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）：今年在美国预计将有50,000例新病例和10,000例死亡，膀胱癌是一个重大的健康问题。可变形态，自然史和预后表明，膀胱的过渡细胞癌（TCC）不是一种疾病，而是以三种不同形式发生，每种形式都具有特征性特征（即低级毛细血管，无侵入性，无创癌；高地；等级，入侵）。最近的研究已经开始阐明这些不同表现的膀胱癌的形态和生物学特征的基本遗传决定因素。在形态学变化之前的分子和遗传改变，并导致TCC的肿瘤发生和进展。了解这些遗传变化应最终导致TCC的诊断和基因治疗。最近报道了Coxsackie和腺病毒受体（CAR）的鉴定，这是5型腺病毒的高受体。在几个TCC和前列腺癌细胞系中检测到CAR的异质表达。该表达是由CAR基因转录的下调产生的。通过增加其汽车水平，抗性细胞可能对腺病毒感染高度敏感。因此，汽车不仅是监测基因治疗结果的替代标记，而且还促进了基因治疗的效率。在TCC病变中经常看到CAR的下调，而在相邻的正常组织中却没有看到，这表明CAR在TCC的进展中可能起病理生理的作用。同样，汽车与分化极化细胞中的紧密连接蛋白有关。此外，增加的汽车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细胞系中降低汽车表达（使用反义载体）可以促进体外和体内生长速率。这些数据表明汽车是TCC细胞中的肿瘤抑制剂。为了进一步阐明TCC细胞中CAR的潜在机制，初步数据表明（1）CAR是典型的细胞粘附分子；（2）汽车与紧密连接络合物有关；（3）CAR的粘附活性与其生长抑制功能相似；（4）CAR的细胞内结构域对于诱导其在TCC细胞中诱导其生长抑制信号至关重要；（5）CAR能够抑制环氧合酶2（COX-2）表达。基于这些结果，我们假设CAR可以通过重新建立TCC的细胞间相互作用来抑制细胞的生长，而汽车作用的机理是抑制TCC中COX-2的表达。由于CAR和COX-2的生物学在很大程度上未知，因此我们计划（1）从不同等级和阶段的TCC标本中建立CAR和COX-2之间的相互关系；（2）由CAR引起的下游途径（S）激活其肿瘤抑制并确定能够激活CAR信号传导的任何其他配体；（3）确定CAR抑制COX-2的生物学意义；（4）通过增强其内源性汽车表达来提高TCC基因治疗的治疗功效。这项研究的结果应有助于我们了解CAR在TCC发展中的生物学作用，并制定新的TCC治疗策略。

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

Surrogate marker for predicting the virus binding of urogenital cancer cells during adenovirus-based gene therapy.

在基于腺病毒的基因治疗期间预测泌尿生殖癌细胞的病毒结合的替代标记。