The role of MDM2-MTBP axis in cancer metastasis

MDM2-MTBP轴在癌症转移中的作用

• 批准号: 8694358
• 负责人: Tomoo Iwakuma
• 金额: $ 31.33万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8694358
• 关键词: Actinin; Actins; Affect; Alleles; Binding; Binding Proteins; Biochemical; Biological; Biological Assay; Blood Vessels; Cancer Etiology; Cancer Patient; Carcinogens; Cells; Cessation of life; Data; Diagnosis; Diethylnitrosamine; Double Minutes; Embryo; Family; Fibroblasts; Filopodia; Goals; Head and Neck Squamous Cell Carcinoma; Hepatocyte; Human; Knowledge; Liver neoplasms; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Mediator of activation protein; Metastasis Suppression; Mitogen Activated Protein Kinase 1; Modeling; Molecular; Mus; Neoplasm Metastasis; Oncogene Proteins; Oncogenes; Pathway interactions; Patients; Phenotype; Play; Primary carcinoma of the liver cells; Protein p53; Proteins; Public Health; Quality of life; Role; Series; Survival Rate; Testing; Tissues; Transgenic Mice; United States; Wild Type Mouse; alpha Actinin; base; cancer type; cell motility; in vivo; insight; lymph nodes; migration; mortality; mouse model; novel; osteosarcoma; outcome forecast; overexpression; protein crosslink; public health relevance; sarcoma; transcription factor; tumor; tumor progression

DESCRIPTION (provided by applicant): The mouse double minute (MDM2) oncogene enhances cancer metastasis via pathways other than the tumor suppressor p53. However, the mechanisms underlying p53-independent MDM2-mediated cancer progression remain unclear. Through the efforts to understand the p53-independent function of MDM2, MDM2 Binding Protein (MTBP) was identified. We previously demonstrated that MTBP suppresses cancer migration and metastasis independently of p53 through the following findings: 1) MTBP haploinsufficiency in mice increases metastasis of hepatocellular carcinoma (HCC), sarcoma, and other types of cancer; 2) MTBP overexpression inhibits the migration and metastasis of osteosarcoma cells lacking wild-type p53 activity; 3) MTBP endogenously binds to a migration-inducing actin-crosslinking protein alpha-actinin-4 (ACTN4) and inhibits the migration and filopodia formation mediated by ACTN4. Clinically, reduced MTBP expression in head and neck squamous cell carcinoma tissues is shown to be associated with reduced survival of patients. The goal of this proposal is to determine the roles of MTBP and its functional association with MDM2, if any, in cancer metastasis. HCC is a rising cause of cancer-related death in the United States with 5-year survival rate below 12%. The leading cause of this poor prognosis is metastatic spread. For these reasons, we will use HCC as a model for examining the contributions of MDM2 and MTBP in cancer migration and metastasis. Our preliminary results demonstrated the following: 1) reduced MTBP expression in human HCC tissues was associated with the presence of vascular/capsular invasion and lymph node metastasis, 2) MTBP inhibited HCC cell migration, 3) MTBP inhibited the filopodia formation and migration mediated by ACTN4, and 4) MTBP inhibited the activity of Elk-1, an Ets oncogene family transcription factor and a target of Erk1/2 MAP kinase. Based on these observations, we hypothesize that MTBP inhibits HCC metastasis by suppressing ACTN4 and Elk-1 activities; whereas, MDM2 promotes cancer metastasis by its inhibitory binding to MTBP. We will test this hypothesis by achieving the following two Specific Aims: Aim 1 is to determine the inhibitory effects of MDM2 on the metastasis suppression by MTBP in HCC by exploring downstream mediators of MDM2-MTBP interactions that affect metastasis; Aim 2 is to determine the in vivo contributions of MDM2 and MTBP to HCC progression in mouse models by using our recently generated hypomorphic MTBPH mice that express MTBP at only 20% of wild-type levels. Completion of this project will fill the knowledge gaps pertaining to the mechanisms by which MTBP inhibits cancer metastasis and MDM2 promotes tumor progression in a p53- independent manner through inhibition of MTBP. Given that reduced MTBP expression is found in about 70% of HCC tissues, MDM2 overexpression is detected in 30% of HCC, and metastasis is the major cause of cancer mortality, our study has the potential to significantly impact the diagnosis, treatment, and prognosis for HCC and likely other types of cancer having altered expression of MDM2 and/or MTBP.

描述（由申请人提供）：小鼠双分钟（MDM2）癌基因通过肿瘤抑制p53以外的途径增强了癌症转移。然而，尚不清楚与p53介导的MDM2介导的癌症进展的基础机制尚不清楚。通过了解MDM2的p53独立函数的努力，确定了MDM2结合蛋白（MTBP）。我们先前证明，MTBP通过以下发现独立于p53抑制癌症的迁移和转移：1）小鼠的MTBP单倍体弥补会增加肝细胞癌（HCC），肉瘤），肉瘤和其他类型的癌症的转移； 2）MTBP过表达抑制缺乏野生型p53活性的骨肉瘤细胞的迁移和转移； 3）MTBP内源与诱导另一个诱导的肌动蛋白 - 链接蛋白α-肌动蛋白4（ACTN4）结合，并抑制由ACTN4介导的迁移和丝状形成。在临床上，头部和颈部鳞状细胞癌组织中的MTBP表达降低与患者存活率降低有关。该提案的目的是确定MTBP及其与MDM2（如果有的话）在癌症转移中的作用。 HCC是美国与癌症相关死亡的兴起，5年生存率低于12％。这种不良预后的主要原因是转移性传播。由于这些原因，我们将使用HCC作为检查MDM2和MTBP在癌症迁移和转移中的贡献的模型。 Our preliminary results demonstrated the following: 1) reduced MTBP expression in human HCC tissues was associated with the presence of vascular/capsular invasion and lymph node metastasis, 2) MTBP inhibited HCC cell migration, 3) MTBP inhibited the filopodia formation and migration mediated by ACTN4, and 4) MTBP inhibited the activity of Elk-1, an Ets oncogene family转录因子和ERK1/2 MAP激酶的靶标。基于这些观察结果，我们假设MTBP通过抑制ACTN4和ELK-1活性来抑制HCC转移。而MDM2通过与MTBP的抑制作用促进癌症转移。我们将通过实现以下两个具体目的来检验这一假设：目标1是确定MDM2对MTBP在HCC中抑制转移的抑制作用，通过探索影响转移的MDM2-MTBP相互作用的下游介体； AIM 2是通过使用我们最近生成的近形型MTBPH小鼠在小鼠模型中确定MDM2和MTBP对HCC进展的体内贡献，该型仅在野生型水平的20％时表达MTBP。该项目的完成将填补与MTBP抑制癌症转移和MDM2的机制有关的知识差距，从而通过抑制MTBP以p53-独立的方式促进肿瘤进展。鉴于在大约70％的HCC组织中发现了MTBP表达降低，因此在30％的HCC中检测到MDM2过表达，转移是癌症死亡率的主要原因，我们的研究有可能显着影响HCC的诊断，治疗和预后，并可能改变了MDM2和/或/或MTBP的癌症的其他类型。