Opposite roles of cannabinoid receptors 1 and 2 in hepatocarcinogenesis.
Opposite roles of cannabinoid receptors 1 and 2 in hepatocarcinogenesis.
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DOI：
10.1136/gutjnl-2015-310212
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发表时间：
2016-10
期刊：
影响因子：
24.5
通讯作者：
Schwabe RF
中科院分区：
文献类型：
--
作者：
Suk KT;Mederacke I;Gwak GY;Cho SW;Adeyemi A;Friedman R;Schwabe RF
内源性大麻素系统（ECS）在肝纤维化和脂肪肝这两种促进肝细胞癌（HCC）发展的疾病的发展中发挥着关键作用。尽管大麻素在体外发挥有效的抗肿瘤作用，但 ECS 对体内致癌作用的贡献仍然难以捉摸。在健康肝脏和肿瘤中测定了 ECS 关键成分的表达，包括内源性大麻素、内源性大麻素降解酶和内源性大麻素受体。在脂肪酸酰胺水解酶（FAAH）（主要的大麻素（AEA）降解酶）缺陷的小鼠中，在大麻素受体（CB）1-、CB2-或瞬时受体电位阳离子通道亚家族V成员1（Trpv1）缺陷的小鼠中，确定了二乙基亚硝胺诱导的肝癌发生。小鼠和人类 HCC 显示 ECS 激活，CB1 和 CB2 表达强烈升高，但内源性大麻素水平仅适度改变。与体外大麻素的抗肿瘤作用相反，我们观察到 FAAH 缺陷小鼠（AEA 水平升高的小鼠模型）的肝癌发生增加。因此，在野生型或FAAH缺陷小鼠中，AEA的主要受体CB1失活可抑制肝癌的发生。相反，CB2 失活会增加肝癌的发生。 CB1 在 HCC 病变内强烈表达，其失活抑制增殖和肝纤维化。 CB2主要在巨噬细胞中表达。 CB2 失活降低了 T 细胞募集趋化因子的表达，并抑制肝 T 细胞募集，包括特定的 CD4+ T 细胞，这是已知在 HCC 中具有抗肿瘤作用的群体。 TRPV1 缺失不会改变 HCC 的发展。与它们在纤维形成中的作用类似，CB1和CB2对肝癌发生发挥相反的作用，并可能提供新的治疗靶点。
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 anti-tumor effects in vitro, the contribution of the ECS to carcinogenesis in vivo remains elusive. Expression of key components of the ECS, including endocannanabinoids, endocannabinoid-degrading enzymes and endocannabinoid receptors, was determined in healthy liver and tumors. 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. 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 anti-tumor 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 anti-tumor effects in HCC. TRPV1 deletion did not alter HCC development. Similar to their role in fibrogenesis, CB1 and CB2 exert opposite effects on hepatocarcinogenesis, and may provide novel therapeutic targets.
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影响因子：
82.9
作者：
Galve-Roperh, I;Sánchez, C;Guzmán, M
通讯作者：
Guzmán, M
影响因子：
29.4
作者：
Ligresti, A;Bisogno, T;Di Marzo, V
通讯作者：
Di Marzo, V
影响因子：
4.8
作者：
Bifulco, M;Laezza, C;Di Marzo, V
通讯作者：
Di Marzo, V
影响因子：
64.8
作者：
Kang, Tae-Won;Yevsa, Tetyana;Zender, Lars
通讯作者：
Zender, Lars
影响因子：
64.8
作者：
MUNRO, S;THOMAS, KL;ABUSHAAR, M
通讯作者：
ABUSHAAR, M