Phosphorylation of p70S6 kinase predicts overall survival in patients with clear margin-resected hepatocellular carcinoma.
OBJECTIVE
The mammalian target of rapamycin (mTOR) inhibitors play a key role in regulating signal transduction by blocking the mTOR pathway and combining anticancer and immunosuppressive properties. This study was undertaken to determine the prevalence and clinicopathological relevance of phospho-p70S6 (p-p70S6) kinase in hepatocellular carcinoma (HCC) and to investigate the effects of rapamycin on HCC in vitro.


METHODS
A total of 196 patients with HCCs were treated either with surgical resection (n=106) or liver transplantation (n=90). Tumour tissue was investigated for p-p70S6, phospho-AKT, Ki-67, Cyclin-D1 and apoptosis, and staining results were correlated with clinicopathologically relevant parameters.


RESULTS
Overall, p-p70S6 was detected in 24.5% (48/196) of HCCs. In the resection group, 26.4% (28/106) of HCC were positive and 22.2% (20/90) in the transplant group. p-p70S6 was significantly associated with elevated Cyclin-D1 immunoexpression and was correlated with decreased overall survival (P=0.011) in patients resected with a clear margin. In multivariate COX regression analysis, p-p70S6 was identified as an independent prognostic parameter in patients resected with a clear margin. Rapamycin induced apoptosis and growth inhibition by G0/G1 cell cycle arrest in vitro. However, in HCC patients p-p70S6 kinase was not associated with proliferation or apoptosis.


CONCLUSIONS
Activation of p70S6 kinase indicates aggressive tumour behaviour in patients with clear margin-resected HCC. Identification of p-p70S6 kinase in HCC selects high-risk patients who may benefit from drugs targeting the mTOR pathway.
Baba
Hideo A
HA
Institute of Pathology and Neuropathology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany. hideo.baba@uk-essen.de
Wohlschlaeger
Jeremias
J
Cicinnati
Vito R
VR
Hilgard
Philip
P
Lang
Hauke
H
Sotiropoulos
Georgios C
GC
Takeda
Atsushi
A
Beckebaum
Susanne
S
Schmitz
Klaus J
KJ
D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D019938:Cyclin D1 / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D020287:In Situ Nick-End Labeling; D008297:Male; D046228:Microarray Analysis; D010766:Phosphorylation / Q000187:drug effects; D011379:Prognosis; D012044:Regression Analysis; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000494:pharmacology*; D016019:Survival Analysis
D007166:Immunosuppressive Agents; D019938:Cyclin D1; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D020123:Sirolimus