Subcellular compartmentalization of docking protein-1 contributes to progression in colorectal cancer.
Subcellular compartmentalization of docking protein-1 contributes to progression in colorectal cancer.
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DOI：
10.1016/j.ebiom.2016.05.003
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发表时间：
2016-06
期刊：
影响因子：
11.1
通讯作者：
Burgermeister E
中科院分区：
文献类型：
--
作者：
Friedrich T;Söhn M;Gutting T;Janssen KP;Behrens HM;Röcken C;Ebert MPA;Burgermeister E
全长对接蛋白-1 （Full-length docking protein-1, DOK1）是一种在正常组织中抑制生长因子和免疫反应通路的适配蛋白，但在人类癌症中经常缺失。小的DOK1变异仍然存在于实体瘤和白血病细胞中，尽管它们的功能是难以捉摸的。为了评估DOK1在结直肠癌（CRC）中迄今未知的作用，我们生成了模仿白血病患者DOK1蛋白变异的结构域结构和亚细胞分布的DOK1突变体。我们发现细胞质DOK1激活过氧化物酶体增殖物激活受体γ (PPARγ)，导致c-FOS启动子抑制和细胞增殖，而核DOK1是无活性的。PPARγ激动剂增加内源性DOK1的表达和与PPARγ的相互作用。这种基于细胞的信号模型的正向翻译预测了患者DOK1的区隔化。在大量CRC患者中，DOK1蛋白的缺失与早期肿瘤预后不良相关（*p = 0.001; n = 1492）。在细胞质表达DOK1的肿瘤中，生存率提高，而DOK1的核定位与预后差相关，表明DOK1的区隔化对结直肠癌的进展至关重要。因此，DOK1被确定为非转移性结直肠癌的预后因素，并且通过其ppar γ激动剂的可药物性，可能构成未来癌症治疗的潜在靶点。基于细胞的信号模型的正向翻译预测了DOK1在结直肠癌（CRC）中的临床相关性。DOK1是结直肠癌患者的独立预后因素，其缺失与生存率低相关。ppar γ-激动剂增加了DOK1对癌细胞生长的抑制作用（“可用药”）。由于对临床治疗无效而导致的低生存率阻碍了癌症的有效治疗。因此，对新的药物靶点和生物标志物有很高的医学需求。DOK1在健康身体中阻断促癌信号，但在肿瘤中经常丢失。我们发现，DOK1阳性的结直肠癌患者比阴性的患者有更好的生存结果。抗糖尿病药物上调DOK1，促进其对肿瘤细胞的保护作用。因此，我们的研究表明，DOK1是一个预后良好的标志物，也是治疗结直肠癌的潜在药物靶点。
Full-length (FL) docking protein-1 (DOK1) is an adapter protein which inhibits growth factor and immune response pathways in normal tissues, but is frequently lost in human cancers. Small DOK1 variants remain in cells of solid tumors and leukemias, albeit, their functions are elusive. To assess the so far unknown role of DOK1 in colorectal cancer (CRC), we generated DOK1 mutants which mimic the domain structure and subcellular distribution of DOK1 protein variants in leukemia patients. We found that cytoplasmic DOK1 activated peroxisome-proliferator-activated-receptor-gamma (PPARγ) resulting in inhibition of the c-FOS promoter and cell proliferation, whereas nuclear DOK1 was inactive. PPARγ-agonist increased expression of endogenous DOK1 and interaction with PPARγ. Forward translation of this cell-based signaling model predicted compartmentalization of DOK1 in patients. In a large series of CRC patients, loss of DOK1 protein was associated with poor prognosis at early tumor stages (*p = 0.001; n = 1492). In tumors with cytoplasmic expression of DOK1, survival was improved, whereas nuclear localization of DOK1 correlated with poor outcome, indicating that compartmentalization of DOK1 is critical for CRC progression. Thus, DOK1 was identified as a prognostic factor for non-metastatic CRC, and, via its drugability by PPARγ-agonist, may constitute a potential target for future cancer treatments. Forward translation of a cell-based signaling model predicted clinical relevance for DOK1 in colorectal cancer (CRC). DOK1 is an independent prognostic factor in CRC patients, and its loss associated with poor survival. Cancer cell growth inhibition by DOK1 was increased (“drugable”) by PPARγ-agonist. Poor survival due to failure to respond to clinical therapies prevents effective treatment of cancer. Thus, there is a high medical need for novel drug targets and biomarkers. DOK1 blocks pro-cancer signaling in the healthy body, but is often lost in tumors. We show that colorectal cancer patients who are positive for DOK1 have a better survival outcome than patients who are negative. Anti-diabetic drugs up-regulated DOK1 and promoted its protective actions against tumor cells. Our study therefore suggests DOK1 as a marker for good prognosis and as a potential drug target for therapy of colorectal cancer.