PMID- 28030819
OWN - NLM
STAT- MEDLINE
DCOM- 20170828
LR  - 20211204
IS  - 1949-2553 (Electronic)
IS  - 1949-2553 (Linking)
VI  - 8
IP  - 9
DP  - 2017 Feb 28
TI  - Hyperhomocysteinemia results from and promotes hepatocellular carcinoma via 
      CYP450 metabolism by CYP2J2 DNA methylation.
PG  - 15377-15392
LID - 10.18632/oncotarget.14165 [doi]
AB  - Hyperhomocysteinemia (HHcy) can result from liver disease or dysfunction and 
      further alters intracellular lipid metabolism. Cytochrome P450 (CYP) arachidonic 
      acid epoxygenases are expressed in human cancers and promote cancer metastasis. 
      This study explored the interaction of Hcy and CYP450 metabolism in 
      hepatocellular carcinoma (HCC). The levels of 4-epoxyeicosatrienoic acid (EET) 
      isomers and their generative enzyme CYP2J2 level as well as intracellular Hcy 
      level were higher in 42 cases of HCC than in paired non-tumor tissue. Elevated 
      Hcy-decreased DNA methylation on SP1/AP1 binding motifs and enhancement on the 
      CYP2J2 promoter via ERK1/2 signaling was essential for CYP2J2 upregulation and 
      EET metabolism. Increased Hcy level enhanced the neoplastic cellular phenotype, 
      which was reversed by CYP2J2 knockdown in vitro. Furthermore, tumor growth and 
      size as well as patterns of CYP2J2 expression and DNA demethylation were 
      increased with HHcy in mice induced orthotopically by 2% (wt/wt) L-methionine 
      with or without folate deficiency. Moreover, the effect was attenuated by shRNA 
      knockdown of CYP2J2. Thus, HHcy results from but can also promote 
      hepatocarcingenesis via CYP450-EET metabolism by crosstalk of DNA demethylation 
      of CYP2J2 and ERK1/2 signaling.
FAU - Zhang, Donghong
AU  - Zhang D
AD  - Department of Clinical Laboratory, Cancer Hospital, Chinese Academy of Medical 
      Sciences, Beijing, 100021, China.
AD  - Department of Clinical Laboratory, Peking Union Medical College Hospital and 
      Peking Union Medical College, Beijing, 100730, China.
AD  - Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, 
      USA.
FAU - Lou, Jinli
AU  - Lou J
AD  - Department of Clinical Laboratory, Beijing You An Hospital, Capital Medical 
      University, Beijing, 100069, China.
FAU - Zhang, Xu
AU  - Zhang X
AD  - Department of Physiology and Pathophysiology, Tianjin Medical University, 
      Tianjin, 300070, China.
FAU - Zhang, Lin
AU  - Zhang L
AD  - Department of Clinical Laboratory, Peking Union Medical College Hospital and 
      Peking Union Medical College, Beijing, 100730, China.
FAU - Wang, Fei
AU  - Wang F
AD  - Department of Clinical Laboratory, Peking Union Medical College Hospital and 
      Peking Union Medical College, Beijing, 100730, China.
FAU - Xu, Danfei
AU  - Xu D
AD  - Department of Clinical Laboratory, Cancer Hospital, Chinese Academy of Medical 
      Sciences, Beijing, 100021, China.
AD  - Department of Clinical Laboratory, Peking Union Medical College Hospital and 
      Peking Union Medical College, Beijing, 100730, China.
FAU - Niu, Na
AU  - Niu N
AD  - Department of Pathology, The University of Texas MD Anderson Cancer Center, 
      Houston, TX, 77030, USA.
FAU - Wang, Yidong
AU  - Wang Y
AD  - Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, 
      USA.
FAU - Wu, Yue
AU  - Wu Y
AD  - Department of Clinical Laboratory, Cancer Hospital, Chinese Academy of Medical 
      Sciences, Beijing, 100021, China.
AD  - Department of Clinical Laboratory, Peking Union Medical College Hospital and 
      Peking Union Medical College, Beijing, 100730, China.
FAU - Cui, Wei
AU  - Cui W
AD  - Department of Clinical Laboratory, Cancer Hospital, Chinese Academy of Medical 
      Sciences, Beijing, 100021, China.
AD  - Department of Clinical Laboratory, Peking Union Medical College Hospital and 
      Peking Union Medical College, Beijing, 100730, China.
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Oncotarget
JT  - Oncotarget
JID - 101532965
RN  - 0 (CYP2J2 protein, human)
RN  - 0 (Eicosanoids)
RN  - 0LVT1QZ0BA (Homocysteine)
RN  - 9035-51-2 (Cytochrome P-450 Enzyme System)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP2J2)
SB  - IM
MH  - Adult
MH  - Animals
MH  - Blotting, Western
MH  - Carcinoma, Hepatocellular/*genetics/metabolism/pathology
MH  - Cell Line
MH  - Cell Line, Tumor
MH  - Cytochrome P-450 CYP2J2
MH  - Cytochrome P-450 Enzyme System/*genetics/metabolism
MH  - *DNA Methylation
MH  - Eicosanoids/metabolism
MH  - Female
MH  - Hep G2 Cells
MH  - Homocysteine/blood/metabolism
MH  - Humans
MH  - Hyperhomocysteinemia/*genetics/metabolism
MH  - Immunohistochemistry
MH  - Liver Neoplasms/*genetics/metabolism/pathology
MH  - Male
MH  - Mice, Inbred BALB C
MH  - Mice, Nude
MH  - Middle Aged
MH  - RNA Interference
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Transplantation, Heterologous
PMC - PMC5362492
OTO - NOTNLM
OT  - CYP2J2
OT  - CYP450
OT  - DNA methylation
OT  - hepatocellular carcinoma
OT  - homocysteine
COIS- CONFLICTS OF INTEREST The authors declare no conflicts of interest.
EDAT- 2016/12/29 06:00
MHDA- 2017/08/29 06:00
PMCR- 2017/02/28
CRDT- 2016/12/29 06:00
PHST- 2016/09/20 00:00 [received]
PHST- 2016/11/24 00:00 [accepted]
PHST- 2016/12/29 06:00 [pubmed]
PHST- 2017/08/29 06:00 [medline]
PHST- 2016/12/29 06:00 [entrez]
PHST- 2017/02/28 00:00 [pmc-release]
AID - 14165 [pii]
AID - 10.18632/oncotarget.14165 [doi]
PST - ppublish
SO  - Oncotarget. 2017 Feb 28;8(9):15377-15392. doi: 10.18632/oncotarget.14165.