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
Open accessAbstract
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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
PDCD4 loss is diagnostic for human cancer staging and prognostic for survival in colon, lung, liver, breast, glioma and esophageal cancers.
“its loss is diagnostic for human cancer staging and prognostic for survival in colon, lung, liver, breast, glioma and esophageal cancers (6–11).”
From Tumor suppressor PDCD4 inhibits NF-κB-dependent transcription in human glioblastoma cells by direct interaction with p65 (2014) · cites this paper as [10]
The Multivariate Analysis section finds that PDCD4 loss predicts survival in patients with colorectal cancer, and the Correlation With Established Patient and Tumor Characteristics section links it to pT stage. The Discussion proposes PDCD4 staining as an additional tool for distinguishing normal tissue, adenomas, and carcinomas; it does not establish PDCD4 loss as a diagnostic test for cancer staging. This paper addresses colorectal cancer, while the sentence cites multiple sources for the other cancers. (LLM, conf=0.86)
Experimental — accuracy not yet measuredLoss of PDCD4 expression is correlated with poor prognosis and survival in breast cancer, colorectal cancer, lung cancer, ovarian cancer, and renal cell carcinoma.
“the loss of PDCD4 expression is correlated with poor prognosis and survival in breast cancer [89], colorectal cancer [90], lung cancer [17], ovarian cancer [91] and renal cell carcinoma [92] (Table 2).”
From Control Mechanisms of the Tumor Suppressor PDCD4: Expression and Functions (2019) · cites this paper as [90]
PDCD4 localizes both to the nucleus and the cytoplasm in cancer cells.
“PDCD4 is known to localize both to the nucleus and the cytoplasm in cancer cells (10).”
From Tumor suppressor PDCD4 inhibits NF-κB-dependent transcription in human glioblastoma cells by direct interaction with p65 (2014) · cites this paper as [10]
PDCD4 is known to localize both to the nucleus and the cytoplasm in cancer cells.
“PDCD4 is known to localize both to the nucleus and the cytoplasm in cancer cells (10).”
From Tumor suppressor PDCD4 inhibits NF-κB-dependent transcription in human glioblastoma cells by direct interaction with p65 (2014) · cites this paper as [10]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
The citation lists haven’t been fetched yet
References 30 · Cited by 196
Research works printed but not linked: 22
- Cmarik JL, Min H, Hegamyer G, et al. Differentially expressed protein Pdcd4 inhibits tumor promoter-induced neoplastic transformation. Proc Natl Acad Sci USA. 1999; 96:14037-14042.
- Jansen AP, Camalier CE, Colburn NH. Epidermal expression of the translation inhibitor programmed cell death 4 sup- presses tumorigenesis. Cancer Res. 2005;65:6034-6041.
- Shibahara K, Asano M, Ishida Y, Aoki T, Koike T, Honjo T. Isolation of a novel mouse gene MA-3 that is induced upon programmed cell death. Gene. 1995;166:297-301.
- Onishi Y, Kizaki H. Molecular cloning of the genes sup- pressed in RVC lymphoma cells by topoisomerase inhibi- tors. Biochem Biophys Res Commun. 1996;228:7-13.
- Yoshinaga H, Matsuhashi S, Fujiyama C, Masaki Z. Novel human PDCD4 (H731) gene expressed in proliferative cells is expressed in the small duct epithelial cells of the breast as revealed by an anti-H731 antibody. Pathol Int. 1999; 49:1067-1077.
- Soejima H, Miyoshi O, Yoshinaga H. Assignment of the programmed cell death 4 gene (PDCD4) to human chro- mosome band 10q24 by in situ hybridization. Cytogenet Cell Genet. 1999;87:113-114.
- Chen Y, Knosel T, Kristiansen G, et al. Loss of PDCD4 expression in human lung cancer correlates with tumour progression and prognosis. J Pathol. 2003;200:640-646.
- Kang MJ, Ahn HS, Lee JY, Matsuhashi S, Park WY. Up-regu- lation of PDCD4 in senescent human diploid fibroblasts. Biochem Biophys Res Commun. 2002;293:617-621.
- Zhang Z, DuBois RN. Detection of differentially expressed genes in human colon carcinoma cells treated with a selec- tive COX-2 inhibitor. Oncogene. 2001;20:4450-4456.
- Goke R, Barth P, Schmidt A, Samans B, Lankat-Buttgereit B. Programmed cell death protein 4 suppresses CDK1/cdc2 via induction of p21(Waf1/Cip1). Am J Physiol Cell Physiol. 2004;287:1541-1546.
- Lankat-Buttgereit B, Gregel C, Knolle A, Hasilik A, Arnold R, Goke R. Pdcd4 inhibits growth of tumor cells by sup- pression of carbonic anhydrase type II. Mol Cell Endocri- nol. 2004;214:149-153.
- Yang HS, Cho MH, Zakowicz H, Hegamyer G, Sonenberg N, Colburn NH. A novel function of the MA-3 domains in transformation and translation suppressor Pdcd4 is essen- tial for its binding to eukaryotic translation initiation factor 4A. Mol Cell Biol. 2004;24:3894-3906.
- Zakowicz H, Yang HS, Stark C, Wlodawer A, Laronde- Leblanc N, Colburn NH. Mutational analysis of the DEAD- box RNA helicase eIF4AII characterizes its interaction with transformation suppressor Pdcd4 and eIF4GI. RNA. 2005; 11:261-274.
- Onishi Y, Hashimoto S, Kizaki H. Cloning of the TIS gene suppressed by topoisomerase inhibitors. Gene. 1998;215:453- 459.
- Schlichter U, Kattmann D, Appl H, Miethe J, Brehmer-Fas- tnacht A, Klempnauer KH. Identification of the myb-induc- ible promoter of the chicken Pdcd4 gene. Biochim Biophys Acta. 2001;1520:99-104.
- Ossowski L, Clunie G, Masucci MT, Blasi F. In vivo para- crine interaction between urokinase and its receptor: effect on tumor cell invasion. J Cell Biol. 1991;115:1107-1112.
- Schewe DM, Leupold JH, Boyd DD, et al. Tumor-specific transcription factor binding to an activator protein-2/Sp1 element of the urokinase-type plasminogen activator receptor promoter in a first large series of resected gastro- intestinal cancers. Clin Cancer Res. 2003;9:2267-2276.
- Beyer BC, Heiss MM, Simon EH, et al. Urokinase system expression in gastric carcinoma: prognostic impact in an independent patient series and first evidence of predictive value in preoperative biopsy and intestinal metaplasia spe- cimens. Cancer. 2006;106:1026-1035.
- Laufs S, Schumacher J, Allgayer H. Urokinase-receptor (u- PAR): an essential player in multiple games of cancer: a review on its role in tumor progression, invasion, metasta- sis, proliferation/dormancy, clinical outcome and minimal residual disease. Cell Cycle. 2006;5:1760-1771.
- Dorrello NV, Peschiaroli A, Daniele G, Colburn NH, Sher- man NE, Pagano M. Degradation of PDCD4 promotes pro- tein translation and cell growth. Science. 2006;314:467-471.
- Ahmed NN, Franke TF, Bellacosa A, et al. The proteins encoded by c-Akt and v-Akt differ in post-translational modification, subcellular localization and oncogenic potential. Oncogene. 1993;8:1957-1963.
- Bellacosa A, Chan TO, Ahmed NN, et al. Akt activation by growth factors is a multiple-step process: the role of the PH domain. Oncogene. 1998;17:313-325.
- Authors
- Mudduluru, G., Medved, F., Grobholz, R., Jost, C., Gruber, A., Leupold, J. H., Post, S., Jansen, A., Colburn, N. H., & Allgayer, H.
- Affiliations
- German Cancer Research Center (DE)
- Heidelberg University (DE)
- National Cancer Institute (US)
- Corresponding author
- Allgayer, Heike
- Venue
- Cancer
- Publisher
- Wiley
- Published
- 2007-09-19
- Volume
- 110
- Issue
- 8
- Pages
- 1697-1707
- ISSN
- 0008-543X (ISSN-L)
- 1097-0142
- OpenAlex
- W2027696262
- Cited by
- 196
- References
- 30
- Citations by year
- 2024: 1 · 2023: 2 · 2022: 7 · 2021: 4 · 2020: 9 · 2019: 8 · 2018: 11 · 2017: 10 · 2016: 15 · 2015: 14 · 2014: 19 · 2013: 15 · 2012: 15
- FWCI
- 5.80
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- public-domain
- onlinelibrary.wiley.com/termsAndConditions#vor (vor)
- Locations
- Cancer (publishedVersion, public-domain)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Keywords
- PDCD4, colorectal cancer, adenoma-carcinoma sequence, Akt, Akt phosphorylation, prognostic factors, overall survival, disease-specific survival, nuclear localization, tumor suppressor, colorectal adenoma
- MeSH terms
- Adenocarcinoma, Adenoma, Colon, Humans, Neoplasm Recurrence, Local, Neoplasm Staging, Phosphorylation, Prognosis, Prospective Studies, Rectum, Biomarkers, Tumor, Colorectal Neoplasms, Survival Rate, RNA-Binding Proteins, Apoptosis Regulatory Proteins, Proto-Oncogene Proteins c-akt
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
