Possible associations among expression of p14(ARF), p16(INK4a), p21(WAF1/CIP1), p27(KIP1), and p53 accumulation and the balance of apoptosis and cell proliferation in ovarian carcinomas.
BACKGROUND
Although there are several reports of changes in expression of cyclin-dependent kinase inhibitors in ovarian carcinomas, little is known about their associations with tissue kinetics in the various histologic subtypes.


METHODS
In total, 131 carcinomas were immunohistochemically investigated for expression of p14(ARF) (p14), p16(INK4a) (p16), p21(WAF1/Cip1) (p21), and p27(Kip1) (p27). The results also were compared with data for apoptosis, cell proliferation, p53 status, and survival. Western blot and mRNA analyses were conducted on 35 malignant ovarian tumor samples.


RESULTS
Significant differences in tissue kinetics determined by ratios of apoptotic relative to mitotic indices were observed among histologic subtypes of ovarian carcinomas, showing a shift toward predominance of cell proliferation in serous and cell deletion in clear cell types. The expression of p16, p21, p27, and p53 was associated closely with changes in cell proliferation rather than apoptosis and survival, dependent on the subtype. Positivity for p16 and p21 in the Western blot assay was significantly related to the results for immunohistochemical but not mRNA analyses, indicating possible posttranscriptional regulation of these genes.


CONCLUSIONS
The findings indicate that the several cyclin-dependent kinase inhibitors investigated are expressed differently among histologic subtypes of ovarian carcinomas, associated with differences in tissue kinetics and the balance of apoptosis and cell proliferation.
Saegusa
M
M
Department of Pathology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan. msaegusa@med.kitasato-u.ac.jp
Machida B
D
D
Okayasu
I
I
D000328:Adult; D000368:Aged; D017209:Apoptosis; D015139:Blotting, Southern; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002455:Cell Division; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D008940:Mitotic Index; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology*; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins
C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D011506:Proteins; D012333:RNA, Messenger; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases