- Cell cycle regulator
- Gastric cancer
- Tissue array
Objective: We aimed to investigate the biological significance of cell cycle regulators in gastric carcinoma. Methods: Immunohistochemistry and TUNEL staining were performed on tissue array slides containing 293 gastric carcinoma specimens. The relationship between the protein expression of each of the cell cycle regulators and prognosis, clinicopathological features, proliferation, or apoptosis was evaluated. Results: The nuclear immunoreactivity for cyclin D1, cyclin E, p21, and p27 was observed in 22, 14, 31 and 27% of cases, respectively. The expression of cyclin D1, p21, or p27 positively correlated with early pTNM stages, tumor cell proliferation (represented by Ki-67 labeling) and good prognosis, whereas it inversely correlated with the lymph node metastasis (p < 0.05). On the other hand, p27 expression inversely correlated with the apoptosis index represented by TUNEL staining (p < 0.001). In addition, the expression of cyclin D1 positively correlated with that of p21 or p27 (p < 0.05). Conclusions: Our results showed that the expression of cyclin D1, p21 and p27, alone or in combination, are early events in gastric tumorigenesis and may serve as a candidate molecular marker for the early gastric carcinoma.
Copyright © 2008 S. Karger AG, Basel
- Morgan DO: Cyclin-dependent kinases: engines, clocks, and microprocessors. Annu Rev Cell Dev Biol 1997;13:261–291.
- Aaltomaa S, Lipponen P, Ala-Opas M, Eskelinen M, Syrjänen K, Kosma VM: Expression of cyclins A and D and p21WAF1/CIP1 proteins in renal cell cancer and their relation to clinicopathological variables and patient survival. Br J Cancer 1999;80:2001–2007.
- Gansauge S, Gansauge F, Ramadani M, Stobbe H, Rau B, Harada N, Beger HG: Overexpression of cyclin D1 in human pancreatic carcinoma is associated with poor prognosis. Cancer Res 1997;77:1634–1637.
- Maeda K, Chung Y, Kang S, Ogawa M, Onoda N, Nishiguchi Y, Ikehara T, Nakata B, Okuno M, Sowa M: Cyclin D1 overexpression and prognosis in colorectal adenocarcinoma. Oncology 1998;55:145–151.
- Ishikawa T, Furihata M, Ohtsuki Y, Murakami H, Inoue A, Ogoshi S: Cyclin D1 overexpression related to retinoblastoma protein expression as a prognostic marker in human esophageal squamous cell carcinoma. Br J Cancer 1998;77:92–97.
- Gillett CE, Lee AH, Millis RR, Barnes DM: Cyclin D1 and associated proteins in mammary ductal carcinoma in situ and atypical ductal hyperplasia. J Pathol 1998;184:396–400.
- Allal AS, Gervaz P, Bründler MA: Cyclin D1, cyclin E, and p21 have no apparent prognostic value in anal carcinomas treated by radiotherapy with or without chemotherapy. Br J Cancer 2004;91:1239–1244.
- Van de Putte G, Kristensen GB, Lie AK, Baekelandt M, Holm R: Cyclins and proliferation markers in early squamous cervical carcinoma. Gynecol Oncol 2004;92:40–46.
- Nakamura N, Yamamoto H, Yao T, Oda Y, Nishiyama K, Imamura M, Yamada T, Nawata H, Tsuneyoshi M: Prognostic significance of expressions of cell-cycle regulatory proteins in gastrointestinal stromal tumor and the relevance of the risk grade. Hum Pathol 2005;36:828–837.
- Ohashi Y, Sasano H, Yamaki H, Shizawa S, Shineha R, Akaishi T, Satomi S, Nagura H: Cell cycle inhibitory protein p27 in esophageal squamous cell carcinoma. Anticancer Res 1999;19:1843–1848.
- Takano Y, Kato Y, van Diest PJ, Masuda M, Mitomi H, Okayasu I: Cyclin D2 overexpression and lack of p27 correlate positively and cyclin E inversely with a poor prognosis in gastric cancer cases. Am J Pathol 2000;156:585–594.
- Tenderenda M: A study on the prognostic value of cyclins D1 and E expression levels in resectable gastric cancer and on some correlations between cyclin expression, histoclinical parameters and selected protein products of cell-cycle regulatory genes. J Exp Clin Cancer Res 2005;24:405–414.
- Jang SJ, Park YW, Park MH, Lee JD, Lee YY, Jung TJ, Kim IS, Choi IY, Ki M, Choi BY, Ahn MJ: Expression of cell-cycle regulators, cyclin E and p21WAF1/CIP1, potential prognostic markers for gastric cancer. Eur J Surg Oncol 1999;25:157–163.
- Chetty R, Sitti CW: Cyclin E immunoexpression in gastric cancer does not correlate with clinicopathological parameters. Histopathology 2003;42:66–69.
- Gamboa-Dominguez A, Seidl S, Reyes-Gutierrez E, Hermannstädter C, Quintanilla-Martinez L, Busch R, Höfler H, Fend F, Luber B: Prognostic significance of p21WAF1/CIP1, p27Kip1, p53 and E-cadherin expression in gastric cancer. J Clin Pathol 2007;60:756–761.
- Mattioli E, Vogiatzi P, Sun A, Abbadessa G, Angeloni G, D’Ugo D, Trani D, Gaughan JP, Vecchio FM, Cevenini G, Persiani R, Giordano A, Claudio PP: Immunohistochemical analysis of pRb2/p130, VEGF, EZH2, p53, p16INK4A, p27Kip1, p21WAF1/CIP1, Ki-67 expression patterns in gastric cancer. J Cell Physiol 2007;210:183–191.
- Kaye PV, Radebold K, Isaacs S, Dent DM: Expression of p53 and p21WAF1/CIP1 in gastric carcinoma: lack of inter-relationship or correlation with prognosis. Eur J Surg Oncol 2000;26:39–43.
- Al-Moundhri MS, Nirmala V, Al-Hadabi I, Al-Mawaly K, Burney I, Al-Nabhani M, Thomas V, Ganguly SS, Grant C: The prognostic significance of p53, p27Kip1, p21WAF1/CIP1, HER-2/neu, and Ki67 proteins expression in gastric cancer: a clinicopathological and immunohistochemical study of 121 Arab patients. J Surg Oncol 2005;91:243–252.
- Feakins RM, Mulcahy HE, Quaglia A, Jawhari A, Zhang Z, Patchett SE: p27Kip1 loss does not predict survival in patients with advanced gastric carcinoma. Cancer 2000;89:1684–1691.
- Wiksten JP, Lundin J, Nordling S, Kokkola A, von Boguslawski K, Haglund C: The prognostic value of p27 in gastric cancer. Oncology 2002;63:180–184.
- Lee HS, Lee HK, Kim HS, Yang HK, Kim YI, Kim WH: MUC1, MUC2, MUC5AC, and MUC6 expressions in gastric carcinomas: their roles as prognostic indicators. Cancer 2001;92:1427–1434.
- Adachi Y, Kamakura T, Mori M, Baba H, Maehara Y, Sugimachi K: Prognostic significance of the number of positive lymph nodes in gastric carcinoma. Br J Surg 1994;81:414–416.
- Mishina T, Dosaka-Akita H, Kinoshita I, Hommura F, Morikawa T, Katoh H, Kawakami Y: Cyclin D1 expression in non-small-cell lung cancers: its association with altered p53 expression, cell proliferation and clinical outcome. Br J Cancer 1999;80:1289–1295.
- Tut VM, Braithwaite KL, Angus B, Neal DE, Lunec J, Mellon JK: Cyclin D1 expression in transitional cell carcinoma of the bladder: correlation with p53, waf1, pRb and Ki67. Br J Cancer 2001;84:270–275.
- McKay JA, Douglas JJ, Ross VG, Curran S, Loane JF, Ahmed FY, Cassidy J, McLeod HL, Murray GI: Analysis of key cell cycle checkpoint proteins in colorectal tumors. J Pathol 2002;196:386–393.
- Nam SY, Lee HS, Jung GA, Choi J, Cho SJ, Kim MK, Kim WH, Lee BL: Akt/PKB activation in gastric carcinomas correlates with clinicopathologic variables and prognosis. APMIS 2003;111:1105–1113.
- Lee BL, Kim WH, Jung J, Cho SJ, Park JW, Kim J, Chung HY, Chang MS, Nam SY: A hypoxia-independent up-regulation of hypoxia-inducible factor-1 by AKT contributes to angiogenesis in human gastric cancer. Carcinogenesis 2008;29:44–51.
- Banerji L, Glassford J, Lea NC, Thomas NS, Klaus GG, Lam EW: BCR signals target p27Kip1 and cyclin D2 via the PI3-K signalling pathway to mediate cell cycle arrest and apoptosis of WEHI 231 B cells. Oncogene 2001;20:7352–7367.
- Fredersdorf S, Burns J, Milne AM, Packham G, Fallis L, Gillett CE, Royds JA, Peston D, Hall PA, Hanby AM, Barnes DM, Shousha S, O’Hare MJ, Lu X: High level expression of p27Kip1 and cyclin D1 in some human breast cancer cells: inverse correlation between the expression of p27Kip1 and degree of malignancy in human breast and colorectal cancers. Proc Natl Acad Sci USA 1997;94:6380–6385.
- Han EK, Begemann M, Sgambato A, Soh JW, Doki Y, Xing WQ, Liu W, Weinstein IB: Increased expression of cyclin D1 in a murine mammary epithelial cell line induces p27Kip1, inhibits growth, and enhances apoptosis. Cell Growth Differ 1996;7:699–710.
- Coleman ML, Marshall CJ, Olson MF: Ras promotes p21WAF1/CIP1 protein stability via a cyclin D1-imposed block in proteasome-mediated degradation. EMBO J 2003;22:2036–2046.
- Lipponen P, Aaltomaa S, Eskelinen M, Ala-Opas M, Kosma VM: Expression of p21WAF1/CIP1 protein in transitional cell bladder tumours and its prognostic value. Eur Urol 1998;34:237–243.
- Peschos D, Tsanou E, Stefanou D, Damala C, Vougiouklakis T, Mitselou A, Agnantis NJ: Expression of cyclin-dependent kinases inhibitors p21WAF1/CIP1 and p27Kip1 in benign, premalignant and malignant laryngeal lesions. Correlation with cell cycle regulatory proteins. In Vivo 2004;18:719–724.
- Zheng JY, Wang WZ, Li KZ, Guan WX, Yan W: Effect of p27Kip1 on cell cycle and apoptosis in gastric cancer cells. World J Gastroenterol 2005;11:7072–7077.
- Eymin B, Sordet O, Droin N, Munsch B, Haugg M, Van de Craen M, Vandenabeele P, Solary E: Caspase-induced proteolysis of the cyclin dependent kinase inhibitor p27Kip1 mediates its anti-apoptotic activity. Oncogene 1999;18:4839–4847.
- Masuda A, Osada H, Yatabe Y, Kozaki K, Tatematsu Y, Takahashi T, Hida T, Takahashi T, Takahashi T: Protective function of p27Kip1 against apoptosis in small cell lung cancer cells in unfavorable microenvironments. Am J Pathol 2001;158:87–96.
Dr. Byung Lan Lee
Department of Anatomy, Seoul National University College of Medicine
28 Yeongon-dong, Chongno-gu
Seoul 110-799 (Korea)
Tel. +82 2 740 8206, Fax +82 2 745 9528, E-Mail firstname.lastname@example.org
K.-H. Lee and H.E. Lee contributed equally to this work.
Received: May 6, 2008
Accepted after revision: August 18, 2008
Published online: December 15, 2008
Number of Print Pages : 9
Number of Figures : 3, Number of Tables : 3, Number of References : 36
Pathobiology (Exploring the basis of disease)
Vol. 75, No. 6, Year 2008 (Cover Date: December 2008)
Journal Editor: Borisch B. (Geneva), Yasui W. (Hiroshima)
ISSN: 1015-2008 (Print), eISSN: 1423-0291 (Online)
For additional information: http://www.karger.com/PAT
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