| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Regular Articles |
From the Department of Pathology,*
Kitasato University
School of Medicine, Sagamihara, Japan; the Department of
Pathology,
Cancer Institute, Tokyo,
Japan; the Department of Pathology,
Free
University, Amsterdam, the Netherlands; and the Department of
Urology,§
Yokohama City University School of
Medicine, Yokohama, Japan
G1 cyclins and cyclin-dependent kinase (CDK) complexes play important roles in G1 cell cycle transition, and their overexpression is implicated for neoplasia. The p27 protein (p27) negatively regulates G1 progression by binding to G1 cyclins/CDK complexes and inhibits their activity, resulting in inhibition of entry to the cell cycle. We investigated overexpression of cyclin D1 (CCND1), cyclin D2 (CCND2), cyclin E (CCNE), CDK2, and CDK4, in addition to p27, in 260 gastric cancer cases on the basis of Western blots, reverse transcriptase-polymerase chain reaction Southern blots, and immunohistochemistry to clarify the roles of these proteins in tumor progression and prognosis. Examination of 20 cases of fresh cancer and matched normal tissues demonstrated a clear tendency for increased mRNA synthesis to be more frequent than expected from protein levels, and a direct correlation between p27 protein and mRNA was not found. Immunohistochemistry demonstrated 21.5%, 34.2%, 30.4%, 44.2%, and 48.0% positivity for CCND1, CCND2, CCNE, CDK2, and CDK4, respectively, in the 260 gastric cancer cases. Overexpression of CCND2 and CDK4 significantly correlated with tumor progression. Moreover, CCND2 cytoplasmic staining (26.2%) appeared to be strictly linked with progression, whereas nuclear staining (7.8%) demonstrated an inverse correlation. Survival curves showed CCND2 (especially cytoplasmic staining) and CDK4 positivity to be associated with a poor prognosis and CCNE positivity with a better prognosis. Tumors with high p27 labeling indices (LIs) were well differentiated, with low levels of invasion and lymph node metastasis. p27-negative cases (37.3%) demonstrated a poor prognosis. Multivariate analysis revealed positivity for CCND2 and negativity for p27 to be independent prognostic factors. There were no direct links among CCND2, CCNE, CDK4, and p27. The results indicate that CCND2 cytoplasmic localization might reflect an important physiological role in tumor progression, whereas CCNE overexpression correlates with differentiation and a good prognosis, possibly because of accumulation of inactive forms of CCNE-CDK2 complexes. Loss of p27 caused by degradation activity may affect tumor cell growth in the presence of an altered extracellular matrix, facilitating metastasis. Cell-cycle-regulatory proteins appear to work independently.
This article has been cited by other articles:
 |
|
 |
|
  H. Kashima, T. Shiozawa, T. Miyamoto, A. Suzuki, J. Uchikawa, M. Kurai, and I. Konishi Autocrine stimulation of IGF1 in estrogen-induced growth of endometrial carcinoma cells: involvement of the mitogen-activated protein kinase pathway followed by up-regulation of cyclin D1 and cyclin E Endocr. Relat. Cancer, March 1, 2009; 16(1): 113 - 122. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A N A Milne, R Carvalho, M Jansen, E K Kranenbarg, C J H van de Velde, F M Morsink, A R Musler, M A J Weterman, and G J A Offerhaus Cyclin E low molecular weight isoforms occur commonly in early-onset gastric cancer and independently predict survival J. Clin. Pathol., March 1, 2008; 61(3): 311 - 316. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Mao, A. K. Stewart, R. Hurren, A. Datti, X. Zhu, Y. Zhu, C. Shi, K. Lee, R. Tiedemann, Y. Eberhard, et al. A chemical biology screen identifies glucocorticoids that regulate c-maf expression by increasing its proteasomal degradation through up-regulation of ubiquitin Blood, December 1, 2007; 110(12): 4047 - 4054. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Li, H. Wen, C. Brayton, P. Das, L. A. Smithson, A. Fauq, X. Fan, B. J. Crain, D. L. Price, T. E. Golde, et al. Epidermal Growth Factor Receptor and Notch Pathways Participate in the Tumor Suppressor Function of {gamma}-Secretase J. Biol. Chem., November 2, 2007; 282(44): 32264 - 32273. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Susaki, K. Nakayama, and K. I. Nakayama Cyclin D2 Translocates p27 out of the Nucleus and Promotes Its Degradation at the G0-G1 Transition Mol. Cell. Biol., July 1, 2007; 27(13): 4626 - 4640. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Gamboa-Dominguez, S. Seidl, E. Reyes-Gutierrez, C. Hermannstadter, L. Quintanilla-Martinez, R. Busch, H. Hofler, F. Fend, and B. Luber Prognostic significance of p21WAF1/CIP1, p27Kip1, p53 and E-cadherin expression in gastric cancer J. Clin. Pathol., July 1, 2007; 60(7): 756 - 761. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Weber, L. Shen, M. A. Aldred, C. D. Morrison, A. Frilling, M. Saji, F. Schuppert, C. E. Broelsch, M. D. Ringel, and C. Eng Genetic Classification of Benign and Malignant Thyroid Follicular Neoplasia Based on a Three-Gene Combination J. Clin. Endocrinol. Metab., May 1, 2005; 90(5): 2512 - 2521. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Furuya, H. Kato, N. Nishimura, I. Ishiwata, H. Ikeda, R. Ito, T. Yoshiki, and H. Ishikura Down-regulation of CD9 in Human Ovarian Carcinoma Cell Might Contribute to Peritoneal Dissemination: Morphologic Alteration and Reduced Expression of {beta}1 Integrin Subsets Cancer Res., April 1, 2005; 65(7): 2617 - 2625. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. E. Bani-Hani, N. M. Almasri, Y. S. Khader, F. M. Sheyab, and H. N. Karam Combined Evaluation of Expressions of Cyclin E and p53 Proteins as Prognostic Factors for Patients with Gastric Cancer Clin. Cancer Res., February 15, 2005; 11(4): 1447 - 1453. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W K Leung, A H C Bai, V Y W Chan, J Yu, M W Y Chan, K-F To, J-R Wu, K-K Chan, Y-G Fu, F K L Chan, et al. Effect of peroxisome proliferator activated receptor {gamma} ligands on growth and gene expression profiles of gastric cancer cells Gut, March 1, 2004; 53(3): 331 - 338. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Padar, U. G. Sathyanarayana, M. Suzuki, R. Maruyama, J.-T. Hsieh, E. P. Frenkel, J. D. Minna, and A. F. Gazdar Inactivation of Cyclin D2 Gene in Prostate Cancers by Aberrant Promoter Methylation Clin. Cancer Res., October 15, 2003; 9(13): 4730 - 4734. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. GOUKASSIAN, A. DIEZ-JUAN, T. ASAHARA, P. SCHRATZBERGER, M. SILVER, T. MURAYAMA, J. M. ISNER, and V. ANDRES Overexpression of p27Kip1 by doxycycline-regulated adenoviral vectors inhibits endothelial cell proliferation and migration and impairs angiogenesis FASEB J, September 1, 2001; 15(11): 1877 - 1885. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Andres, J. Urena, E. Poch, D. Chen, and D. Goukassian Role of Sp1 in the Induction of p27 Gene Expression in Vascular Smooth Muscle Cells In Vitro and After Balloon Angioplasty Arterioscler Thromb Vasc Biol, March 1, 2001; 21(3): 342 - 347. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Evron, C. B. Umbricht, D. Korz, V. Raman, D. M. Loeb, B. Niranjan, L. Buluwela, S. A. Weitzman, J. Marks, and S. Sukumar Loss of Cyclin D2 Expression in the Majority of Breast Cancers Is Associated with Promoter Hypermethylation Cancer Res., March 1, 2001; 61(6): 2782 - 2787. [Abstract] [Full Text]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
