Novel Role of XIAP in Bladder Cancer Invasion

XIAP 在膀胱癌侵袭中的新作用

• 批准号: 8596899
• 负责人: CHUANSHU HUANG
• 金额: $ 34.93万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-12 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8596899
• 关键词: Apoptosis; Apoptosis Inhibitor; Attenuated; Automobile Driving; Binding; Biological Markers; Biological Process; Bladder Neoplasm; Butylhydroxybutylnitrosamine; Cancer cell line; Carcinogens; Carcinoma in Situ; Cell Culture Techniques; Cells; Cessation of life; Clinical; Collaborations; Colon Carcinoma; Complement; Data; Development; Disease; Dissociation; Family; Human; In Situ Lesion; In Vitro; Inhibition of Apoptosis; Knock-out; Knockout Mice; Life; Little' s Disease; Lung; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Mediating; Metastatic Neoplasm to the Lung; Molecular; Moon; Mus; Mutate; Mutation; NF-kappa B; Neoplasm Metastasis; Oncogenic; Outcome; Papillary; Pathway interactions; Patients; Play; Principal Investigator; Prognostic Marker; Promoter Regions; Protein Overexpression; Proteins; Resistance; Role; Testing; Tissues; Transactivation; Transgenic Mice; Transgenic Organisms; Up-Regulation; Urothelium; Variant; Western World; Wild Type Mouse; attenuation; base; bladder transitional cell carcinoma; cDNA Expression; cancer cell; cell motility; colon cancer cell line; human BIRC4 protein; human tissue; improved; in vivo; inhibitor-of-apoptosis protein; inhibitor/antagonist; member; migration; molecular domain; mortality; mouse model; mutant; novel; overexpression; protein expression; rho; small hairpin RNA; therapeutic target; tumorigenesis

Bladder cancer (BC) is among the most common cancers in the Western world. Because high-grade invasive bladder cancers (HGIBC) can progress to life threatening metastases, understanding the molecular mechanisms underlying BC Invasion is of tremendous Importance for reducing the mortality of this disease. The X-linked inhibitor of apoptosis protein (XIAP) is a member ofthe inhibitors of apoptosis protein (lAP) family. In addition to its well-established role in apoptosis inhibition, we recently discovered a new role of XIAP in regulating cancer cell Invasion in vitro. First, knockout of XIAP decreased colon cancer cell migration and invasion in vitro and metastasis of these cells to the lungs in vivo. Conversely, resumption of XIAP expression in XIAP-depleted cancer cells restored their migration. Second, Rho dissociation Inhibitor (RhoGDI) is a principal downstream target of XIAP in regulating cancer cell migration. XIAP Interacted with RhoGDI and in so doing inhibited RhoGDI SUMOylation via its RING domain. Third, XIAP was highly expressed in human invasive BC tissues, but not in adjacent normal urothelial tissues. XIAP expression was also markedly elevated in N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-lnduced invasive BC tissues in p53- l-lpRb-l- mice, while it was almost undetectable in wild-type mouse urothelia and was low in oncogenic Ras- induced low-grade BCs. Fourth, knockdown of XIAP led to a marked decrease of HGIBC cell migration. Finally, XIAP was significantly up-regulated in the cells harboring p53 mutations, a genetic alteration highly prevalent in HGIBC. Our data from cell culture, transgenic mice and human tissues, demonstrating XIAP over-expression in the invasive BCs, prompt us to hypothesize that XIAP plays an important role in promoting/enhancing BC invasion. We will examine this hypothesis with three Specific Aims: 1: To test the hypothesis that p53 mutations activate XIAP expression via the upregulation of Spl and/or NFKB in BC cells; 2: To define the functional domain and molecular mechanisms whereby XIAP regulates BC cell invasion; 3: To examine the hypothesis that urothelium-specific over-expression of XIAP in transgenic mice can promote BC Invasion in vivo and that loss of XIAP in knockout mice or its RING domain in XIAPARNG knockin mice renders these mice resistant to invasive BC development. Our proposed studies will contribute in a major way to the understanding of the molecular basis of invasive BC. They will also pave the way for us to use XIAP as a novel prognostic biomarker and a therapeutic target for invasive BC. This should in turn help improve the clinical outcome of these patients. RELEVANCE (See instmctions): Although the invasive form of bladder cancer (BC) is responsible for all the deaths resulting from this disease, little is known biologically about what triggers BC invasion. We recently found a new role of XIAP previously known as an inhibitor of apoptosis, in cell migration and invasion. By studying the mechanisms leading to increased XIAP in BC cells and the role of XIAP in BC invasion using mouse models, we hope to determine whether XIAP can be used a prognostic marker and/or a therapeutic target of Invasive BC.

膀胱癌是西方世界最常见的癌症之一。因为高级侵入性 膀胱癌(HGIBC)可以进展到危及生命的转移，了解分子 BC的侵袭机制对于降低该病的死亡率具有重要意义。 X连锁凋亡抑制蛋白(XIAP)是凋亡抑制蛋白(LAP)中的一员 一家人。除了它在抑制细胞凋亡方面已经确立的作用外，我们最近还发现了一个新的作用 XIAP对癌细胞体外侵袭的调控作用首先，XIAP基因敲除减少了结肠癌细胞的迁移 体外侵袭和体内肺转移。相反，XIAP的恢复 在XIAP耗尽的癌细胞中的表达恢复了它们的迁移。第二，Rho解离抑制剂 (RhoGDI)是XIAP调控癌细胞迁移的主要下游靶点。XIAP与 RhoGDI并通过其环区抑制RhoGDI的SUMO化。第三，XIAP高度 在人浸润性膀胱癌组织中表达，而在邻近正常尿路上皮组织中不表达。XIAP表达为 在N-丁基-N-(4-羟基丁基)亚硝胺(BBN)诱导的侵袭性BC组织中，P53- L-lpRb-L-小鼠，而野生型小鼠尿路中几乎检测不到它，致癌RAS-2含量较低。 诱发低度BCS。第四，XIAP基因敲除导致HGIBC细胞迁移明显减少。 最后，XIAP在含有P53突变的细胞中显著上调，这是一种高度的基因改变 流行于HGIBC。我们来自细胞培养、转基因小鼠和人类组织的数据，证明了XIAP 在侵袭性BCS中的过度表达，提示我们假设XIAP在 促进/增强BC入侵。我们将以三个具体目标来检验这一假说：1：检验 P53突变通过上调Bc细胞SPL和/或NFKB激活XIAP表达的假说 细胞；2：确定XIAP调节BC细胞的功能结构域和分子机制 侵袭；3：验证转基因小鼠尿路上皮特异性XIAP过度表达的假说 可促进BC体内侵袭和XIAP基因敲除小鼠或XIAP环状结构域丢失 Knockin小鼠使这些小鼠对BC的侵袭性发育具有抵抗力。我们建议的研究将有助于 在很大程度上有助于了解侵袭性BC的分子基础。他们还将为我们铺平道路 目的：将XIAP作为侵袭性BC的一种新的预后生物标志物和治疗靶点。这应该反过来 有助于改善这些患者的临床结果。 相关性(请参阅说明)： 尽管浸润性膀胱癌(BC)是由此导致的所有死亡的原因 疾病，从生物学上来说，人们对是什么触发了BC的入侵知之甚少。我们最近发现了XIAP的新角色 以前被认为是细胞凋亡的抑制因子，在细胞的迁移和侵袭中起作用。通过对机制的研究 导致BC细胞中XIAP的增加以及XIAP在BC侵袭中的作用，我们希望 确定XIAP是否可以作为侵袭性BC的预后标志和/或治疗靶点。