The role of MDM2-MTBP axis in cancer metastasis

MDM2-MTBP轴在癌症转移中的作用

基本信息

批准号：
8842602
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
项目类别：
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/8842602
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

项目摘要

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）：小鼠双微体（MDM2）癌基因通过肿瘤抑制因子p53以外的途径增强癌症转移。然而，不依赖 p53 的 MDM2 介导的癌症进展的机制仍不清楚。通过努力了解 MDM2 的 p53 独立功能，鉴定出 MDM2 结合蛋白 (MTBP)。我们之前通过以下发现证明MTBP独立于p53抑制癌症迁移和转移：1）小鼠中MTBP单倍体不足会增加肝细胞癌（HCC）、肉瘤和其他类型癌症的转移； 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 内源性结合迁移诱导肌动蛋白交联蛋白 α-actinin-4 (ACTN4)，并抑制 ACTN4 介导的迁移和丝状伪足形成。临床上，头颈鳞状细胞癌组织中MTBP表达降低与患者生存率降低相关。该提案的目标是确定 MTBP 的作用及其与 MDM2（如果有）在癌症转移中的功能关联。 HCC 是美国癌症相关死亡的一个上升原因，其 5 年生存率低于 12%。这种不良预后的主要原因是转移扩散。由于这些原因，我们将使用 HCC 作为模型来检查 MDM2 和 MTBP 在癌症迁移和转移中的贡献。我们的初步结果表明：1）人肝癌组织中MTBP表达降低与血管/被膜侵袭和淋巴结转移的存在相关，2）MTBP抑制肝癌细胞迁移，3）MTBP抑制丝状伪足的形成和迁移， ACTN4 和 4) MTBP 抑制 Elk-1 的活性，Elk-1 是一种 Ets 癌基因家族转录因子，也是 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的抑制性结合来促进癌症转移。我们将通过实现以下两个具体目标来检验这一假设：目标 1 是通过探索影响转移的 MDM2-MTBP 相互作用的下游介质，确定 MDM2 对 MTBP 抑制 HCC 转移的抑制作用；目标 2 是通过使用我们最近生成的亚等位性 MTBPH 小鼠（其 MTBP 表达水平仅为野生型水平的 20%）来确定 MDM2 和 MTBP 对小鼠模型中 HCC 进展的体内贡献。该项目的完成将填补有关 MTBP 抑制癌症转移和 MDM2 通过抑制 MTBP 以独立于 p53 的方式促进肿瘤进展的机制的知识空白。鉴于约 70% 的 HCC 组织中发现 MTBP 表达减少，30% 的 HCC 中检测到 MDM2 过表达，而转移是癌症死亡的主要原因，我们的研究有可能对诊断、治疗和预后产生重大影响用于 HCC 和可能具有 MDM2 和/或 MTBP 表达改变的其他类型的癌症。