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

被引:177
作者
Mudduluru, Giridhar
Medved, Fabian
Grobhoz, Rainer
Jost, Camela
Gruber, Anette
Leupold, Joerg H.
Post, Stefan
Jansen, Aaron
Colburn, Nancy H.
Allgayer, Heike [1 ]
机构
[1] Heidelberg Univ, Dept Expt Surg mol Oncol Solid Tumors, Mannheim Med Fac,German Canc Res Ctr, Collaborat Unit,Deutsch Krebforsch Zentrum Heidel, D-68167 Mannheim, Germany
[2] Univ Homburg, Dept Pathol, Saar, Germany
[3] Heidelberg Univ, Mannheim Fac, Dept Surg, D-6800 Mannheim, Germany
[4] Natl Canc Inst, Gene Regulat Sect, Bethesda, MD USA
关键词
colorectal cancer; programmed cell death 4; adenoma; protein kinase B; prognosis;
D O I
10.1002/cncr.22983
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
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收藏
页码:1697 / 1707
页数:11
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