PMID- 31666108
OWN - NLM
STAT- MEDLINE
DCOM- 20200324
LR  - 20200324
IS  - 1756-9966 (Electronic)
IS  - 0392-9078 (Print)
IS  - 0392-9078 (Linking)
VI  - 38
IP  - 1
DP  - 2019 Oct 30
TI  - GSTZ1 deficiency promotes hepatocellular carcinoma proliferation via activation 
      of the KEAP1/NRF2 pathway.
PG  - 438
LID - 10.1186/s13046-019-1459-6 [doi]
LID - 438
AB  - BACKGROUND: Glutathione S-transferase zeta 1 (GSTZ1) is the penultimate enzyme in 
      phenylalanine/tyrosine catabolism. GSTZ1 is dysregulated in cancers; however, its 
      role in tumorigenesis and progression of hepatocellular carcinoma (HCC) is 
      largely unknown. We aimed to assess the role of GSTZ1 in HCC and to reveal the 
      underlying mechanisms, which may contribute to finding a potential therapeutic 
      strategy against HCC. METHODS: We first analyzed GSTZ1 expression levels in 
      paired human HCC and adjacent normal tissue specimens and the prognostic effect 
      of GSTZ1 on HCC patients. Thereafter, we evaluated the role of GSTZ1 in aerobic 
      glycolysis in HCC cells on the basis of the oxygen consumption rate (OCR) and 
      extracellular acidification rate (ECAR). Furthermore, we assessed the effect of 
      GSTZ1 on HCC proliferation, glutathione (GSH) concentration, levels of reactive 
      oxygen species (ROS), and nuclear factor erythroid 2-related factor 2 (NRF2) 
      signaling via gain- and loss- of GSTZ1 function in vitro. Moreover, we 
      investigated the effect of GSTZ1 on diethylnitrosamine (DEN) and carbon 
      tetrachloride (CCl(4)) induced hepatocarcinogenesis in a mouse model of HCC. 
      RESULTS: GSTZ1 was downregulated in HCC, thus indicating a poor prognosis. GSTZ1 
      deficiency significantly promoted hepatoma cell proliferation and aerobic 
      glycolysis in HCC cells. Moreover, loss of GSTZ1 function depleted GSH, increased 
      ROS levels, and enhanced lipid peroxidation, thus activating the NRF2-mediated 
      antioxidant pathway. Furthermore, Gstz1 knockout in mice promoted 
      DEN/CCl(4)-induced hepatocarcinogenesis via activation of the NRF2 signaling 
      pathway. Furthermore, the antioxidant agent N-acetylcysteine and NRF2 inhibitor 
      brusatol effectively suppressed the growth of Gstz1-knockout HepG2 cells and HCC 
      progression in Gstz1(-/-) mice. CONCLUSIONS: GSTZ1 serves as a tumor suppressor 
      in HCC. GSH depletion caused by GSTZ1 deficiency elevates oxidative stress, thus 
      constitutively activating the NRF2 antioxidant response pathway and accelerating 
      HCC progression. Targeting the NRF2 signaling pathway may be a promising 
      therapeutic approach for this subset of HCC.
FAU - Li, Jingjing
AU  - Li J
AD  - Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of 
      Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The 
      Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
AD  - Department of Blood Transfusion, The Second Affiliated Hospital, Chongqing 
      Medical University, Chongqing, China.
FAU - Wang, Qiujie
AU  - Wang Q
AD  - Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of 
      Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The 
      Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
FAU - Yang, Yi
AU  - Yang Y
AD  - Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of 
      Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The 
      Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
FAU - Lei, Chong
AU  - Lei C
AD  - Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of 
      Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The 
      Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
FAU - Yang, Fan
AU  - Yang F
AD  - Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of 
      Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The 
      Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
FAU - Liang, Li
AU  - Liang L
AD  - Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of 
      Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The 
      Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
FAU - Chen, Chang
AU  - Chen C
AD  - Institute of Life Sciences, Chongqing Medical University, Chongqing, China.
FAU - Xia, Jie
AU  - Xia J
AD  - Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of 
      Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The 
      Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
FAU - Wang, Kai
AU  - Wang K
AD  - Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of 
      Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The 
      Second Affiliated Hospital, Chongqing Medical University, Chongqing, China. 
      wangkai@cqmu.edu.cn.
FAU - Tang, Ni
AU  - Tang N
AD  - Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of 
      Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The 
      Second Affiliated Hospital, Chongqing Medical University, Chongqing, China. 
      nitang@cqmu.edu.cn.
LA  - eng
GR  - 81872270, 81572683/National Natural Science Foundation of China/
GR  - 81602417/National Natural Science Foundation of China/
GR  - 2017ZX10202203-004/National Science and Technology Infrastructure Program (CN)/
GR  - cstc2018jcyjAX0254/Natural Science Foundation Project of CQ CSTC/
GR  - CXTDX201601015/Program for Innovation Team of Higher Education in Chongqing/
GR  - CSTCCXLJRC201719/the Leading Talent Program of CQ CSTC/
GR  - cstc2019jcyj-msxmX0587/Natural Science Foundation Project of Chongqing/
GR  - CYS19192/the Scientific Research Innovation Project for Postgraduate in 
      Chongqing/
GR  - CYS18207/the Scientific Research Innovation Project for Postgraduate in 
      Chongqing/
PT  - Journal Article
DEP - 20191030
PL  - England
TA  - J Exp Clin Cancer Res
JT  - Journal of experimental & clinical cancer research : CR
JID - 8308647
RN  - 0 (KEAP1 protein, human)
RN  - 0 (Kelch-Like ECH-Associated Protein 1)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (NFE2L2 protein, human)
RN  - 3IQ78TTX1A (Diethylnitrosamine)
RN  - CL2T97X0V0 (Carbon Tetrachloride)
RN  - EC 2.5.1.- (GSTZ1 protein, human)
RN  - EC 2.5.1.18 (Glutathione Transferase)
SB  - IM
MH  - Animals
MH  - Carbon Tetrachloride/adverse effects
MH  - Carcinoma, Hepatocellular/chemically induced/genetics/metabolism/*pathology
MH  - Cell Line, Tumor
MH  - Cell Proliferation
MH  - Diethylnitrosamine/adverse effects
MH  - Down-Regulation
MH  - Gene Expression Regulation, Neoplastic
MH  - Glutathione Transferase/*genetics/*metabolism
MH  - Hep G2 Cells
MH  - Humans
MH  - Kelch-Like ECH-Associated Protein 1/metabolism
MH  - Lipid Peroxidation
MH  - Liver Neoplasms/chemically induced/genetics/metabolism/*pathology
MH  - Mice
MH  - NF-E2-Related Factor 2/metabolism
MH  - Neoplasm Transplantation
MH  - Oxidative Stress
MH  - Prognosis
MH  - *Signal Transduction
PMC - PMC6822483
OTO - NOTNLM
OT  - Glutathione
OT  - Glutathione S-transferase zeta 1
OT  - Hepatocellular carcinoma
OT  - KEAP1/NRF2 pathway
OT  - Oxidative stress
COIS- The authors declare that they have no competing interest.
EDAT- 2019/11/02 06:00
MHDA- 2020/03/25 06:00
PMCR- 2019/10/30
CRDT- 2019/11/01 06:00
PHST- 2019/07/14 00:00 [received]
PHST- 2019/10/17 00:00 [accepted]
PHST- 2019/11/01 06:00 [entrez]
PHST- 2019/11/02 06:00 [pubmed]
PHST- 2020/03/25 06:00 [medline]
PHST- 2019/10/30 00:00 [pmc-release]
AID - 10.1186/s13046-019-1459-6 [pii]
AID - 1459 [pii]
AID - 10.1186/s13046-019-1459-6 [doi]
PST - epublish
SO  - J Exp Clin Cancer Res. 2019 Oct 30;38(1):438. doi: 10.1186/s13046-019-1459-6.