的表达水平低于其正常对照组织并具有抑制肿瘤细胞生长和转移的能力。由此我们推测DACT1可能作为一个新的抑癌基因从而影响乳腺癌的发生和发展。本研究以DACT1为研究目标，通过逆转录聚合酶链式反应（Reverse transcription polymerase chain reaction,RT-PCR）、实时荧光定量聚合酶链式反应（Real-time fluorescencequantitative polymerase chain reaction, Real-time PCR）、免疫组织化学（Immunohistochemistry, IHC）、甲基化特异性聚合酶链式反应（Methylation specific PCR, MSP）方法，分析人乳腺癌细胞株、乳腺癌组织和正常乳腺组织中DACT1基因的表达差异及其甲基化状态；通过细胞体外及体内实验评估DACT1对乳腺癌细胞增殖及迁移性能力的影响，并进一步采用蛋白免疫印迹法（Western blot，WB）方法检测DACT1对Wnt/β-catenin信号通路的影响。研究结果显示，在88.9%（8/9）的乳腺癌细胞株和乳腺癌组织中，DACT1的表达水平都有不同程度的下调。同时，55.6%（5/9）的乳腺癌细胞株和29.9%（40/134）的乳腺癌组织存在DACT1基因启动子甲基化。通过采用5-氮杂-2-脱氧胞苷（5-aza-2’-deoxycytidine,5-Aza-dC）联合组蛋白去乙酰化酶抑制剂曲古菌素A（TrichostatinA, TSA）的方法处理DACT1表达沉默或是下调的乳腺癌细胞株（MB231、MCF7和T47D）。结果显示，DACT1基因启动子去甲基的同时伴随其mRNA表达水平的上调，从而证实了DACT1启动子甲基化是导致其表达下调的原因之一。细胞功能试验结果显示，DACT1能够通过促进凋亡从而有效地抑制乳腺癌细胞体外和体内的生长，并且能够通过调控Wnt/β-catenin信号通路从而抑制乳腺癌的迁移能力。
综上所述，DACT1作为一个新的抑癌基因，参与了乳腺癌的发生和发展。
According to global cancer statistics, the morbidity and mortality ofbreast cancer have ranked the top in females worldwide. Although thecomprehensive therapies for breast cancer had been improved during thepast decade, there is no promising therapy for advanced breast cancer inwhich Disease-Free Survival and Overall survival is worse than that in breastcancer at early stage. Actively and effectively improving the early diagnosisof breast cancer had been proved to be the key element of treatment of breastcancer. Epigenetic is the hot spot of the medical basic scientific research, andvery important for better understanding the occurrence and development ofbreast cancer. Among them, the studies of DNA methylation of tumorsuppressor genes (TSGs) have provided a potentially possibility for the earlydiagnosis of breast cancer.
DACT1(dapper, antagonist of beta-catenin, homolog1Xenopuslaevis) belongs to DAPPER family. Previous study had indicated thatDACT1was downregulated and regarded as a TSG in hepatic carcinoma, lung cancer and gastric cancer. These results had suggested that DACT1could act as a new TSG in breast cancer. To demonstrate our hypothesis,RT-PCR, immunohistochemistry, MSP were performed to examine DACT1expression and its promoter methylation status in breast cancer cell lines,primary breast carcinomas and normal breast tissues, and then cellularfunction assays were used to verify whether DACT1could inhibit breastcancer cell proliferation and migration. Besides, we had use western blot toanalyse the effect of DACT1on Wnt/β-catenin signaling pathway. Resultsshowed that mRNA expression level of DACT1was frequentlydownregulated or silenced in89%(8/9) of breast cancer cell lines andprimary breast tumors, and the protein level was also lower in primary breastcancers when compared to paired adjacent tissues. Furthermore, promotermethylation of DACT1was detected in55.6%(5/9) of breast cancer celllines and29.9%(40/134) of primary tumors, but not in any tumor adjacenttissues or normal breast tissues. Treatment of breast cancer cell lines with5-aza-2’-deoxycytidine and trichostatin A can activate DACT1expressionalong with promoter demethylation. The functional assays showed thatectopic expression of DACT1can inhibit cell proliferation and migrationthrough antagonizing Wnt/β-catenin signaling pathway.
In summary, our study demonstrated that DACT1was epigeneticallyinactivated by promoter methylation and could be considered as a TSG inbreast cancer
DACT1(dapper, antagonist of beta-catenin, homolog1Xenopuslaevis)，又名HDPR1，属于DAPPER家族，文献提示它在肝癌、肺癌、胃结肠癌中的表达水平低于其正常对照组织并具有抑制肿瘤细胞生长和转移的能力。由此我们推测DACT1可能作为一个新的抑癌基因从而影响乳腺癌的发生和发展。本研究以DACT1为研究目标，通过逆转录聚合酶链式反应（Reverse transcription polymerase chain reaction,RT-PCR）、实时荧光定量聚合酶链式反应（Real-time fluorescencequantitative polymerase chain reaction, Real-time PCR）、免疫组织化学（Immunohistochemistry, IHC）、甲基化特异性聚合酶链式反应（Methylation specific PCR, MSP）方法，分析人乳腺癌细胞株、乳腺癌组织和正常乳腺组织中DACT1基因的表达差异及其甲基化状态；通过细胞体外及体内实验评估DACT1对乳腺癌细胞增殖及迁移性能力的影响，并进一步采用蛋白免疫印迹法（Western blot，WB）方法检测DACT1对Wnt/β-catenin信号通路的影响。研究结果显示，在88.9%（8/9）的乳腺癌细胞株和乳腺癌组织中，DACT1的表达水平都有不同程度的下调。同时，55.6%（5/9）的乳腺癌细胞株和29.9%（40/134）的乳腺癌组织存在DACT1基因启动子甲基化。通过采用5-氮杂-2-脱氧胞苷（5-aza-2’-deoxycytidine,5-Aza-dC）联合组蛋白去乙酰化酶抑制剂曲古菌素A（TrichostatinA, TSA）的方法处理DACT1表达沉默或是下调的乳腺癌细胞株（MB231、MCF7和T47D）。结果显示，DACT1基因启动子去甲基的同时伴随其mRNA表达水平的上调，从而证实了DACT1启动子甲基化是导致其表达下调的原因之一。细胞功能试验结果显示，DACT1能够通过促进凋亡从而有效地抑制乳腺癌细胞体外和体内的生长，并且能够通过调控Wnt/β-catenin信号通路从而抑制乳腺癌的迁移能力。
综上所述，DACT1作为一个新的抑癌基因，参与了乳腺癌的发生和发展。
According to global cancer statistics, the morbidity and mortality ofbreast cancer have ranked the top in females worldwide. Although thecomprehensive therapies for breast cancer had been improved during thepast decade, there is no promising therapy for advanced breast cancer inwhich Disease-Free Survival and Overall survival is worse than that in breastcancer at early stage. Actively and effectively improving the early diagnosisof breast cancer had been proved to be the key element of treatment of breastcancer. Epigenetic is the hot spot of the medical basic scientific research, andvery important for better understanding the occurrence and development ofbreast cancer. Among them, the studies of DNA methylation of tumorsuppressor genes (TSGs) have provided a potentially possibility for the earlydiagnosis of breast cancer.
DACT1(dapper, antagonist of beta-catenin, homolog1Xenopuslaevis) belongs to DAPPER family. Previous study had indicated thatDACT1was downregulated and regarded as a TSG in hepatic carcinoma, lung cancer and gastric cancer. These results had suggested that DACT1could act as a new TSG in breast cancer. To demonstrate our hypothesis,RT-PCR, immunohistochemistry, MSP were performed to examine DACT1expression and its promoter methylation status in breast cancer cell lines,primary breast carcinomas and normal breast tissues, and then cellularfunction assays were used to verify whether DACT1could inhibit breastcancer cell proliferation and migration. Besides, we had use western blot toanalyse the effect of DACT1on Wnt/β-catenin signaling pathway. Resultsshowed that mRNA expression level of DACT1was frequentlydownregulated or silenced in89%(8/9) of breast cancer cell lines andprimary breast tumors, and the protein level was also lower in primary breastcancers when compared to paired adjacent tissues. Furthermore, promotermethylation of DACT1was detected in55.6%(5/9) of breast cancer celllines and29.9%(40/134) of primary tumors, but not in any tumor adjacenttissues or normal breast tissues. Treatment of breast cancer cell lines with5-aza-2’-deoxycytidine and trichostatin A can activate DACT1expressionalong with promoter demethylation. The functional assays showed thatectopic expression of DACT1can inhibit cell proliferation and migrationthrough antagonizing Wnt/β-catenin signaling pathway.
In summary, our study demonstrated that DACT1was epigeneticallyinactivated by promoter methylation and could be considered as a TSG inbreast cancer
引文
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