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（BC）是西方世界最常见的癌症之一。因为高级别的侵入性 膀胱癌（HGIBC）可以进展为危及生命的转移，了解分子生物学 BC侵袭的潜在机制对于降低这种疾病的死亡率具有巨大的重要性。 X连锁凋亡抑制蛋白（XIAP）是凋亡抑制蛋白（IAP）的一员 家人除了其在细胞凋亡抑制中的作用外，我们最近发现了一种新的作用， XIAP在体外调控癌细胞侵袭中的作用首先，XIAP的敲除减少了结肠癌细胞的迁移 以及这些细胞在体外的侵袭和在体内向肺的转移。相反，恢复XIAP 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在调节癌细胞迁移中的主要下游靶标。XIAP与 RhoGDI通过其RING结构域抑制RhoGDI SUMO化。第三，XIAP高度 在人浸润性膀胱癌组织中表达，但在邻近的正常尿路上皮组织中不表达。XIAP表达为 在N-butyl-N-（4-hydroxybutyl）nitrosamine（BBN）-induced invasive BC tissue中，p53- l-lpRb-l-小鼠中，而在野生型小鼠尿路上皮中几乎检测不到，并且在致癌Ras-1小鼠中低。 导致低等级的BC。第四，敲低XIAP导致HGIBC细胞迁移显著减少。 最后，XIAP在携带p53突变的细胞中显著上调，这是一种高度遗传改变。 在HGIBC中流行。我们从细胞培养、转基因小鼠和人体组织中获得的数据表明，XIAP XIAP在侵袭性BCs中的过度表达，提示我们假设XIAP在BCs中起重要作用。 促进/增强BC入侵。我们将通过三个具体目的来检验这一假设：1.检验 p53突变通过上调BC中Spl和/或NF κ B激活XIAP表达的假设 2.确定XIAP调控BC细胞的功能域和分子机制 3：检验转基因小鼠中尿路特异性XIAP过表达的假设， 可促进BC在体内侵袭，并促进XIAP基因敲除小鼠中XIAP或XIAPARNG中其RING结构域的缺失 敲入小鼠使这些小鼠对侵入性BC发展具有抗性。我们提出的研究将有助于 在一个主要的方式来理解的分子基础上侵入性BC。他们也会为我们铺平道路 将XIAP作为一种新的预后生物标志物和侵袭性BC的治疗靶点。反过来，这应该 帮助改善这些患者的临床结果。 相关性（见说明）： 虽然膀胱癌（BC）的侵袭性形式是导致所有死亡的原因， 疾病，生物学上对什么触发BC入侵知之甚少。我们最近发现了XIAP的一个新作用 以前被认为是细胞迁移和侵袭中的细胞凋亡抑制剂。通过研究 导致BC细胞中XIAP的增加以及XIAP在使用小鼠模型的BC侵袭中的作用，我们希望 确定XIAP是否可以用作侵袭性BC的预后标志物和/或治疗靶标。