Premium
Phosphorylation of p70S6 kinase predicts overall survival in patients with clear margin‐resected hepatocellular carcinoma
Author(s) -
Baba Hideo A.,
Wohlschlaeger Jeremias,
Cicinnati Vito R.,
Hilgard Philip,
Lang Hauke,
Sotiropoulos Georgios C.,
Takeda Atsushi,
Beckebaum Susanne,
Schmitz Klaus J.
Publication year - 2009
Publication title -
liver international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.873
H-Index - 110
eISSN - 1478-3231
pISSN - 1478-3223
DOI - 10.1111/j.1478-3231.2008.01798.x
Subject(s) - hepatocellular carcinoma , hccs , apoptosis , pi3k/akt/mtor pathway , cyclin d1 , cancer research , protein kinase b , biology , kinase , cell cycle , medicine , biochemistry
Background/Aims: 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.