RT Journal Article
SR Electronic
T1 Opposite roles of cannabinoid receptors 1 and 2 in hepatocarcinogenesis
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP 1721
OP 1732
DO 10.1136/gutjnl-2015-310212
VO 65
IS 10
A1 Ki-Tae Suk
A1 Ingmar Mederacke
A1 Geum-Youn Gwak
A1 Sung Won Cho
A1 Adebowale Adeyemi
A1 Richard Friedman
A1 Robert F Schwabe
YR 2016
UL http://gut.bmj.com/content/65/10/1721.abstract
AB Objective The endocannabinoid system (ECS) exerts key roles in the development of liver fibrosis and fatty liver, two diseases that promote the development of hepatocellular carcinoma (HCC). Although cannabinoids exert potent antitumour effects in vitro, the contribution of the ECS to carcinogenesis in vivo remains elusive.Design Expression of key components of the ECS, including endocannanabinoids, endocannabinoid-degrading enzymes and endocannabinoid receptors, was determined in healthy liver and tumours. Diethylnitrosamine-induced hepatocarcinogenesis was determined in mice deficient in fatty acid amide hydrolase (FAAH), the main anandamide (AEA)-degrading enzyme, in cannabinoid receptor (CB)1, CB2, or transient receptor potential cation channel subfamily V member 1 (TRPV1)-deficient mice.Results Murine and human HCCs displayed activation of the ECS with strongly elevated expression of CB1 and CB2 but only moderately altered endocannabinoid levels. Contrary to the antitumour effects of cannabinoids in vitro, we observed increased hepatocarcinogenesis in FAAH-deficient mice, a mouse model with increased AEA levels. Accordingly, inactivation of CB1, the main receptor for AEA, in wild-type or FAAH-deficient mice suppressed hepatocarcinogenesis. In contrast, inactivation of CB2 increased hepatocarcinogenesis. CB1 was strongly expressed within HCC lesions and its inactivation suppressed proliferation and liver fibrosis. CB2 was predominantly expressed in macrophages. CB2 inactivation decreased the expression of T-cell-recruiting chemokines and inhibited hepatic T-cell recruitment including particular CD4+ T cells, a population with known antitumour effects in HCC. TRPV1 deletion did not alter HCC development.Conclusions Similar to their role in fibrogenesis, CB1 and CB2 exert opposite effects on hepatocarcinogenesis and may provide novel therapeutic targets.