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.
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 localization by pAkt in vivo. Pdcd4 immunohistochemistry may be useful as a supportive diagnostic tool for the transition between normal, adenoma, and tumor tissues.
Mudduluru
Giridhar
G
Department of Experimental Surgery Mannheim/Molecular Oncology of Solid Tumors, Deutsches Krebsforschungszentrum and University Heidelberg, Mannheim, Germany.
Medved
Fabian
F
Grobholz
Rainer
R
Jost
Camela
C
Gruber
Anette
A
Leupold
Joerg H
JH
Post
Stefan
S
Jansen
Aaron
A
Colburn
Nancy H
NH
Allgayer
Heike
H
D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D000236:Adenoma / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D003106:Colon / Q000378:metabolism / Q000473:pathology; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D006801:Humans; D009364:Neoplasm Recurrence, Local / Q000378:metabolism / Q000473:pathology; D009367:Neoplasm Staging; D010766:Phosphorylation; D011379:Prognosis; D011446:Prospective Studies; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism*; D012007:Rectum / Q000378:metabolism / Q000473:pathology; D015996:Survival Rate
D051017:Apoptosis Regulatory Proteins; D014408:Biomarkers, Tumor; C114487:PDCD4 protein, human; D016601:RNA-Binding Proteins; D051057:Proto-Oncogene Proteins c-akt