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。该项目侧重于UBXN2A，这是一种泛素样（UBX）含有域的蛋白质有效的肿瘤抑制在结直肠癌（CRC）中的功能。我们表明了诱导 UBXN2A将结肠异种移植的增长率降低50％，并杂合破坏小鼠中的ubxn2a足以促进肿瘤发生。在细胞水平，我们的结果表明 UBXN2A对肿瘤细胞迁移和侵袭具有重大抑制作用。因此，ubxn2a 通过双靶向原发性肿瘤以及信号传导，可能具有主导的抗癌作用与肿瘤转移相关的途径。该应用的目的是双重的。第一个目的是确定MTORC2/PAKT信号通路中的UBXN2A的调节功能在癌细胞迁移和入侵期间。第二个目标是了解UBXN2A的反 - 在原位结肠癌中结肠癌细胞入侵/迁移期间的癌症机制模仿人CRC转移的小鼠模型。因为我们的蛋白质阵列数据表明 50％的CRC肿瘤具有较低的UBXN2A，该提议的长期目标是发展使用UBXN2A作为治疗靶点的CRC患者的一种新的治疗策略。基于在我们发布的结果和初步数据上，我们的中心假设将在两个特定的特定方面进行测试目的：1）确定UBXN2A的损失是否足以增强迁移和入侵以MTORC2/PAKT依赖性方式转移性结肠癌细胞，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鼠标模型。设计在体外和体内实验和可用的Tet- 在可控的表达细胞系以及我们的3D超声成像技术中将是一种有力的方法，可以获得对Ubxn2a在调节CRC转移并评估UBXN2A的治疗潜力 CRC。