Abstract：
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Pregnane X receptor (PXR), a xenobiotic-sensing nuclear receptor, plays a critical role in the metabolism of endogenous and exogenous substances in the liver. Here, we investigate whether PXR plays a role in pathogenesis of HCC. We show that liver tumors were developed in diethylnitrosamine (DEN)-treated in PXR knockout (KO) mice. Hepatic levels of prostaglandin F2α (PGF2α) and aldo-keto reductase family 1 member C18 (Akr1c18), a prostaglandin synthase of catalyzing reduction of PGH2 to PGF2α, were significantly elevated in DEN-treated PXR KO mice. Hepatic mRNA levels of alpha fetoprotein (AFP), cyclin D1 (Ccnd1), fibroblast growth factor 21 (FGF21), and inflammatory cytokine interleukin 6 (IL-6) were significantly increased in DEN-treated PXR KO mice. Other members of Akr1c family, liver metabolizing enzymes including Cyp1a2, Cyp2b10 and Cyp3a11, and bile acid synthesis enzyme Cyp7a1 mRNA levels were significantly decreased in DEN-treated PXR KO mice. Our findings revealed that PXR deficiency promoted DEN-induced HCC in mice via induction of Akr1c18 expression and PGF2α levels and the increased PGF2α levels synthetized by Akr1c18 enhanced hepatocytes proliferation and induced inflammatory cytokine production, which accelerated liver tumor development after DEN treatment, suggesting that PXR deficiency may create a microenvironment that is more prone to DEN-induced liver tumors and targeting PXR and Akr1c18 to reduce PGF2α biosynthesis may be a potential and novel therapeutic strategy for HCC.
摘要：
肝细胞癌（HCC）是全球最常见的癌症之一。孕烷X受体(PXR),一种异源生物感知核受体，在肝脏内源性和外源性物质的代谢中起着至关重要的作用。这里,我们研究PXR是否在HCC的发病机制中起作用。我们表明，在PXR敲除（KO）小鼠中，二乙基亚硝胺（DEN）治疗的肝脏肿瘤发展。前列腺素F2α（PGF2α）和aldo-keto还原酶家族1成员C18（Akr1c18）的肝脏水平，一种催化PGH2还原为PGF2α的前列腺素合酶，在DEN处理的PXRKO小鼠中显著升高。甲胎蛋白（AFP）的肝脏mRNA水平，细胞周期蛋白D1(Ccnd1)，成纤维细胞生长因子21（FGF21），在DEN处理的PXRKO小鼠中，炎性细胞因子白介素6（IL-6）显着增加。Akr1c家族的其他成员,在DEN处理的PXRKO小鼠中，肝脏代谢酶包括Cyp1a2，Cyp2b10和Cyp3a11以及胆汁酸合成酶Cyp7a1mRNA水平显着降低。我们的发现表明，PXR缺乏通过诱导Akr1c18表达和PGF2α水平以及Akr1c18合成的PGF2α水平增加促进小鼠DEN诱导的HCC，增强肝细胞增殖并诱导炎性细胞因子的产生，这加速了DEN治疗后肝脏肿瘤的发展，提示PXR缺乏可能产生更容易发生DEN诱导的肝肿瘤的微环境,靶向PXR和Akr1c18以减少PGF2α的生物合成可能是HCC的一种潜在和新颖的治疗策略.
