Nuclear DICKKOPF-1 as a biomarker of chemoresistance and poor clinical outcome in colorectal cancer.
Nuclear DICKKOPF-1 as a biomarker of chemoresistance and poor clinical outcome in colorectal cancer.
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DOI：
10.18632/oncotarget.3464
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发表时间：
2015-03-20
期刊：
影响因子：
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通讯作者：
Muñoz A
中科院分区：
文献类型：
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作者：
Aguilera Ó;González-Sancho JM;Zazo S;Rincón R;Fernández AF;Tapia O;Canals F;Morte B;Calvanese V;Orgaz JL;Niell N;Aguilar S;Freije JM;Graña O;Pisano DG;Borrero A;Martínez-Useros J;Jiménez B;Fraga MF;García-Foncillas J;López-Otín C;Lafarga M;Rojo F;Muñoz A
散发性结直肠癌（CRC）的发生和发展依赖于Wnt/β-catenin信号通路的激活。Dickkopf（DKK）-1是Wnt/β-catenin信号传导的细胞外抑制剂，其也具有不确定的β-catenin独立作用。在这里，我们报告的第一次，DKK-1的比例位于细胞核内的健康小肠和结肠粘膜，并在特定的染色质活性转录位点的CRC细胞。此外，我们发现DKK-1调节几个癌症相关基因，包括癌症干细胞标志物乙醛脱氢酶1A 1（ALDH 1A 1）和Ral-binding蛋白1相关的Eps结构域2（REPS 2），这些基因参与化疗药物的解毒。随着沿着CRC进展，核DKK-1表达丢失;然而，在一个亚组（15%）的CRC患者（n = 699）中，其表达仍然较高，并与化疗后无进展生存期（PFS）和总生存期（OS）降低相关[校正HR，1.65; 95%置信区间（CI），1.23-2.21; P = 0.002）]。ALDH 1A 1和REPS 2的过表达与肿瘤细胞核DKK-1表达相关，并与OS（P = 0.001和0.014）和PFS降低相关。总之，我们的研究结果证明了DKK-1在细胞核内的新位置，并支持核DKK-1作为结直肠癌化疗耐药性的预测生物标志物的作用。
Sporadic colorectal cancer (CRC) insurgence and progression depend on the activation of Wnt/β-catenin signaling. Dickkopf (DKK)-1 is an extracellular inhibitor of Wnt/β-catenin signaling that also has undefined β-catenin-independent actions. Here we report for the first time that a proportion of DKK-1 locates within the nucleus of healthy small intestine and colon mucosa, and of CRC cells at specific chromatin sites of active transcription. Moreover, we show that DKK-1 regulates several cancer-related genes including the cancer stem cell marker aldehyde dehydrogenase 1A1 (ALDH1A1) and Ral-binding protein 1-associated Eps domain-containing 2 (REPS2), which are involved in detoxification of chemotherapeutic agents. Nuclear DKK-1 expression is lost along CRC progression; however, it remains high in a subset (15%) of CRC patients (n = 699) and associates with decreased progression-free survival (PFS) after chemotherapy administration and overall survival (OS) [adjusted HR, 1.65; 95% confidence interval (CI), 1.23-2.21; P = 0.002)]. Overexpression of ALDH1A1 and REPS2 associates with nuclear DKK-1 expression in tumors and correlates with decreased OS (P = 0.001 and 0.014) and PFS. In summary, our findings demonstrate a novel location of DKK-1 within the cell nucleus and support a role of nuclear DKK-1 as a predictive biomarker of chemoresistance in colorectal cancer.
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影响因子：
64.8
作者：
Glinka, A;Wu, W;Niehrs, C
通讯作者：
Niehrs, C
影响因子：
2.6
作者：
Freitas N;Cunha C
通讯作者：
Cunha C
影响因子：
3.4
作者：
Huang, Yan;Yang, Xinrong;Qin, Wenxin
通讯作者：
Qin, Wenxin
影响因子：
11.5
作者：
Gerger, Armin;Zhang, Wu;Lenz, Heinz-Josef
通讯作者：
Lenz, Heinz-Josef
DOI：
10.1038/modpathol.2011.172
发表时间：
2012-03
期刊：
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc
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作者：
通讯作者：
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