UBXN2A represses migration and invasion of colorectal cancer cells

摘要 标题：UBXN2A抑制结直肠癌细胞的迁移和侵袭。 这个项目的重点是UBXN2A，它是一种含有泛素样域(UBX)的蛋白质，具有 结直肠癌(CRC)中强大的肿瘤抑制功能。我们证明了诱导 UBXN2A使异种结肠移植物生长速度降低50%，杂合子干扰 小鼠体内的UBXN2A足以促进肿瘤的发生。在细胞水平上，我们的结果表明 提示UBXN2A对肿瘤细胞的迁移和侵袭有明显的抑制作用。因此，UBXN2A 可能通过双靶向原发肿瘤以及信号转导而具有显性的抗癌作用 与肿瘤转移相关的通路。这个应用程序的目标有两个；第一个 目的是确定UBXN2A在mTORC2/PACK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的反- 原位结肠癌中癌细胞侵袭/迁移过程中的肿瘤机制 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显示 50%的结直肠癌UBXN2A水平较低，这项提议的长期目标是发展 以UBXN2A为靶点治疗结直肠癌的新策略基座 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具体的方面进行检验 目标：1)确定UBXN2A的丢失是否足以增强 转移性结肠癌细胞以mTORC2/PACT依赖的方式，以及2)检查 UBXN2A诱导对人结直肠癌侵袭转移的抑制作用 原位结直肠癌小鼠模型。设计的体内外实验和可利用的粉防己碱。 活体动物可控表达细胞系及其三维超声成像技术研究 将是一种强有力的方法，可以从新的机制上洞察UBXN2A在 UBXN2A对结直肠癌转移的调控及治疗潜力的评价 CRC。

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.