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因子P53以外的途径促进癌症转移。然而，p53非依赖性MDM2介导的癌症进展的机制仍不清楚。通过对MDM2非p53功能的研究，发现了MDM2结合蛋白(MTBP)。我们先前通过以下发现证明了MTBP独立于p53抑制肿瘤的迁移和转移：1)MTBP在小鼠中的单倍性不足增加了肝细胞癌、肉瘤和其他类型癌症的转移；2)MTBP过表达抑制了缺乏野生型p53活性的骨肉瘤细胞的迁移和转移；3)MTBP内源性地与迁移诱导的肌动蛋白交联蛋白α-肌动蛋白4(ACTN4)结合，并抑制了ACTN4介导的迁移和丝状足的形成。临床上，头颈部鳞状细胞癌组织中MTBP表达减少与患者存活率降低有关。这项建议的目的是确定MTBP的作用及其与MDM2的功能关联，如果有的话，在癌症转移中。在美国，肝细胞癌是癌症相关死亡的一个上升原因，5年存活率低于12%。这种预后不良的主要原因是转移性扩散。出于这些原因，我们将使用肝细胞癌作为一个模型来研究MDM2和MTBP在癌症转移和转移中的作用。我们的初步结果表明：1)MTBP在人肝癌组织中的表达减少与血管/包膜侵袭和淋巴结转移有关；2)MTBP抑制肝癌细胞的迁移；3)MTBP抑制ACTN4介导的丝状足突的形成和迁移；4)MTBP抑制ETS癌基因家族转录因子和ERK1/2 MAP激酶靶标Elk-1的活性。基于这些观察，我们假设MTBP通过抑制ACTN4和ELK-1的活性来抑制肝癌的转移；而MDM2通过与MTBP的抑制结合来促进肿瘤的转移。我们将通过实现以下两个特定目标来验证这一假说：目的1是通过探索影响转移的MDM2-MTBP相互作用的下游介质来确定MDM2对MTBP抑制肝癌转移的抑制作用；目标2是通过使用我们最近建立的MTBPH亚型小鼠(其MTBP表达水平仅为野生型的20%)来确定MDM2和MTBP在小鼠模型中对肝癌进展的贡献。该项目的完成将填补有关MTBP抑制癌症转移的机制的知识空白，而MDM2通过抑制MTBP以不依赖于p53的方式促进肿瘤进展。鉴于MTBP在约70%的肝细胞癌组织中表达降低，在30%的肝细胞癌中检测到MDM2的过度表达，转移是癌症死亡的主要原因，我们的研究有可能显著影响肝细胞癌和其他可能改变MDM2和/或MTBP表达的癌症的诊断、治疗和预后。