Overexpression of cyclin D1 and p53 associated with disease recurrence in colorectal adenocarcinoma

Maeda, Kiyoshi; Chung, Yong‐Suk; Kang, Soon-Myoung; Ogawa, Masafumi; Onoda, Naoyoshi; Nakata, Bunzo; Nishiguchi, Yukio; Ikehara, Teruyuki; Okuno, Masahiro; Sowa, Michio

doi:10.1002/(sici)1097-0215(19970620)74:3<310::aid-ijc13>3.0.co;2-f

Cited by 62 publications

(67 citation statements)

References 17 publications

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“…In 22 out of 34 cases of colon adenocarcinomas cyclin D1 expression was obviously increased in tumor margins. Our ®ndings agree well with the results of others demonstrating that cyclin D1 is often overexpressed in colorectal adenocarcinomas (Maeda et al, 1997). However, since in 12 cases with eIF-4E elevation only occasional cells were expressing cyclin D1, we conclude that eIF-4E is not the only factor that regulates the level of cyclin D1 in colon epithelium and that cyclin D1 is not the only target mediating the eects of eIF-4E on cell proliferation and transformation.…”

Section: Discussionsupporting

confidence: 92%

Upregulation of protein synthesis initiation factor eIF-4E is an early event during colon carcinogenesis

et al. 1999

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A general increase in protein synthesis and a speci®c increase in the synthesis of growth-promoting proteins are necessary for mitogenesis. Regulation of protein synthesis, as well as preferential translation of some mRNAs coding for growth promoting proteins (e.g. cyclin D1), involves the essential protein synthesis initiation factor eIF-4E. This factor is induced by various oncoproteins, and, when overexpressed, it can transform cultured cells. In this report we explore the roles of eIF-4E in human neoplastic disorders of the colon and in the regulation of general and speci®c protein synthesis. We ®nd that eIF-4E is increased in colon adenomas and carcinomas, and this increase is accompanied in most but not all cases by elevation of cyclin D1 levels. While general protein synthesis is increased by eIF-4E overexpression in cultured cells, only a small proportion of proteins is preferentially upregulated by eIF-4E, as revealed by two-dimensional gel electrophoresis. These results are consistent with the view that eIF-4E plays a role in carcinogenesis by increasing general protein synthesis and by preferentially upregulating a subset of putative growth promoting proteins. Our results, taken together with the recent ®ndings that cmyc transcription is negatively regulated by APC and our earlier data on transcriptional activation of eIF-4E expression by c-Myc suggest that eIF-4E is a downstream target of the APC/b-catenin/Tcf-4 pathway, and is strongly involved in colon tumorigenesis.

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Section: Discussionsupporting

confidence: 92%

Upregulation of protein synthesis initiation factor eIF-4E is an early event during colon carcinogenesis

et al. 1999

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“…Although in two studies cyclin D1 overexpression has been associated with poor prognosis and in another two studies with good prognosis, most studies have shown no prognostic value of cyclin D1 overexpression. 19,22,[28][29][30][31] In the present study, cyclin D1 overexpression was associated with improved outcome. The biological background supporting this association remains subject of debate.…”

Section: Discussionsupporting

confidence: 61%

Cell Cycle Proteins Predict Recurrence in Stage II and III Colon Cancer

et al. 2012

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Purpose. To investigate the prognostic value of multiple cell cycle-associated proteins in a large series of stage II and III colon cancers. Methods. From formalin-fixed, paraffin-embedded tumor samples of 386 patients with stage II and III colon cancer, DNA was isolated and tissue microarrays were constructed. Tissue microarray slides were immunohistochemically stained for p21, p27, p53, epidermal growth factor receptor, Her2/Neu, b-catenin, cyclin D1, Ki-67, thymidylate synthase, and Aurora kinase A (AURKA). Polymerase chain reaction-based microsatellite instability analysis was performed to allow for stratification of protein expression by microsatellite instability status. Results. Overall, low p21, high p53, low cyclin D1, and high AURKA expression were significantly associated with recurrence (P = 0.01, P \ 0.01, P = 0.04, and P \ 0.01, respectively). In stage II patients who did not receive adjuvant chemotherapy (n = 190), significantly more recurrences were observed in case of low-p21 and highp53-expressing tumors (P \ 0.01 and P = 0.03, respectively). In stage III patients who did not receive chemotherapy, high p53 expression was associated with recurrence (P = 0.02), and in patients who received chemotherapy, high AURKA expression was associated with relapse (P \ 0.01). In patients with microsatellite stable tumors, high levels of p53 and AURKA were associated with recurrence (P = 0.01 and P \ 0.01, respectively). Multivariate analysis showed p21 (odds ratio 1.6, 95% confidence interval 0.9-2.8) and AURKA (odds ratio 2.7, 95% confidence interval 1.3-5.6) to be independently associated with disease recurrence. Conclusions. p21, p53, cyclin D1, and AURKA could possibly be used as prognostic markers to identify colon cancer patients with high risk of disease recurrence.

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“…19 No data are available, however, on the prognostic significance of loss of BAX in relation to the p53 status in primary colorectal cancer. Some reports in the literature show a prognostic impact of p53 mutation 20 -23 or p53 protein overexpression 24,25 in large series of colorectal carcinoma patients, others do not. 13,26 -30 One of the possible reasons for these diverse findings may be that the function of p53 to induce apoptosis depends at least in part on an intact BAX effector gene.…”

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confidence: 97%

Analysis of p53/BAX in primary colorectal carcinoma: Low BAX protein expression is a negative prognostic factor in UICC stage III tumors

Schelwies

Sturm

Grabowski

et al. 2002

Intl Journal of Cancer

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Deregulation of cell death pathways contributes to tumor development and to the clinical course of cancer disease. In patients with liver metastases of colorectal cancer, we have previously shown that an intact p53/BAX apoptotic pathway is a positive prognostic factor. Therefore, the purpose of our study was to determine the prognostic value of BAX protein expression and the mutational status of its upstream regulator p53 in primary colorectal adenocarcinoma. To this end, we analyzed retrospectively tumor samples of 116 patients who underwent surgery for colorectal adenocarcinoma and had a follow-up for a minimum of 5 years or until death (UICC Stage III: 59 patients, UICC Stage IV: 57 patients). Tumors were screened for p53 mutations and investigated for BAX protein expression. Overall median survival was 17 months. As expected, patients with UICC III tumors survived longer than patients with UICC IV tumors: 69 months vs. 8 months (p < 0.0001). UICC III tumors with high BAX expression were associated with a significantly better prognosis (p ‫؍‬ 0.009) than BAX low expressing tumors. The combined p53/BAX pathway analysis for the UICC Stage III group revealed the worst outcome for patients with a disrupted p53/ BAX pathway (i.e., BAX low/p53 mutated; p ‫؍‬ 0.004). In contrast, no significant effect of the p53/BAX status on survival was found in UICC IV tumors. Our study in primary adenocarcinoma of the colorectum shows for the first time that a disrupted p53/BAX pathway is associated with a poor clinical outcome in UICC III tumors. These data also confirm our previous report on the relevance of an intact p53/BAX pathway in liver metastasis of colorectal cancer. Nevertheless, we were not able to confirm this finding in the heterogenous subgroup of UICC IV tumors of the colorectum. Our study therefore provides the basis for the analysis of defects in p53/BAX (and additional genes) in a prospective trial that is the logical basis for future risk-adapted therapies.

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Overexpression of cyclin D1 and p53 associated with disease recurrence in colorectal adenocarcinoma

Cited by 62 publications

References 17 publications

Upregulation of protein synthesis initiation factor eIF-4E is an early event during colon carcinogenesis

Upregulation of protein synthesis initiation factor eIF-4E is an early event during colon carcinogenesis

Cell Cycle Proteins Predict Recurrence in Stage II and III Colon Cancer

Analysis of p53/BAX in primary colorectal carcinoma: Low BAX protein expression is a negative prognostic factor in UICC stage III tumors

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