【原】Hepatology：大麻素受体1通过多种机制促进肝细胞癌的发生和进展

肝细胞癌（HCC）死亡率高和治疗方法有限。内源性大麻素与肝大麻素1受体相互作用（CB1Rs）诱导参与有丝分裂的细胞周期蛋白，促进再生的肝细胞增殖，其中包括叉头框M1。

由于该蛋白在肝癌组织中高表达，有助于其发生、发展过程，我们分析了小鼠及人类肝癌中内源性大麻素系统/ CB1R。出生后二乙基亚硝胺诱导野生型小鼠8个月建立肝癌模型。观察连续磁共振成像，在CBIR（-/-）小鼠或外周CB1R拮抗剂jd5037处理的野生型小鼠体内发现较少和较小的肿瘤。全基因组转录组分析显示CB1R依赖，肿瘤诱导的肝表达调控区，其内源性配体大麻素，和一些肿瘤促进基因，包括Grb2的作用以及Forkhead box M1和其下游的目标，即色氨酸催化吲哚胺2,3-双加氧酶。吲哚胺2,3-双加氧酶活性的增加促进肿瘤组织中免疫抑制调节性T细胞诱导免疫耐受的产生。

内源性大麻素系统/ CB1R在化学诱导的肝癌上调，导致各种肿瘤促进基因的诱导，包括吲哚胺2,3-双加氧酶；通过阻断或基因剔除CB1R抑制肝癌，并为外周CB1R阻断治疗带来曙光。

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Cannabinoid receptor 1 promotes hepatocellular carcinoma initiation and progression through multiplemechanisms.

Abstract:

Hepatocellular carcinoma (HCC) has high mortality and no adequate treatment. Endocannabinoids interact with hepatic cannabinoid 1 receptors (CB1Rs) to promote hepatocyte proliferation in liver regeneration by inducing cell cycle proteins involved in mitotic progression, including Forkhead Box M1. Because this protein is highly expressed in HCC and contributes to its genesis and progression, we analyzed the involvement of the endocannabinoid/CB1R system in murine and human HCC. Postnatal diethylnitrosamine treatment induced HCC within 8 months in wild-type mice but fewer and smaller tumors in CB1R(-/-) mice or in wild-type mice treated with the peripheral CB1R antagonist JD5037, as monitored in vivo by serial magnetic resonance imaging. Genome-wide transcriptome analysis revealed CB1R-dependent, tumor-induced up-regulation of the hepatic expression of CB1R, its endogenous ligand anandamide, and a number of tumor-promoting genes, including the GRB2 interactome as well as Forkhead Box M1 and its downstream target, the tryptophan-catalyzing enzyme indoleamine 2,3-dioxygenase. Increased indoleamine 2,3-dioxygenase activity and consequent induction of immunosuppressive T-regulatory cells in tumor tissue promote immune tolerance.