MiRNAs in hepatocellular carcinoma development and treatment

肝细胞癌（HCC）是最常见的肝脏恶性肿瘤，也是第三大病因 死于癌症。然而，目前对HCC没有有效的治疗方法。因此，迫切需要 开发治疗HCC的新治疗方法。越来越多的证据表明， 调节特定的miRNAs可能会导致新的癌症疗法的发展。我们的研究（和其他） 表明微小RNA，miR-26 a，抑制促炎细胞因子，特别是白细胞介素6（IL-6）及其 下游介质，信号转导和转录激活因子3（STAT 3），表明肿瘤 miR-26 a对HCC发展抑制作用然而，miR-26 a在HCC发展中的作用在肝癌中的表达并不明显。 在适当的HCC小鼠模型中，由肝细胞和枯否细胞组成的设置尚未被 测定此外，调节肝细胞和/或枯否细胞中的miR-26 a是否是有效的治疗方法， 用于治疗HCC的治疗方法尚未测试。本提案的目的是调查 miR-26 a在肝细胞和枯否细胞中过表达抑制 HCC开发。此外，我们还鉴定了小分子，并开发了体内靶向siRNA/RNA。 该技术可以增加肝脏中miR-26 a的表达。在目标1中，我们将确定 miR-26 a在肝细胞和枯否细胞中的过表达对HCC发展的抑制。我们有 产生肝细胞特异性以及枯否细胞特异性miR-26 a过表达转基因小鼠。我们将 使用这些独特的转基因小鼠系来确定miR-26 a 对HCC有一定的作用。在目标2中，我们将确定小分子对miR-26 a诱导的作用， HCC抑制。我们还开发了一种创新的siRNA/RNA体内靶向递送技术-- CpG-siRNA/RNA-使RNA能够在体内递送到Toll样受体9阳性Kupffer细胞中， 炎症/恶性肝细胞。CpG-Stat 3 siRNA正走向神经胶质瘤的临床试验， 希望之城的淋巴瘤患者我们将评估CpG-miR-26 a和CpG-Stat 3 siRNA对人肝癌细胞系中的细胞凋亡的影响。 动物模型中肝细胞或/和枯否细胞中的HCC发展。这些研究不仅将 为HCC的潜在途径提供机制性见解，同时也有助于开发有效的治疗方法 HCC的战略。

Hepatocellular carcinoma (HCC) is the most common malignant tumor of the liver and the third leading cause of death from cancer. However, currently there is no effective treatment for HCC. It is therefore urgent to develop novel therapeutic approaches for the treatment of HCC. Increasing evidence suggests that being able to modulate specific miRNAs may lead to the development of novel cancer therapies. Our studies (and others) indicate that a microRNA, miR-26a, represses proinflammatory cytokines, especially interleukin 6 (IL-6) and its downstream mediator, signal transducer and activator of transcription 3 (STAT3), suggesting a tumor suppressive role of miR-26a on HCC development. However, the role of miR-26a in HCC development in the setting consisting of both hepatocytes and Kupffer cells in appropriate HCC mouse models has not been determined. Furthermore, whether modulating miR-26a in hepatocytes and/or Kupffer cells can be an effective therapeutic approach for treating HCC has not been tested. The objective of this proposal is to investigate the molecular and cellular mechanisms by which miR-26a overexpression in hepatocytes and Kupffer cells inhibits HCC development. In addition, we have identified small molecules and developed siRNA/RNA in vivo targeted delivery technology that can increase miR-26a expression in the liver. In Aim 1, we will determine the effect of overexpression of miR-26a in hepatocytes and in Kupffer cells on suppression of HCC development. We have generated hepatocyte-specific as well as Kupffer cell-specific miR-26a overexpression transgenic mice. We will use these unique transgenic mouse lines to define the cellular and molecular mechanisms by which miR-26a exerts its effect on HCC. In Aim 2, we will determine the effect of small molecules on miR-26a induction and HCC suppression. We have also developed an innovative siRNA/RNA in vivo targeted delivery technology-- CpG-siRNA/RNA—that enables RNA in vivo delivery into Toll-like Receptor 9-positive Kupffer cells and inflammatory/malignant hepatocytes. CpG-Stat3 siRNA is moving towards clinical trials for glioma and lymphoma patients at City of Hope. We will assess the effect of both CpG-miR-26a and CpG-Stat3 siRNA on HCC development in hepatocytes or/and Kupffer cells in animal models. The proposed studies will not only provide mechanistic insights into pathways underlying HCC but also help to develop effective treatment strategies for HCC.