The mechanism of gp78 ubiquitin ligase in suppressing hepatocellular carcinoma

gp78泛素连接酶抑制肝细胞癌的机制

• 批准号: 10112369
• 负责人: YOUMING XIE
• 金额: $ 7.7万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10112369
• 关键词: Affect; American Cancer Society; Apoptosis; BAY 54-9085; CRISPR/Cas technology; Cancer Etiology; Cell Cycle Progression; Cell Line; Cell Proliferation; Cessation of life; Development; Diagnosis; Disease; Excision; Gene Expression; Genes; Goals; Hepatocyte; Knock-in; Light; Liver; Lysine; MYBL2 gene; Malignant neoplasm of liver; Measures; Mediating; Molecular; Oncoproteins; Operative Surgical Procedures; Pathogenesis; Patients; Pharmaceutical Preparations; Play; Prevention approach; Primary Malignant Neoplasm of Liver; Primary carcinoma of the liver cells; Proteins; Proteome; Proteomics; Reporting; Research; Resistance; Role; Signal Pathway; Signal Transduction; Site; System; Techniques; Testing; Therapeutic; Time; Tumor Suppressor Proteins; Ubiquitin; United States; activating transcription factor; cell motility; cell transformation; experimental study; insight; liver transplantation; multicatalytic endopeptidase complex; mutant; novel; overexpression; statistics; tool; transcriptome sequencing; tumorigenesis; ubiquitin ligase; ubiquitin-protein ligase

SUMMARY The goal of this project is to elucidate the mechanism by which the gp78 E3 ubiquitin (Ub) ligase suppresses the progression of hepatocellular carcinoma (HCC). Liver cancer is among the most common causes of cancer death worldwide. According to the statistics from American Cancer Society, an estimated 42,810 new cases of liver cancer will be diagnosed, and 30,160 people will die of this disease in the United States in 2020. HCC is the predominant form of primary liver cancer and is extremely difficult to treat because most patients are diagnosed in a late stage and few can benefit from surgery (liver resection and liver transplantation). Sorafenib remains the only drug available for HCC and increases survival time by mere 3 months. Thus, it is imperative to develop new and efficient approaches for the treatment and diagnosis of HCC. However, this task has been hampered by poor understanding of the molecular mechanism behind the progression of HCC. Our recent study demonstrated that the gp78 E3 Ub ligase is a tumor suppressor of HCC. As an E3 Ub ligase, the main function of gp78 is to target protein substrates for degradation by the Ub-proteasome system. Loss of gp78 likely leads to accumulation of substrate proteins, thereby contributing to the pathogenesis of HCC. To gain insight into the role of gp78 in suppressing HCC, we have initiated a proteomic analysis for liver proteins that are degraded in a gp78- dependent manner. Here we report the identification of MYBL2 as a novel gp78 substrate. MYBL2 is a transcription factor that activates multiple genes whose protein products promote cell cycle progression and cell proliferation. Overexpression of MYBL2 has been observed in liver cancer and is associated with poor survival of HCC patients. Thus, MYBL2 is a potential liver oncoprotein. We hypothesize that gp78-mediated degradation of MYBL2 may play an important role in suppressing HCC. To test this hypothesis, we will investigate the mechanism underlying gp78-mediated ubiquitylation of MYBL2 (Aim 1) and demonstrate the effects of blocking MYBL2 degradation on liver cell tumorigenesis (Aim 2). The proposed research will not only shed light on the role of gp78 in suppressing HCC, but potentially identify a target for the treatment and diagnosis of this dreadful disease.

概括 该项目的目标是阐明 gp78 E3 泛素 (Ub) 连接酶抑制 肝细胞癌（HCC）的进展。肝癌是最常见的癌症原因之一 全世界的死亡。根据美国癌症协会的统计，估计有 42,810 例新发病例 肝癌将被诊断出来，2020 年美国将有 30,160 人死于这种疾病。HCC 是 原发性肝癌的主要形式，并且极难治疗，因为大多数患者都是被诊断出来的 在晚期，很少有人可以从手术（肝切除和肝移植）中受益。索拉非尼仍然是唯一 该药物可用于治疗 HCC，仅将生存时间延长 3 个月。因此，开发新的和 治疗和诊断 HCC 的有效方法。然而，这项任务却因贫困而受到阻碍 了解 HCC 进展背后的分子机制。我们最近的研究表明 gp78 E3 Ub 连接酶是 HCC 的肿瘤抑制因子。作为 E3 Ub 连接酶，gp78 的主要功能是靶向 Ub-蛋白酶体系统降解的蛋白质底物。 gp78 的丢失可能会导致 底物蛋白，从而促进 HCC 的发病机制。深入了解 gp78 在 为了抑制 HCC，我们已经开始对 gp78- 中降解的肝脏蛋白进行蛋白质组学分析。 依赖方式。在这里，我们报告了 MYBL2 作为新型 gp78 底物的鉴定。 MYBL2 是 激活多个基因的转录因子，其蛋白质产物促进细胞周期进展和细胞 增殖。在肝癌中观察到 MYBL2 过度表达，并且与较差的生存率相关 的 HCC 患者。因此，MYBL2是一种潜在的肝脏癌蛋白。我们假设 gp78 介导 MYBL2 的降解可能在抑制 HCC 中发挥重要作用。为了检验这个假设，我们将 研究 gp78 介导的 MYBL2 泛素化的机制（目标 1）并证明 阻断 MYBL2 降解对肝细胞肿瘤发生的影响（目标 2）。拟议的研究不会 仅揭示了 gp78 在抑制 HCC 中的作用，但有可能确定治疗靶点 诊断这种可怕的疾病。