Dikkopf-1 as a novel serologic and prognostic biomarker for lung and esophageal carcinomas
Dikkopf-1 as a novel serologic and prognostic biomarker for lung and esophageal carcinomas
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DOI：
10.1158/0008-5472.can-06-3369
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发表时间：
2007-03-15
期刊：
影响因子：
11.2
通讯作者：
Daigo, Yataro
中科院分区：
文献类型：
--
作者：
Yamabuki, Takumi;Takano, Atsushi;Daigo, Yataro
对肺癌和食管癌的基因表达谱分析显示，Dikkopf - 1（DKK1）在绝大多数肺癌和食管鳞状细胞癌（ESCC）中高度转录激活。利用由279例存档的非小细胞肺癌（NSCLC）和280例ESCC标本组成的肿瘤组织微阵列进行免疫组化染色表明，DKK1的高表达水平与NSCLC以及ESCC患者的不良预后相关，多变量分析证实了其对NSCLC的独立预后价值。此外，我们发现DKK1的外源表达增加了哺乳动物细胞的迁移活性，这表明DKK1可能在人类癌症的进展中起重要作用。我们建立了一个酶联免疫吸附测定（ELISA）系统来测量DKK1的血清水平，发现肺癌和食管癌患者的血清DKK1水平显著高于健康对照组。在180例NSCLC患者中，DKK1阳性病例的比例为126例（70.0%），在85例小细胞肺癌（SCLC）患者中为59例（69.4%），在81例ESCC患者中为51例（63.0%），而在207例健康志愿者中只有10例（4.8%）被误判为阳性。对DKK1和癌胚抗原进行联合ELISA检测提高了敏感性，将82.2%的NSCLC患者归类为阳性，而只有7.7%的健康志愿者被误判为阳性。同时使用DKK1和胃泌素释放肽前体（ProGRP）检测SCLCs的敏感性提高到89.4%，而健康供体的假阳性率仅为6.3%。我们的数据表明，DKK1作为一种新的临床诊断/预后生物标志物是有用的，并且可能作为肺癌和食管癌的治疗靶点。
Gene expression profile analysis of lung and esophageal carcinomas revealed that Dikkopf-1 (DKK1) was highly transactivated in the great majority of lung cancers and esophageal squamous cell carcinomas (ESCC). Immunohistochemical staining using tumor tissue microarrays consisting of 279 archived non-small cell lung cancers (NSCLC) and 280 ESCC specimens showed that a high level of DKK1 expression was associated with poor prognosis of patients with NSCLC as well as ESCC, and multivariate analysis confirmed its independent prognostic value for NSCLC. In addition, we identified that exogenous expression of DKK1 increased the migratory activity of mammalian cells, suggesting that DKK1 may play a significant role in progression of human cancer. We established an ELISA system to measure serum levels of DKK1 and found that serum DKK1 levels were significantly higher in lung and esophageal cancer patients than in healthy controls. The proportion of the DKK1-positive cases was 126 of 180 (70.0%) NSCLC, 59 of 85 (69.4%) SCLC, and 51 of 81 (63.0%) ESCC patients, whereas only 10 of 207 (4.8%) healthy volunteers were falsely diagnosed as positive. A combined ELISA assays for both DKK1 and carcinoembryonic antigen increased sensitivity and classified 82.2% of the NSCLC patients as positive whereas only 7.7% of healthy volunteers were falsely diagnosed to be positive. The use of both DKK1 and ProGRP increased sensitivity to detect SCLCs up to 89.4%, whereas false-positive rate in healthy donors was only 6.3%. Our data imply that DKK1 should be useful as a novel diagnostic/prognostic biomarker in clinic and probably as a therapeutic target for lung and esophageal cancer.