Liver-specific glucocorticoid action in liver cancer.

项目摘要 长期目标是开发治疗肝癌的新药物疗法，肝癌是导致癌症死亡的第二大原因。 全世界。磷酸酶和张力蛋白同源物(PTEN)是一种关键的肿瘤抑制和代谢调节因子，是 在人类肝癌中经常发生突变/沉默。肝脏特异性Pten基因敲除(LKO)小鼠发生 进行性脂肪性肝炎、肝硬变和肝癌。分子机制与组织学 Pten基因缺失小鼠的特征与非酒精性脂肪性肝炎(NASH)和肝脏的发病机制非常相似 人类的癌症。糖皮质激素受体(GR)对肝脏的病理生理起着重要的调节作用。文艺节目 在人类肝细胞癌中，GR信号在很大程度上受损，我们的初步数据 显示肝脏GR靶基因在Pten LKO发生的肝肿瘤中显著下调 老鼠。然而，肝脏GR在PTEN缺乏症的发病机制和治疗中的作用 NASH和肝癌之间的关系尚不清楚；这项研究将弥合这些认识上的差距。文献报道 我们的初步数据有力地表明，激活GR不仅可以治疗肝癌，而且还可以保护 抗肝损伤和肝纤维化。然而，肝外组织中GR的激活可引起许多副作用 抵消了糖皮质激素(GC)治疗肝癌益处的效果。胆汁酸(BA)-药物结合物 已经成功地开发出通过肝脏特异性BA转运体Na+-来靶向肝脏药物 牛磺胆酸共转运多肽(NTCP)。我们成功地合成了两个一流的胆酸 地塞米松的酸(CA)结合物(DEX-CA)及其NTCP依赖的转运和细胞 活动。该R03提案的目的是开发DEX-CAS作为新的肝脏前药候选药物 并揭示肝脏特异性GR缺陷和激活如何调节肝脏基因表达和 从NASH到肝癌的进展。中心假说是肝细胞中的GR对 预防NASH和肝癌。通过减少肝外组织中GCs的不良反应和 NTCP介导的肝脏发挥细胞保护、抗炎、抗纤维化和抗癌作用 肝脏特异性GR激活剂将是治疗NASH诱导的肝癌的一种高度新颖的治疗方法。目标1将描述 小鼠肝脏糖皮质激素受体基因剂量依赖性缺陷对脂肪变性进展的影响 Pten缺乏症诱发肝癌。目标2将描述DEX-CAS如何在肝脏特异性激活GR 对Pten LKO小鼠NASH和肝癌的影响。此R03提案具有很高的创新性，因为它 概念上的进步和最新的方法。这项研究将开发新的DEX-CA偶联物作为新的 前药候选者和第一个肝脏特异性激活GR的药理学工具。它将揭开小说的面纱 肝脏特异性基因剂量依赖性GR缺陷和GR激活在肝纤维化发病机制中的作用 PTEN缺乏性NASH和肝癌的治疗。这将有助于开发创新的治疗方法 NASH和肝癌通过NTCP介导的DEX-CA偶联物的肝脏特异性激活GR。

Project Summary The long-term goal is to develop novel drug therapy for liver cancer, the 2rd leading cause of cancer death worldwide. Phosphatase and tensin homolog (PTEN), a key tumor suppressor and metabolic regulator, is frequently mutated/silenced in human liver cancers. Mice with liver-specific knockout (LKO) of Pten develop progressive steatohepatitis, cirrhosis, and liver carcinoma. The molecular mechanisms and histological feature in Pten-null mice closely resemble the pathogenesis of non-alcoholic steatohepatitis (NASH) and liver cancer in humans. Glucocorticoid receptor (GR) critically regulates liver pathophysiology. Literature shows that GR signaling is largely impaired in human hepatocellular carcinoma (HCC), and our preliminary data showed that hepatic GR-target genes were markedly down-regulated in liver tumors developed in Pten LKO mice. However, the roles of hepatic GR in the pathogenesis and treatment of PTEN-deficiency-induced NASH and liver cancer remain unclear; such knowledge gaps will be bridged by this study. Literature reports and our preliminary data strongly suggest that activation of GR can not only treat liver cancer, but also protect against liver injury and liver fibrosis. However, activation of GR in extrahepatic tissues can cause many side effects that negate the benefits of glucocorticoid (GC) therapy in liver cancer. Bile acid (BA)-drug conjugates have been successfully developed for liver-specific drug targeting via the liver-specific BA transporter Na+- taurocholate cotransporting polypeptide (NTCP). We have successfully synthesized two first-in-class cholic acid (CA) conjugates of dexamethasone (DEX-CA) and verified their NTCP-dependent transport and cellular activity. The objective of this R03 proposal is to develop DEX-CAs as new prodrug candidates for liver cancer, and uncover how liver-specific deficiency and activation of GR regulate hepatic gene expression and the progression from NASH to liver cancer. The central hypothesis is that GR in hepatocytes is essential to protect against NASH and liver cancer. By decreasing the adverse effects of GCs in extrahepatic tissues and exerting cytoprotection, anti-inflammation, anti-fibrotic, and anti-cancer effects in the liver, NTCP-mediated liver-specific GR activators will be a highly novel therapy for NASH-induced liver cancer. Aim 1 will delineate how gene-dosage-dependent liver-specific deficiency of GR in mice affects the progression from steatosis to liver cancer induced by Pten deficiency. Aim 2 will delineate how liver-specific activation of GR by DEX-CAs affects NASH and liver cancer in Pten LKO mice. This R03 proposal is highly innovative because of its conceptual advances and up-to-date approaches. This study will develop novel DEX-CA conjugates as new prodrug candidates and the first pharmacological tool for liver-specific activation of GR. It will uncover novel roles of liver-specific gene-dosage-dependent GR deficiency and activation of GR in the pathogenesis and treatment of PTEN-deficiency-induced NASH and liver cancer. This will help develop innovative therapy of NASH and liver cancer via NTCP-mediated delivery of DEX-CA conjugates for liver-specific activation of GR.