UBXN2A represses migration and invasion of colorectal cancer cells

UBXN2A抑制结直肠癌细胞的迁移和侵袭

基本信息

批准号：
9910369
负责人：
Khosrow Samuel Rezvani
金额：
$ 7.35万
依托单位：
UNIVERSITY OF SOUTH DAKOTA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-08 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9910369
关键词：
3D ultrasound AKT Signaling Pathway AKT1 gene AKT2 gene AKT3 gene Address Affect Animals Biochemical Biological Sciences Cell Death Cell Line Cessation of life Colon Colon Carcinoma Colonic Neoplasms Colorectal Cancer Colorectal Neoplasms Data Development Diagnosis Disease Doxycycline E-Cadherin Enhancers Family member Fluorouracil Genetic Transcription Goals Growth HCT116 Cells Hand Human Imaging Techniques In Vitro Intercept Lead Mediating Modeling Molecular Mus Neoplasm Metastasis Optics Outcome PI3K/AKT Pathologic Pathway interactions Patients Pharmacology Phosphorylation Plant alkaloid Primary Neoplasm Process Property Protein Array Protein Isoforms Proteins Proto-Oncogene Proteins c-akt Publishing Regulation Reporter Role Signal Pathway Signal Transduction Survival Rate System Testing Tetanus Helper Peptide Therapeutic Treatment Protocols Tumor Cell Invasion Tumor Cell Migration Tumor Suppressor Genes Tumor Suppressor Proteins Ubiquitin Veratridine Xenograft procedure advanced disease anti-cancer base cancer cell cell motility chemotherapeutic agent colon cancer cell line colon cancer patients colon tumorigenesis colorectal cancer metastasis colorectal cancer treatment design effective therapy experimental study high-throughput drug screening improved in vivo in vivo evaluation inducible gene expression inhibitor/antagonist insight knock-down member metastatic colorectal migration mouse model novel novel therapeutic intervention novel therapeutics outcome forecast prevent programs protein expression public health relevance targeted treatment tumor tumorigenesis

项目摘要

Abstract Title: UBXN2A represses migration and invasion of colorectal cancer cells. This project focuses on UBXN2A, which is a ubiquitin-like (UBX) domain-containing protein with potent tumor suppressor functions in colorectal cancer (CRC). We showed that induction of UBXN2A decreases colon xenograft growth rate by 50%, and heterozygous disruption of UBXN2A in mice is sufficient to promote tumorigenesis. At the cellular level, our results indicate that UBXN2A has a major inhibitory effect on tumor cell migration and invasion. Thus, UBXN2A may have a dominant anti-cancer effect by dual-targeting primary tumors as well as signaling pathways associated with tumor metastasis. The objective of this application is twofold; the first objective is to identify the UBXN2A's regulatory function in the mTORC2/pAKT signaling pathway during cancer cell migration and invasion. The second objective is to understand UBXN2A's anti- cancer mechanisms during colon cancer cell invasion/migration in an orthotopic colon cancer mouse model that mimics human CRC metastasis. Because our protein array data showed that 50% of CRC tumors have low levels of UBXN2A, the long-term goal of this proposal is to develop a new therapeutic strategy for patients with CRC using UBXN2A as a target for therapy. Based on our published results and preliminary data, our central hypothesis will be tested in two specific aims: 1) Determine whether loss of UBXN2A is sufficient to enhance migration and invasion in metastatic colon cancer cells in a mTORC2/pAKT-dependent manner, and 2) Examine the inhibitory effect of UBXN2A induction on human colorectal tumor invasion and metastasis in an orthotopic CRC mouse model. The designed in vitro and in vivo experiments and available Tet- on controllable expression cell lines as well as our 3D ultrasound imaging technique in live animals will be a powerful approach for gaining new mechanistic insight into the role of UBXN2A in the regulation of CRC metastasis and assessing the therapeutic potential of UBXN2A in patients with CRC.

抽象的标题：UBXN2A 抑制结直肠癌细胞的迁移和侵袭。该项目重点关注 UBXN2A，它是一种含有泛素样 (UBX) 结构域的蛋白质，在结直肠癌 (CRC) 中具有有效的肿瘤抑制功能。我们证明了归纳 UBXN2A 使结肠异种移植物生长率降低 50%，并且杂合性破坏小鼠体内的UBXN2A足以促进肿瘤发生。在细胞水平上，我们的结果表明表明UBXN2A对肿瘤细胞的迁移和侵袭具有主要的抑制作用。因此，UBXN2A 可能通过双靶向原发肿瘤以及信号传导而具有显着的抗癌作用与肿瘤转移相关的途径。该应用程序的目的有两个：第一个目的是确定 UBXN2A 在 mTORC2/pAKT 信号通路中的调节功能在癌细胞迁移和侵袭过程中。第二个目标是了解 UBXN2A 的抗原位结肠癌结肠癌细胞侵袭/迁移过程中的癌症机制模拟人类结直肠癌转移的小鼠模型。因为我们的蛋白质阵列数据表明 50%的CRC肿瘤具有低水平的UBXN2A，该提案的长期目标是开发使用 UBXN2A 作为治疗靶点的 CRC 患者的新治疗策略。基于根据我们公布的结果和初步数据，我们的中心假设将在两个特定的方面进行检验目的： 1) 确定 UBXN2A 的丢失是否足以增强细胞的迁移和侵袭以 mTORC2/pAKT 依赖性方式检测转移性结肠癌细胞，以及 2) 检查 UBXN2A诱导对人结直肠肿瘤侵袭和转移的抑制作用原位CRC小鼠模型。设计的体外和体内实验以及可用的 Tet- 可控表达细胞系以及我们在活体动物中的 3D 超声成像技术将是一种强有力的方法，可以深入了解 UBXN2A 在 CRC 转移的调节并评估 UBXN2A 对 CRC 患者的治疗潜力 CRC。