PMID- 22859060
OWN - NLM
STAT- MEDLINE
DCOM- 20130304
LR  - 20211203
IS  - 1527-3350 (Electronic)
IS  - 0270-9139 (Print)
IS  - 0270-9139 (Linking)
VI  - 57
IP  - 1
DP  - 2013 Jan
TI  - Disordered purinergic signaling and abnormal cellular metabolism are associated 
      with development of liver cancer in Cd39/ENTPD1 null mice.
PG  - 205-16
LID - 10.1002/hep.25989 [doi]
AB  - Liver cancer is associated with chronic inflammation, which is linked to immune 
      dysregulation, disordered metabolism, and aberrant cell proliferation. Nucleoside 
      triphosphate diphosphohydrolase-1; (CD39/ENTPD1) is an ectonucleotidase that 
      regulates extracellular nucleotide/nucleoside concentrations by scavenging 
      nucleotides to ultimately generate adenosine. These properties inhibit antitumor 
      immune responses and promote angiogenesis, being permissive for the growth of 
      transplanted tumors. Here we show that Cd39 deletion promotes development of both 
      induced and spontaneous autochthonous liver cancer in mice. Loss of Cd39 results 
      in higher concentrations of extracellular nucleotides, which stimulate 
      proliferation of hepatocytes, abrogate autophagy, and disrupt glycolytic 
      metabolism. Constitutive activation of Ras-mitogen-activated protein kinase 
      (MAPK) and mammalian target of rapamycin (mTOR)-S6K1 pathways occurs in both 
      quiescent Cd39 null hepatocytes in vitro and liver tissues in vivo. Exogenous 
      adenosine 5'-triphosphate (ATP) boosts these signaling pathways, whereas 
      rapamycin inhibits such aberrant responses in hepatocytes. CONCLUSION: Deletion 
      of Cd39 and resulting changes in disordered purinergic signaling perturb 
      hepatocellular metabolic/proliferative responses, paradoxically resulting in 
      malignant transformation. These findings might impact adjunctive therapies for 
      cancer. Our studies indicate that the biology of autochthonous and transplanted 
      tumors is quite distinct.
CI  - Copyright (c) 2012 American Association for the Study of Liver Diseases.
FAU - Sun, Xiaofeng
AU  - Sun X
AD  - Department of Medicine, Gastroenterology/Hepatology, Beth Israel Deaconess 
      Medical Center, Harvard Medical School, Boston, MA 02215, USA.
FAU - Han, Lihui
AU  - Han L
FAU - Seth, Pankaj
AU  - Seth P
FAU - Bian, Shu
AU  - Bian S
FAU - Li, Linglin
AU  - Li L
FAU - Csizmadia, Eva
AU  - Csizmadia E
FAU - Junger, Wolfgang G
AU  - Junger WG
FAU - Schmelzle, Moritz
AU  - Schmelzle M
FAU - Usheva, Anny
AU  - Usheva A
FAU - Tapper, Elliot B
AU  - Tapper EB
FAU - Baffy, Gyorgy
AU  - Baffy G
FAU - Sukhatme, Vikas P
AU  - Sukhatme VP
FAU - Wu, Yan
AU  - Wu Y
FAU - Robson, Simon C
AU  - Robson SC
LA  - eng
GR  - R01 HL062458/HL/NHLBI NIH HHS/United States
GR  - R21 CA164970/CA/NCI NIH HHS/United States
GR  - R01 HL094400/HL/NHLBI NIH HHS/United States
GR  - R01 GM051477/GM/NIGMS NIH HHS/United States
GR  - R01-HL094400/HL/NHLBI NIH HHS/United States
GR  - P01-HL076540/HL/NHLBI NIH HHS/United States
GR  - P01 HL076540/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - United States
TA  - Hepatology
JT  - Hepatology (Baltimore, Md.)
JID - 8302946
RN  - 0 (Antigens, CD)
RN  - 0 (Receptors, Purinergic)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 90-kDa)
RN  - EC 2.7.11.1 (Rps6ka1 protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.6.1.5 (Apyrase)
RN  - EC 3.6.1.5 (CD39 antigen)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Antigens, CD/genetics/*metabolism
MH  - Apyrase/genetics/*metabolism
MH  - Autophagy
MH  - Carcinoma, Hepatocellular/*etiology/metabolism
MH  - Cell Proliferation
MH  - Gene Deletion
MH  - Gene Expression Regulation, Neoplastic
MH  - Glycolysis
MH  - Hepatocytes/physiology
MH  - Liver/enzymology
MH  - Liver Neoplasms, Experimental/*etiology/metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Receptors, Purinergic/*metabolism
MH  - Ribosomal Protein S6 Kinases, 90-kDa/metabolism
MH  - Signal Transduction
MH  - Sirolimus
MH  - TOR Serine-Threonine Kinases/metabolism
PMC - PMC3505255
MID - NIHMS397289
EDAT- 2012/08/04 06:00
MHDA- 2013/03/05 06:00
PMCR- 2014/01/01
CRDT- 2012/08/04 06:00
PHST- 2012/03/06 00:00 [received]
PHST- 2012/07/20 00:00 [accepted]
PHST- 2012/08/04 06:00 [entrez]
PHST- 2012/08/04 06:00 [pubmed]
PHST- 2013/03/05 06:00 [medline]
PHST- 2014/01/01 00:00 [pmc-release]
AID - 10.1002/hep.25989 [doi]
PST - ppublish
SO  - Hepatology. 2013 Jan;57(1):205-16. doi: 10.1002/hep.25989.