Cyclin D2 overexpression and lack of p27 correlate positively and cyclin E inversely with a poor prognosis in gastric cancer cases.
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.
Takano
Y
Y
Department of Pathology, Kitasato University School of Medicine, Sagamihara, Japan. ytakano@ms.toyamampu.ac.jp
Kato
Y
Y
van Diest
P J
PJ
Masuda
M
M
Mitomi
H
H
Okayasu
I
I
D000230:Adenocarcinoma / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D056742:Cyclin D2; D019927:Cyclin E / Q000378:metabolism*; D056746:Cyclin G; D056766:Cyclin G1; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism*; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism*; D008875:Middle Aged; D009124:Muscle Proteins; D011379:Prognosis; D012016:Reference Values; D013274:Stomach Neoplasms / Q000378:metabolism*; D016019:Survival Analysis
C080336:CCND2 protein, human; C534702:CCNG1 protein, human; C534703:Ccng1 protein, mouse; D056742:Cyclin D2; D019927:Cyclin E; D056746:Cyclin G; D056766:Cyclin G1; D016213:Cyclins; D008840:Microfilament Proteins; D009124:Muscle Proteins; C058992:Tagln protein, mouse; D018844:Cyclin-Dependent Kinases