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The role of CAR and its application in bladder cancer

CAR的作用及其在膀胱癌中的应用

基本信息

批准号：
7013967
负责人：
Jer-Tsong Hsieh
金额：
$ 26.13万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-02-01 至 2008-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7013967
关键词：
role CAR its application bladder

项目摘要

DESCRIPTION (provided by applicant): With over 50,000 new cases and 10,000 deaths expected this year in the U.S, bladder cancer is a significant health concern. Variable morphology, natural history, and prognosis demonstrate that transitional cell carcinoma (TCC) of the bladder is not a single disease, but occurs in three distinct forms, each possessing characteristic features (i.e., low grade papillary, noninvasive; carcinoma in situ; high grade, invasive). Recent studies have begun to elucidate the underlying genetic determinants of the morphologic and biologic characteristics of these different presentations of bladder cancer. Molecular and genetic alterations that precede morphologic changes, and which are responsible for tumorigenesis and progression of TCC. Understanding these genetic changes should eventually lead to improved diagnosis and gene therapy for TCC. Identification of a coxsackie and adenovirus receptor (CAR), a high receptor for adenovirus type 5, was recently reported. The heterogeneous expression of CAR is detected in several TCC and prostate cancer cell lines. This expression resulted from the downregulation of CAR gene transcription. By increasing their CAR levels, resistant cells could become highly sensitive to adenoviral infection. Therefore, CAR not only is a surrogate marker to monitor the outcome of gene therapy, but also facilitate the efficiency of gene therapy. The Down-regulation of CAR is often seen in TCC lesions but not in adjacent normal tissue, which suggests that CAR may play a pathophysiologic role in the progression of TCC. Also, CAR is associated with a tight junction protein in differentiated polarized cell. Moreover, increased CAR gene expression can inhibit the in vitro and in vivo growth of tumor cells. On the other hand, decreasing CAR expression (using antisense vector) in several TCC cell lines can facilitate the in vitro and in vivo growth rate. These data indicate that CAR is a tumor inhibitor in TCC cells. To further elucidate the underlying mechanism of CAR in TCC cells, preliminary data indicated that (1) CAR is a typical cell adhesion molecule; (2) CAR is associated with tight junction complex; (3) adhesion activity of CAR parallels its growth inhibitory function; (4) the intracellular domain of CAR is critical for inducing its growth inhibitory signal in TCC cells; (5) CAR is able to inhibit cyclooxygenase 2 (COX-2) expression. Based on these results, we hypothesize that CAR can inhibit cell growth by reestablishing intercellular interactions of TCC, and the mechanism of CAR action is to inhibit COX-2 expression in TCC. Since the biology of CAR and COX-2 is largely unknown, we plan to (1) establish a reciprocal relationship between CAR and COX-2 from TCC specimens of different grades and stages; (2) unveil downstream pathway(s) elicited by CAR that activates its tumor inhibition and to determine any other ligand(s) capable of activating CAR signaling; (3) determine the biologic significance of the suppression of COX-2 by CAR; (4) increase therapeutic efficacy of TCC gene therapy by enhancing its endogenous CAR expression. The outcome of this study should help us understand the biologic role of CAR in the progression of TCC and develop a new strategy for TCC therapy.

描述（由申请人提供）：预计今年美国将有超过50，000例新发病例和10，000例死亡，膀胱癌是一个重大的健康问题。不同的形态、自然史和预后表明膀胱移行细胞癌（TCC）不是单一疾病，而是以三种不同的形式发生，每种形式都具有特征性特征（即，低级别乳头状，非侵袭性;原位癌;高级别，侵袭性）。最近的研究已经开始阐明这些不同表现的膀胱癌的形态学和生物学特征的潜在遗传决定因素。分子和遗传学改变先于形态学改变，并与TCC的发生和进展有关。了解这些遗传变化最终将有助于改善TCC的诊断和基因治疗。科萨基和腺病毒受体（CAR），一个高受体的5型腺病毒，最近的鉴定报告。在几种TCC和前列腺癌细胞系中检测到CAR的异质性表达。这种表达是由CAR基因转录下调引起的。通过增加它们的CAR水平，抗性细胞可以变得对腺病毒感染高度敏感。因此，CAR不仅可以作为监测基因治疗效果的替代标记物，而且可以促进基因治疗的有效性。CAR在TCC病变组织中表达下调，而在癌旁正常组织中表达不明显，提示CAR可能在TCC的发生发展中起一定的病理生理作用。此外，CAR与分化极化细胞中的紧密连接蛋白相关。此外，增加的CAR基因表达可以抑制肿瘤细胞的体外和体内生长。另一方面，在几种TCC细胞系中降低CAR表达（使用反义载体）可以促进体外和体内生长速率。这些数据表明CAR是TCC细胞中的肿瘤抑制剂。为了进一步阐明CAR在TCC细胞中的作用机制，初步研究表明：（1）CAR是一种典型的细胞粘附分子;（2）CAR与紧密连接复合物相关;（3）CAR的粘附活性与其生长抑制功能平行;（4）CAR的胞内结构域是诱导其在TCC细胞中生长抑制信号的关键;（5）CAR能抑制环氧化酶2（考克斯-2）的表达。基于这些结果，我们推测CAR可以通过重建TCC的细胞间相互作用来抑制细胞生长，并且CAR的作用机制是抑制TCC中考克斯-2的表达。由于CAR和考克斯-2的生物学在很大程度上是未知的，我们计划（1）从不同级别和阶段的TCC标本中建立CAR和考克斯-2之间的相互关系;（2）揭示由CAR引发的激活其肿瘤抑制的下游途径，并确定能够激活CAR信号传导的任何其他配体;（3）确定CAR抑制考克斯-2的生物学意义;（4）通过增强TCC的内源性CAR表达来增加TCC基因治疗的治疗功效。这项研究的结果将有助于我们了解CAR在TCC进展中的生物学作用，并为TCC治疗提供新的策略。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The role of cell adhesion molecule in cancer progression and its application in cancer therapy.

DOI：
10.18388/abp.2004_3583
发表时间：
2004-08
期刊：
Acta biochimica Polonica
影响因子：
1.7
作者：
T. Okegawa;R. Pong;Yingming Li;J. Hsieh
通讯作者：
T. Okegawa;R. Pong;Yingming Li;J. Hsieh

Upregulation of TRAG3 gene in urothelial carcinoma of the bladder.

DOI：
10.1002/ijc.25631
发表时间：
2011-06-15
期刊：
INTERNATIONAL JOURNAL OF CANCER
影响因子：
6.4
作者：
Karam, Jose A.;Huang, Sandra;Fan, Jinhai;Stanfield, Jennifer;Schultz, Roger A.;Pong, Rey-Chen;Sun, Xiankai;Mason, Ralph P.;Xie, Xian-Jin;Niu, Gang;Chen, Xiaoyuan;Frenkel, Eugene P.;Sagalowsky, Arthur I.;Hsieh, Jer-Tsong
通讯作者：
Hsieh, Jer-Tsong

The application of epigenetic modifiers on the treatment of prostate and bladder cancer.

表观遗传修饰剂在前列腺癌和膀胱癌治疗中的应用。