TFAP2E-DKK4 and Chemoresistance in Colorectal Cancer
TFAP2E-DKK4 and Chemoresistance in Colorectal Cancer
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DOI：
10.1056/nejmoa1009473
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发表时间：
2012-01-05
影响因子：
158.5
通讯作者：
Schmid, Roland M.
中科院分区：
文献类型：
--
作者：
Ebert, Matthias P. A.;Taenzer, Marc;Schmid, Roland M.
背景晚期结直肠癌的化疗可提高生存率；然而，尚无系统治疗反应的预测因素。编码转录因子 AP-2 epsilon (TFAP2E) 的基因的基因组和表观遗传改变在人类癌症中很常见。编码 dickkopf 同源物 4 蛋白 (DKK4) 的基因是 TFAP2E 的潜在下游靶标，与化疗耐药有关。我们的目的是进一步评估TFAP2E和DKK4作为结直肠癌化疗反应预测因子的作用。方法我们分析了体外结直肠癌细胞系和结直肠癌患者中TFAP2E的表达、甲基化和功能。我们检查了 74 名患者的初始队列，然后是接受化疗或化放疗的四组患者（总共 220 名）。结果在初始队列中的 74 名患者中，有 38 名患者（51%）的 TFAP2E 高甲基化。高甲基化与原发性和转移性结直肠癌标本和细胞系中 TFAP2E 表达的降低相关。过表达 DKK4 的结直肠癌细胞系显示出对氟尿嘧啶的化疗耐药性增加，但对伊立替康或奥沙利铂的耐药性没有增加。在其他四个患者队列中，TFAP2E 高甲基化与化疗无反应显着相关（P
BACKGROUNDChemotherapy for advanced colorectal cancer leads to improved survival; however, predictors of response to systemic treatment are not available. Genomic and epigenetic alterations of the gene encoding transcription factor AP-2 epsilon (TFAP2E) are common in human cancers. The gene encoding dickkopf homolog 4 protein (DKK4) is a potential downstream target of TFAP2E and has been implicated in chemotherapy resistance. We aimed to further evaluate the role of TFAP2E and DKK4 as predictors of the response of colorectal cancer to chemotherapy.METHODSWe analyzed the expression, methylation, and function of TFAP2E in colorectal-cancer cell lines in vitro and in patients with colorectal cancer. We examined an initial cohort of 74 patients, followed by four cohorts of patients (total, 220) undergoing chemotherapy or chemoradiation.RESULTSTFAP2E was hypermethylated in 38 of 74 patients (51%) in the initial cohort. Hyper-methylation was associated with decreased expression of TFAP2E in primary and metastatic colorectal-cancer specimens and cell lines. Colorectal-cancer cell lines overexpressing DKK4 showed increased chemoresistance to fluorouracil but not irinotecan or oxaliplatin. In the four other patient cohorts, TFAP2E hypermethylation was significantly associated with nonresponse to chemotherapy (P