Reduced expression of cyclin-dependent kinase inhibitor p27Kip1 is an indicator of malignant behavior in oral squamous cell carcinoma.
BACKGROUND
Reduced expression of the cyclin-dependent kinase inhibitor p27Kip1 has been reported to correlate with poor survival in cohorts of breast and colorectal carcinoma patients. Posttranslational ubiquitin-mediated proteasomal proteolysis is related to p27Kip1 protein levels. However, to the authors' knowledge, no previous study has examined the expression of p27Kip1 in oral squamous cell carcinoma (OSCC).


METHODS
To examine the expression of p27Kip1 and its clinicopathologic roles in OSCC, the authors studied the expression of p27Kip1 protein by immunohistochemistry in deparaffinized tissue sections of 20 normal oral mucosa specimens, 22 epithelial dysplasia specimens, and 70 OSCCs, and analyzed its correlation with clinicopathologic parameters. They also studied the expression of p27Kip1 mRNA and protein in six OSCC cell lines by Northern blot and Western blot analysis. To examine the mechanism of reduced expression of p27Kip1, OSCC cell lines were treated with the proteasome inhibitor LLnV.


RESULTS
All the normal oral mucosa specimens and 73% (16 of 22) of the oral epithelial dysplasia specimens expressed p27Kip1 at high levels, whereas 87% of the OSCCs (61 of 70) showed reduced expression of p27Kip1. Furthermore, the levels of expression of this protein were significantly lower in carcinomas with metastasis than those without metastasis. Although OSCC cell lines expressed p27Kip1 mRNA at various levels, most of them expressed p27Kip1 protein at lower or undetectable levels. LLnV induced the expression of p27Kip1 protein in HSC2 cells, in which p27Kip1 protein was originally undetectable.


CONCLUSIONS
These findings suggest that 1) reduced expression of p27Kip1 may correlate with the development and progression of OSCC and can be an indicator of malignant behavior of this neoplasm, and 2) increased proteasome-mediated degradation may play an important role in the reduction of p27Kip1 protein expression.
Kudo
Y
Y
Department of Oral Pathology, Hiroshima University School of Dentistry, Japan.
Takata
T
T
Yasui
W
W
Ogawa
I
I
Miyauchi
M
M
Takekoshi
T
T
Tahara
E
E
Nikai
H
H
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D018797:Cell Cycle Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D018450:Disease Progression; D005260:Female; D006801:Humans; D007976:Leupeptins; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008875:Middle Aged; D009061:Mouth Mucosa / Q000378:metabolism / Q000473:pathology; D009062:Mouth Neoplasms / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D011379:Prognosis; D014407:Tumor Cells, Cultured / Q000187:drug effects; D025521:Tumor Suppressor Proteins
D018797:Cell Cycle Proteins; D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D009842:Oligopeptides; D025521:Tumor Suppressor Proteins; C089486:carbobenzoxy-leucyl-leucyl-norvalinal; D050760:Cyclin-Dependent Kinase Inhibitor p27