Phosphorylated p27Kip1 on Thr157 is an important prognosis in human hepatocellular carcinoma in vivo and in vitro.
The p27(Kip1) cyclin-dependent kinase inhibitor is a negative regulator of cell cycle progression in G(1) phase; recent studies suggested that oncogenically activated kinase Akt/PKB can also phosphorylate p27(kip1) at T157 inducing its relocalization to the cytoplasm. To evaluate the significance of p-p27 Thr157 and PI3K pathway in hepatocellular carcinoma (HCC), we studied 51 hepatocellular carcinomas along with corresponding nontumoral tissue and the HCC cell lines. Immunohistochemistry and western blot analysis suggested that p-p27 Thr157 was overexpressed in HCC, which was positively correlated with proliferation marker Ki-67. Correlation analysis was performed among immunohistochemistry-assessed level of p-p27 Thr157, survival, and major clinical and pathological variables. Overexpressed p-p27 Thr157 was correlated with histological differentiation (P < 0.05). Univariate analysis showed that p-p27 Thr157 and Ki-67 expression were correlated with tumor-specific survival. In a multivariate analysis, p-p27 Thr157 and Ki-67 protein expression were proved to be an independent prognostic for HCC. While in vitro, treatment of LY294002 and transduction of mutant p27 (T157A) could diminish the expression of p-p27 Thr157 protein and arrest cells growth. Our results suggested that p-p27 Thr157 protein expression may be a favorable independent poor prognostic parameter for HCC. Gene therapeutic approaches aimed at PI3K or the pharmacologic inhibitors of PI3K and transduction of mutant p27 (T157A) to down-regulate p-p27 Thr157 expression could be developed for the management of HCC.
He
Song
S
Department of Pathology, Affiliated Cancer Hospital of Nantong University, Medical College of Nantong University, 226001 Nantong, China.
Lu
Mudan
M
Xue
Wenqun
W
Wang
You
Y
Zhao
Yueming
Y
Gao
Shangfeng
S
Ke
Qing
Q
Liu
Yonghua
Y
Li
Peng
P
Cui
Xiaopeng
X
Cheng
Chun
C
Shen
Aiguo
A
D000328:Adult; D000368:Aged; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000556:secondary; D002453:Cell Cycle; D002867:Chromones / Q000494:pharmacology; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D066298:In Vitro Techniques; D019394:Ki-67 Antigen / Q000378:metabolism*; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009025:Morpholines / Q000494:pharmacology; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation; D011379:Prognosis; D013912:Threonine / Q000737:chemistry*; D014407:Tumor Cells, Cultured
C436291:CDKN1B protein, human; D002867:Chromones; D019394:Ki-67 Antigen; D009025:Morpholines; D050505:Mutant Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D013912:Threonine; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one