Loss of programmed cell death 4 expression marks adenoma-carcinoma transition, correlates inversely with phosphorylated protein kinase B, and is an independent prognostic factor in resected colorectal cancer
Loss of programmed cell death 4 expression marks adenoma-carcinoma transition, correlates inversely with phosphorylated protein kinase B, and is an independent prognostic factor in resected colorectal cancer
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DOI：
10.1002/cncr.22983
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发表时间：
2007-10-15
期刊：
影响因子：
6.2
通讯作者：
Allgayer, Heike
中科院分区：
文献类型：
--
作者：
Mudduluru, Giridhar;Medved, Fabian;Allgayer, Heike
背景程序性细胞死亡4（Pdcd 4）抑制恶性转化，初步研究表明Pdcd 4的定位受蛋白激酶B（Akt）的调节。然而，支持患者组织数据缺失，Pdcd 4的诊断/预后潜力很少被研究。目前的目标是1）确定Pdcd 4作为腺瘤-癌序列中的诊断标志物，2）支持磷酸化Akt（pAkt）介导的Pdcd 4体内调节，3）获得Pdcd 4在结直肠癌中的第一个预后证据。采用免疫组化和蛋白质印迹法分析了71例前瞻性随访（中位随访时间为36个月）的结直肠癌患者和42例腺瘤患者的肿瘤样本和正常组织中的Pdcd 4、Akt和pAkt。在正常粘膜和腺瘤之间以及腺瘤和肿瘤样品之间观察到Pdcd 4的显著降低（分别为P <0.01和P <0.01）。Pdcd 4在正常粘膜中表达较强，在腺瘤中表达明显减少（P <0.01），在肿瘤中几乎消失（P <0.01）。pAkt与Pdcd 4和Pdcd 4从细胞核向细胞质的转移呈负相关（P <0.01）。Kaplan-Meier分析（使用Mantel-Cox对数秩检验）表明肿瘤中总Pdcd 4和核Pdcd 4的丢失与总生存率（分别为P <0.05和P <0.02）和疾病特异性生存率（分别为P <0.01和P <0.01）之间存在显著相关性。在多变量分析中，Pdcd 4的总丢失或核丢失是疾病特异性或总生存率的独立预测因子。据作者所知，这是第一项证明Pdcd 4及其表达模式对结直肠癌独立预后影响的研究。本研究的数据支持pAkt在体内对Pdcd 4定位的调节。pdcd 4免疫组化可能是一个有用的支持性诊断工具之间的正常，腺瘤和肿瘤组织的过渡。
BACKGROUND. Programmed cell death 4 (Pdcd4) inhibits malignant transformation, and initial studies of Pdcd4 suggested the regulation of Pdcd4 localization by protein kinase B (Akt). However, supporting patient tissue data are missing, and the diagnostic/prognostic potential of Pdcd4 rarely has been studied. The objectives of the current were 1) to determine Pdcd4 as a diagnostic marker in the adenoma-carcinoma sequence, 2) to support phosphorylated Akt (pAkt)-mediated Pdcd4 regulation in vivo, and 3) to obtain the first prognostic evidence of Pdcd4 in colorectal cancer.METHODS. Tumor samples and normal tissues from 71 patients with colorectal cancer who were followed prospectively (median follow-up, 36 months) and 42 adenomas were analyzed for Pdcd4, Akt, and pAkt in immunohistochemical and Western blot analyses.RESULTS. A significant reduction in Pdcd4 was observed between normal mucosa and adenomas and between adenomas and tumor samples (P < .01 and P < .01, respectively). Normal mucosa demonstrated strong nuclear Pdcd4, which was reduced significantly in adenomas (P < .01) and almost was lost in tumors (P < .01). pAkt was correlated inversely with Pdcd4 and with the transition of Pdcd4 from nucleus to cytoplasm (P < .01). Kaplan-Meier analysis (using the Mantel-Cox log-rank test) indicated a significant correlation between the loss of total and nuclear Pdcd4 in tumors and overall survival (P < .05 and P < .02, respectively) and disease-specific survival (P < .01 and P < .01, respectively). In multivariate analysis, loss of total or nuclear Pdcd4 was an independent predictor of disease-specific or overall survival.CONCLUSIONS. To the authors' knowledge, this is the first study to demonstrate an independent prognostic impact of Pdcd4 and its expression pattern in colorectal cancer. Data from this study support the regulation of Pdcd4 locatization by pAkt in vivo. Pdcd4 immunohistochemistry may be useful as a supportive diagnostic tool for the transition between normal, adenoma, and tumor tissues.