Epigenetic regulation of DACT2, a key component of the Wnt signalling pathway in human lung cancer.
Epigenetic regulation of DACT2, a key component of the Wnt signalling pathway in human lung cancer.
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DOI：
10.1002/path.4073
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发表时间：
2013-06
影响因子：
7.3
通讯作者：
Guo, Mingzhou
中科院分区：
文献类型：
--
作者：
Jia, Yan;Yang, Yunsheng;Brock, Malcolm V.;Zhan, Qimin;Herman, James G.;Guo, Mingzhou
Dapper是一种β-连环蛋白（β-catenin，DACT）的紊乱相关拮抗剂，参与爪蟾胚胎发育。人DACT 2定位于染色体6 q27上，这是人类癌症中杂合性丢失（洛）频繁的区域。然而，DACT 2在人类肺癌中的功能和调控尚不清楚。本研究采用DNA测序、甲基化特异性PCR（MSP）、半定量RT-PCR、蛋白质印迹和异种移植模型。检测了8个肺癌细胞系、106例原发性肺癌、4例非癌患者的正常肺标本和99例健康人的血液标本。我们发现，虽然没有与肺癌相关的SNP，但DACT 2启动子区域在人类肺癌中经常甲基化。DACT 2基因启动子区高甲基化沉默及5-aza-2′-deoxyazacytidine处理肺癌细胞后的再表达DACT 2甲基化与肺癌低分化有关。DACT 2表达缺失与原发性肺癌中启动子区域的高甲基化相关，并与β-catenin表达增加相关。DACT 2表达的恢复在体外和体内均抑制肿瘤增殖。在H727细胞中，通过siRNA敲低下调DACT 2表达。DACT 2抑制T细胞因子/淋巴增强因子（TCF/LEF）及其下游基因。总之，DACT 2甲基化是一种潜在的肺癌检测标志物。DACT 2受启动子区超甲基化调控。DACT 2通过抑制肺癌中的Wnt信号通路来抑制肺癌增殖。
Dapper, Dishevelled-associated antagonist of β-catenin (DACT), is involved in Xenopus embryonic development. Human DACT2 is localized on chromosome 6q27, a region of frequent loss of heterozygosity (LOH) in human cancers. However, the function and regulation of DACT2 in human lung cancer remain unclear. DNA sequencing, methylation-specific PCR (MSP), semi-quantitative RT-PCR, western blotting, and xenograft models were employed in this study. Eight lung cancer cell lines, 106 cases of primary lung cancer, four specimens of normal lung from patients without cancer, and 99 blood samples from healthy individuals were examined. We found that while there was no SNP related to lung cancer, the DACT2 promoter region is frequently methylated in human lung cancer. DACT2 is silenced by promoter region hypermethylation and re-expressed by 5-aza-2′-deoxyazacytidine treatment of lung cancer cell lines. Methylation of DACT2 was associated with poor differentiation of lung cancer. Loss of DACT2 expression was associated with promoter region hypermethylation in primary lung cancer, and was associated with increased β-catenin expression. Restoration of DACT2 expression suppressed tumour proliferation both in vitro and in vivo. DACT2 expression was down-regulated by siRNA knockdown in H727 cells. DACT2 inhibited T-cell factor/lymphoid enhancer factor (TCF/LEF) and its downstream genes. In conclusion, DACT2 methylation is a potential lung cancer detection marker. DACT2 is regulated by promoter region hypermethylation. DACT2 inhibits lung cancer proliferation by suppressing the Wnt signalling pathway in lung cancer.
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DOI：
10.1073/pnas.93.18.9821
发表时间：
1996-09-03
影响因子：
11.1
作者：
Herman, JG;Graff, JR;Baylin, SB
通讯作者：
Baylin, SB
影响因子：
11.8
作者：
Cheyette, BNR;Waxman, JS;Moon, RT
通讯作者：
Moon, RT
影响因子：
4.8
作者：
Su, Ying;Zhang, Long;Chen, Ye-Guang
通讯作者：
Chen, Ye-Guang
影响因子：
64.5
作者：
Lewis, BP;Shih, IH;Burge, CB
通讯作者：
Burge, CB
DOI：
10.1186/1756-9966-27-25
发表时间：
2008-08-02
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
--
作者：
Han CP;Lee MY;Tzeng SL;Yao CC;Wang PH;Cheng YW;Chen SL;Wu TS;Tyan YS;Kok LF
通讯作者：
Kok LF