Targeting oncogenes for hepatocellular carcinoma

靶向肝细胞癌的癌基因

• 批准号: 10361475
• 负责人: DEVANAND SARKAR
• 金额: $ 38.77万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10361475
• 关键词: Astrocytes; Automobile Driving; Binding; Biological Assay; Cancer Etiology; Cell Nucleus; Cessation of life; Clinical Trials; Dendrimers; Development; Endoplasmic Reticulum; FDA approved; Genes; Hepatocyte; Human; Human Cell Line; Knock-out; Knowledge; Malignant Epithelial Cell; Malignant Neoplasms; Membrane; Membrane Proteins; Messenger RNA; Micrococcal Nuclease; Molecular; Molecular Analysis; Monitor; Mus; N-terminal; Oncogenes; Oncogenic; Pathogenesis; Pathway interactions; Patients; Play; Post-Transcriptional Regulation; Pre-Clinical Model; Preventive; Primary carcinoma of the liver cells; Proteins; Protocols documentation; RIPK1 gene; RNA; RNA Interference Therapy; RNA-Induced Silencing Complex; Role; Scaffolding Protein; Signaling Molecule; Site; Small Interfering RNA; System; TRAF2 gene; Therapeutic; Transgenic Organisms; Translating; Translational Regulation; Translations; Transmembrane Domain; Treatment Efficacy; Xenograft procedure; advanced disease; base; combinatorial; design; effective therapy; expectation; experimental study; in vivo; innovation; knock-down; liver cancer model; mRNA Stability; mouse model; mutant; nanocomplexes; nanoparticle delivery; novel; nuclease; overexpression; patient derived xenograft model; pre-clinical; protein activation; recruit; secretory protein; targeted treatment; therapeutically effective; ubiquitin ligase

Summary Hepatocellular carcinoma (HCC), the fifth most common cancer and the second most common cause of cancer-related deaths worldwide, has no effective treatment for advanced disease. The present proposal focuses on two interacting proteins, AEG-1 and SND1, which function as bona fide oncogenes for HCC. AEG-1 and SND1 cooperate to increase RNA-induced silencing complex (RISC) activity where AEG-1 functions as a scaffold protein and SND1 functions as a nuclease. However, there is a gap of knowledge in our understanding of the mechanism(s) driving AEG-1 and SND1 cooperative oncogenic functions. In primary hepatocytes, AEG- 1 is predominantly localized in the nucleus, while in HCC cells AEG-1 is primarily localized in the endoplasmic reticulum (ER) membrane. Preliminary results indicate ER-anchoring is required for AEG-1 oncogenic function. ER-anchored AEG-1 binds specifically to secretory and membrane protein-encoding mRNAs to facilitate their translation. Analysis of SND1 RNA-interactome also identifies membrane protein-encoding mRNAs. Co- localization studies show that both AEG-1 and SND1 are located on ER membrane in HCC cells. Both AEG-1 and SND1 activate NF-κB. ER-anchored AEG-1 functions as a platform for upstream signaling molecules of NF-κB pathway and thus plays an essential role in NF-κB activation. The mechanism by which SND1 activates NF-κB is not known. We hypothesize that in transformed hepatocytes, AEG-1 translocates from the nucleus and anchors into the ER membrane where it recruits SND1 and both cooperate to promote HCC by modulating post-transcriptional regulation of mRNAs in RISC, translational regulation of membrane proteins and activation of NF-κB, AEG-1 and SND1 require each other for optimum functioning and might not exert oncogenic activity alone, and combinatorial inhibition of AEG-1 and SND1 might be an effective therapeutic strategy for HCC. Experiments are designed to interrogate these hypotheses using novel mouse models and targeted nanoplexes delivering siRNA for AEG-1 and SND1. This proposal will contribute to our long-term objectives of identifying key players regulating HCC pathogenesis and translating this knowledge into development of novel and effective targeted therapies. The immediate objective of the proposal is in-depth understanding of the molecular mechanisms by which AEG-1 and SND1 promote HCC and evaluate a combinatorial strategy of inhibiting AEG-1 and SND1 in a mouse model as a potential therapeutic. Thus the proposal has both mechanistic and therapeutic significance and innovation. Successful completion of the proposed studies will establish new targets for developing therapeutics and provide pre-clinical evidence for a targeted protocol.

概括 肝细胞癌（HCC），第五大常见的癌症，第二大常见的原因 全球与癌症相关的死亡没有有效治疗晚期疾病。目前的提议 专注于两个相互作用的蛋白AEG-1和SND1，它们充当HCC的真正癌基因。 AEG-1 SND1合作以增加RNA诱导的沉默复合物（RISC）活性，其中AEG-1充当 支架蛋白和SND1充当核酸酶。但是，我们的理解有一定差距 驱动AEG-1和SND1合作致癌功能的机制。在原发性肝细胞中，AEG- 1主要位于核中，而在HCC细胞中，AEG-1主要定位于内质中 网状（ER）膜。初步结果表明，AEG-1致癌功能需要ER锚定。 ER锚定的AEG-1专门与分泌和膜蛋白编码的mRNA结合，以促进其 翻译。 SND1 RNA相互抗乳组的分析还鉴定了膜蛋白编码的mRNA。共同 定位研究表明，AEG-1和SND1都位于HCC细胞中的ER膜上。两个AEG-1 SND1激活NF-κB。 ER锚定的AEG-1充当上游信号分子的平台 NF-κB途径在NF-κB激活中起着至关重要的作用。 SND1激活的机制 NF-κB尚不清楚。我们假设在转化的肝细胞中，AEG-1从核中转移 并锚定进入急诊膜，在那里招募SND1，并通过调节来促进HCC RISC中mRNA的转录后调节，膜蛋白的翻译调节和激活 NF-κB，AEG-1和SND1需要彼此才能达到最佳功能，并且可能不会发挥致命活性 单独使用AEG-1和SND1的组合抑制可能是HCC的有效治疗策略。 实验旨在使用新型鼠标模型审问这些假设并针对性 为AEG-1和SND1提供siRNA的纳米旋转。该提议将有助于我们的长期目标 确定调节HCC发病机理的关键参与者，并将这种知识转化为新颖的发展 和有效的靶向疗法。该提案的直接目的是对 AEG-1和SND1促进HCC并评估组合策略的分子机制 在小鼠模型中抑制AEG-1和SND1作为潜在疗法。该提议都有 机械和热意义和创新。成功完成拟议的研究将 建立开发治疗的新目标，并为有针对性方案提供临床前证据。