PMID- 25131770
OWN - NLM
STAT- MEDLINE
DCOM- 20160225
LR  - 20141219
IS  - 1600-0641 (Electronic)
IS  - 0168-8278 (Linking)
VI  - 62
IP  - 1
DP  - 2015 Jan
TI  - SIRT1 regulates oncogenesis via a mutant p53-dependent pathway in hepatocellular 
      carcinoma.
PG  - 121-30
LID - S0168-8278(14)00546-7 [pii]
LID - 10.1016/j.jhep.2014.08.007 [doi]
AB  - BACKGROUND & AIMS: SIRT1 is a class III histone deacetylase that plays diverse 
      roles in various cancers. However, the clinical significance of SIRT1 in 
      hepatocellular carcinoma (HCC) remains unknown. METHODS: We analysed p53 
      mutations and the activation of SIRT1 in 252 hepatitis B virus-positive HCC 
      cases. None of the patients had been subjected to pre-operative treatment. 
      RESULTS: We examined 57 p53 mutations from 248 HCC tissues. Activated SIRT1 
      (phosphorylated form of Ser47), in the context of mutant p53, predicted a longer 
      relapse-free survival (RFS) but not a longer overall survival (OS) (RFS: p = 
      0.007, OS: p = 0.280) in HCC tissues harbouring mutant p53. In multivariate 
      analysis, activated SIRT1 remained a significant predictor of longer RFS (OR = 
      0.307, CI: 0.143-0.660, p=0.002). Analysis of 248 paired specimens revealed a 
      significant correlation between activated SIRT1 (Ser47) and activated AMPK 
      (Thr172) in HCC tissues harbouring mutant p53 (p = 0.003, n = 57). The 
      combination of these 2 parameters was a powerful predictor for a good prognosis 
      in these patients. In vitro, SIRT1 inactivation stimulated the growth of HCC 
      cells, bearing mutated p53, by suppressing AMPK activity and subsequently 
      enhancing mammalian target of rapamycin (mTOR) activity, resulting in induction 
      of p70S6K1 activation in HCC cells. Metformin, an AMPK activator, more strongly 
      suppressed cell growth in p53-mutant cell lines with inactive SIRT1 than in 
      p53-mutant cell lines with active SIRT1. CONCLUSIONS: SIRT1 exerted 
      anti-carcinogenic effects via the AMPK-mTOR pathway in HCC in the context of 
      mutant p53. Metformin could be a therapeutic drug for HCC in patients with 
      mutated p53, inactivated SIRT1, and AMPK expression.
CI  - Copyright (c) 2014 European Association for the Study of the Liver. Published by 
      Elsevier B.V. All rights reserved.
FAU - Zhang, Zheng Yun
AU  - Zhang ZY
AD  - Department of Surgery, Shanghai Jiao Tong University Affiliated Sixth People's 
      Hospital, Shanghai, China; Transplantation Research Center, Samsung Medical 
      Center, Samsung Biomedical Research Institute, Sungkyunkwan University School of 
      Medicine, Seoul, Republic of Korea.
FAU - Hong, Doopyo
AU  - Hong D
AD  - Transplantation Research Center, Samsung Medical Center, Samsung Biomedical 
      Research Institute, Sungkyunkwan University School of Medicine, Seoul, Republic 
      of Korea.
FAU - Nam, Seung Hoon
AU  - Nam SH
AD  - Transplantation Research Center, Samsung Medical Center, Samsung Biomedical 
      Research Institute, Sungkyunkwan University School of Medicine, Seoul, Republic 
      of Korea.
FAU - Kim, Jong Man
AU  - Kim JM
AD  - Department of Surgery, Samsung Medical Center, Samsung Biomedical Research 
      Institute, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
FAU - Paik, Yong Han
AU  - Paik YH
AD  - Department of Medicine, Samsung Medical Center, Samsung Biomedical Research 
      Institute, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
FAU - Joh, Jae Won
AU  - Joh JW
AD  - Department of Surgery, Samsung Medical Center, Samsung Biomedical Research 
      Institute, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
FAU - Kwon, Choon Hyuck David
AU  - Kwon CH
AD  - Department of Surgery, Samsung Medical Center, Samsung Biomedical Research 
      Institute, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
FAU - Park, Jae Berm
AU  - Park JB
AD  - Department of Surgery, Samsung Medical Center, Samsung Biomedical Research 
      Institute, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
FAU - Choi, Gyu-Seong
AU  - Choi GS
AD  - Department of Surgery, Samsung Medical Center, Samsung Biomedical Research 
      Institute, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
FAU - Jang, Kyu Yun
AU  - Jang KY
AD  - Department of Pathology, Chonbuk National University Medical School and Research 
      Institute of Clinical Medicine, Jeonju, Republic of Korea.
FAU - Park, Cheol Keun
AU  - Park CK
AD  - Department of Pathology, Samsung Medical Center, Samsung Biomedical Research 
      Institute, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. 
      Electronic address: ckpark@skku.edu.
FAU - Kim, Sung Joo
AU  - Kim SJ
AD  - Transplantation Research Center, Samsung Medical Center, Samsung Biomedical 
      Research Institute, Sungkyunkwan University School of Medicine, Seoul, Republic 
      of Korea; Sarcoma Research Center, Samsung Medical Center, Samsung Biomedical 
      Research Institute, Sungkyunkwan University School of Medicine, Seoul, Republic 
      of Korea; Department of Surgery, Samsung Medical Center, Samsung Biomedical 
      Research Institute, Sungkyunkwan University School of Medicine, Seoul, Republic 
      of Korea. Electronic address: kmhyj111@hotmail.com.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140815
PL  - Netherlands
TA  - J Hepatol
JT  - Journal of hepatology
JID - 8503886
RN  - 0 (DNA, Neoplasm)
RN  - 0 (Tumor Suppressor Protein p53)
RN  - EC 3.5.1.- (SIRT1 protein, human)
RN  - EC 3.5.1.- (Sirtuin 1)
SB  - IM
MH  - Apoptosis
MH  - Blotting, Western
MH  - Carcinogenesis/*genetics
MH  - Carcinoma, Hepatocellular/*genetics/metabolism/pathology
MH  - DNA Mutational Analysis
MH  - DNA, Neoplasm/genetics
MH  - Female
MH  - *Gene Expression Regulation, Neoplastic
MH  - Humans
MH  - Immunohistochemistry
MH  - Liver Neoplasms/*genetics/metabolism/pathology
MH  - Male
MH  - Middle Aged
MH  - *Mutation
MH  - Polymerase Chain Reaction
MH  - Retrospective Studies
MH  - Sirtuin 1/biosynthesis/*genetics
MH  - Tumor Cells, Cultured
MH  - Tumor Suppressor Protein p53/*genetics
OTO - NOTNLM
OT  - AMPK
OT  - Metformin
OT  - SIRT1
OT  - mTOR
OT  - p53
EDAT- 2014/08/19 06:00
MHDA- 2016/02/26 06:00
CRDT- 2014/08/19 06:00
PHST- 2014/01/28 00:00 [received]
PHST- 2014/07/23 00:00 [revised]
PHST- 2014/08/07 00:00 [accepted]
PHST- 2014/08/19 06:00 [entrez]
PHST- 2014/08/19 06:00 [pubmed]
PHST- 2016/02/26 06:00 [medline]
AID - S0168-8278(14)00546-7 [pii]
AID - 10.1016/j.jhep.2014.08.007 [doi]
PST - ppublish
SO  - J Hepatol. 2015 Jan;62(1):121-30. doi: 10.1016/j.jhep.2014.08.007. Epub 2014 Aug 
      15.