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: 10310488
• 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 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10310488
• 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; Persons; 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.

总结 本研究的目的是阐明gp 78 E3泛素连接酶抑制人肝癌细胞凋亡的机制。 肝细胞癌（HCC）的进展。肝癌是最常见的癌症之一 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，并且非常难以治疗，因为大多数患者被诊断为 在晚期，很少有人能从手术（肝切除和肝移植）中受益。索拉非尼仍然是唯一 这种药物可用于HCC，并将生存时间仅延长3个月。因此，必须开发新的和 为肝癌的治疗和诊断提供了有效的方法。然而，这一任务受到了贫困的阻碍。 了解HCC进展背后的分子机制。我们最近的研究表明， gp 78 E3 Ub连接酶是HCC的抑癌基因。作为E3 Ub连接酶，gp 78的主要功能是靶向 蛋白质底物用于通过Ub-蛋白酶体系统降解。gp 78的缺失可能导致 底物蛋白，从而有助于HCC的发病机制。为了深入了解gp 78在 为了抑制HCC，我们已经开始了对肝蛋白的蛋白质组学分析， 依赖的方式。在这里，我们报告的鉴定MYBL 2作为一种新的gp 78底物。MYBL 2是一个 激活多个基因的转录因子，其蛋白质产物促进细胞周期进程和细胞 增殖在肝癌中观察到MYBL 2的过表达，并且与较差的存活率相关 HCC患者。因此，MYBL 2是一种潜在的肝癌蛋白。我们假设gp 78介导的 MYBL 2的降解可能在抑制HCC中起重要作用。为了验证这个假设，我们将 研究gp 78介导的MYBL 2（Aim 1）泛素化的机制，并证明 阻断MYBL 2降解对肝细胞肿瘤发生的影响（Aim 2）。拟议的研究将不会 仅阐明了gp 78在抑制HCC中的作用，但可能确定了治疗的靶点， 诊断出这种可怕的疾病。