UBXN2A represses migration and invasion of colorectal cancer cells

摘要 UBXN2A抑制结直肠癌细胞的迁移和侵袭。 该项目的重点是UBXN2A，这是一种含有泛素样（UBX）结构域的蛋白质， 在结直肠癌（CRC）中的有效肿瘤抑制功能。我们发现， UBXN2A使结肠异种移植物生长率降低50%，并且UBXN2A的杂合破坏使结肠异种移植物生长率降低50%，并且UBXN2A的杂合破坏使结肠异种移植物生长率降低50%。 UBXN2A在小鼠中足以促进肿瘤发生。在细胞水平上，我们的结果表明 UBXN2A对肿瘤细胞的迁移和侵袭具有主要的抑制作用。因此，UBXN2A 可能通过双重靶向原发性肿瘤以及信号传导而具有显性抗癌作用 与肿瘤转移相关的途径。本申请的目的是双重的;第一， 目的是鉴定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- 原位结肠癌中结肠癌细胞侵袭/迁移期间的癌症机制 模拟人CRC转移的小鼠模型。因为我们的蛋白质阵列数据显示， 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 根据我们发表的结果和初步数据，我们的中心假设将在两个具体的实验中得到检验。 目的：1）确定UBXN2A的缺失是否足以增强在大肠杆菌中的迁移和侵袭。 以mTORC2/pAKT依赖性方式检测转移性结肠癌细胞，和2）检测 UBXN2A诱导对人大肠癌侵袭转移抑制作用 原位CRC小鼠模型。设计的体外和体内实验和可用的泰特- 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 将是一个强大的方法，获得新的机制洞察UBXN2A的作用， CRC转移的调节和评估UBXN2A在CRC患者中的治疗潜力 《儿童权利公约》。

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.