Liver-specific glucocorticoid action in liver cancer.

项目摘要 长期目标是为肝癌开发新的药物疗法，肝癌是癌症死亡的第二大原因。 国际吧磷酸酶和张力蛋白同源物（PTEN）是一种重要的肿瘤抑制因子和代谢调节因子， 在人类肝癌中经常突变/沉默。Pten肝脏特异性敲除（LKO）小鼠 进行性脂肪性肝炎、肝硬化和肝癌。分子机制和组织学 Pten基因敲除小鼠的特征与非酒精性脂肪性肝炎（NASH）和肝硬化的发病机制非常相似。 人类的癌症糖皮质激素受体（GR）对肝脏病理生理起重要调节作用。文献显示 GR信号在人肝细胞癌（HCC）中严重受损，我们的初步数据显示， 结果显示，在Pten LKO中发展的肝肿瘤中，肝GR靶基因显著下调 小鼠然而，肝GR在PTEN缺陷诱导的肝细胞癌的发病机制和治疗中的作用尚不清楚。 NASH和肝癌仍然不清楚;这项研究将弥补这些知识差距。文献报告 我们的初步数据有力地表明，GR的激活不仅可以治疗肝癌， 对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， 这些影响否定了糖皮质激素（GC）治疗肝癌的益处。胆汁酸（BA）-药物偶联物 已成功开发用于通过肝脏特异性BA转运蛋白Na+- 牛磺胆酸盐共转运多肽（NTCP）。我们已经成功地合成了两个一流的胆酸 地塞米松的酸性（CA）缀合物（DEX-CA），并验证了它们的NTCP依赖性转运和细胞毒性。 活动本R 03提案的目的是开发DEX-CA作为肝脏的新前药候选物， 癌症，并揭示肝脏特异性GR缺乏和激活如何调节肝脏基因表达， 从NASH到肝癌的进展。核心假设是肝细胞中的GR对于 预防NASH和肝癌。通过减少肝外组织中GC的副作用， 在肝脏中发挥细胞保护、抗炎、抗纤维化和抗癌作用，NTCP介导的 肝特异性GR激活剂将是NASH诱导的肝癌的高度新颖的疗法。目标1将描述 小鼠中基因剂量依赖性肝脏特异性GR缺乏如何影响从脂肪变性到 Pten缺乏诱发肝癌。目的2将描述DEX-CA如何通过肝脏特异性激活GR 影响Pten LKO小鼠中的NASH和肝癌。R 03提案具有高度创新性，因为其 概念上的进步和最新的方法。本研究将开发新的DEX-CA结合物， 前药候选人和第一个药理学工具的肝脏特异性激活GR。 肝脏特异性基因剂量依赖性GR缺乏和GR激活在发病机制中的作用， 治疗PTEN缺陷诱导的NASH和肝癌。这将有助于开发创新的治疗方法， 通过NTCP介导的递送DEX-CA缀合物用于GR的肝脏特异性活化的NASH和肝癌

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.