Novel Role of XIAP in Bladder Cancer Invasion

XIAP 在膀胱癌侵袭中的新作用

基本信息

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
项目类别：
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&apos 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

项目摘要

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。因为高等级侵入性膀胱癌 (HGIBC) 可进展为危及生命的转移，了解分子机制 BC 侵袭的潜在机制对于降低这种疾病的死亡率非常重要。 X连锁凋亡抑制蛋白（XIAP）是凋亡抑制蛋白（lAP）的成员家庭。除了其在细胞凋亡抑制中的既定作用外，我们最近发现了一个新作用 XIAP 在体外调节癌细胞侵袭。首先，XIAP 的敲除减少了结肠癌细胞的迁移以及这些细胞的体外侵袭和体内转移至肺部。相反，恢复 XIAP XIAP 耗尽的癌细胞中的表达恢复了其迁移。二、Rho解离抑制剂 (RhoGDI) 是 XIAP 调节癌细胞迁移的主要下游靶标。 XIAP 互动 RhoGDI 并以此通过其 RING 结构域抑制 RhoGDI SUMOylation。三、XIAP高度评价在人类侵袭性 BC 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 p53- 中 N-丁基-N-(4-羟丁基) 亚硝胺 (BBN) 诱导的侵袭性 BC 组织中也显着升高 l-lpRb-l- 小鼠，而在野生型小鼠尿路上皮中几乎检测不到，并且致癌 Ras- 含量较低诱导低级BC。第四，XIAP 的敲低导致 HGIBC 细胞迁移显着减少。最后，XIAP 在含有 p53 突变的细胞中显着上调，这是一种高度遗传的改变。多见于HGIBC。我们的数据来自细胞培养物、转基因小鼠和人体组织，证明了 XIAP 侵袭性 BC 中的过度表达，促使我们假设 XIAP 在促进/增强BC入侵。我们将通过三个具体目标来检验这个假设： 1：检验 p53 突变通过上调 BC 中 Spl 和/或 NFKB 激活 XIAP 表达的假设细胞； 2：明确XIAP调节BC细胞的功能域和分子机制入侵； 3：检验转基因小鼠尿路上皮特异性 XIAP 过度表达的假设可以促进 BC 体内侵袭以及敲除小鼠中 XIAP 或其 RING 结构域的缺失 XIAPARNG 敲入小鼠使这些小鼠能够抵抗侵入性 BC 的发展。我们提出的研究将有助于这对理解侵袭性 BC 的分子基础有重要意义。他们也将为我们铺平道路使用 XIAP 作为新型预后生物标志物和侵袭性 BC 的治疗靶点。这应该反过来有助于改善这些患者的临床结果。相关性（参见说明）：尽管膀胱癌（BC）的侵袭性形式导致了所有由此导致的死亡疾病，从生物学角度来说，关于触发 BC 入侵的原因知之甚少。我们最近发现了一个新角色 XIAP 以前被称为细胞迁移和侵袭中细胞凋亡的抑制剂。通过研究机制导致 BC 细胞中 XIAP 增加以及 XIAP 在小鼠模型中的 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/或治疗靶点。