The mechanism of the growth-inhibitory effect of coxsackie and adenovirus receptor (CAR) on human bladder cancer: a functional analysis of car protein structure.
The mechanism of the growth-inhibitory effect of coxsackie and adenovirus receptor (CAR) on human bladder cancer: a functional analysis of car protein structure.
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发表时间：
2001-09
期刊：
影响因子：
11.2
通讯作者：
T. Okegawa;R. Pong;Yingming Li;J. Bergelson;A. Sagalowsky;J. Hsieh
中科院分区：
文献类型：
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作者：
T. Okegawa;R. Pong;Yingming Li;J. Bergelson;A. Sagalowsky;J. Hsieh
柯萨奇腺病毒受体（CAR）被鉴定为5型腺病毒的高亲和力受体。我们观察到，与浅表性膀胱癌标本相比，浸润性膀胱癌标本的CAR mRNA水平显着降低，这表明CAR可能在膀胱癌的进展中发挥作用。 T24细胞系（CAR阴性细胞）中CAR表达升高，增加了其对腺病毒感染的敏感性，并显着抑制其体外生长，并伴有p21和低磷酸化视网膜母细胞瘤的积累。相反，RT4 和 253J 细胞系（CAR 阳性细胞）中 CAR 水平的降低促进了它们的体外生长。为了揭示 CAR 的作用机制，我们发现 CAR 的胞外结构域促进细胞间粘附。此外，通过特异性抗体中断CAR的细胞间粘附可以减轻CAR的生长抑制作用。我们还证明了 CAR 的跨膜和细胞内结构域对其生长抑制活性至关重要。这些数据表明，膜结合 CAR 启动的细胞间接触可以引发负信号级联，从而调节膀胱癌细胞核内的细胞周期调节因子。因此，CAR的存在不仅可以促进病毒摄取腺病毒，还可以抑制细胞生长。可以整合这些结果来制定膀胱癌治疗的新策略。
The coxsackie and adenovirus receptor (CAR) is identified as a high-affinity receptor for adenovirus type 5. We observed that invasive bladder cancer specimens had significantly reduced CAR mRNA levels compared with superficial bladder cancer specimens, which suggests that CAR may play a role in the progression of bladder cancer. Elevated CAR expression in the T24 cell line (CAR-negative cells) increased its sensitivity to adenovirus infection and significantly inhibited its in vitro growth, accompanied by p21 and hypophosphorylated retinoblastoma accumulation. Conversely, decreased CAR levels in both RT4 and 253J cell lines (CAR-positive cells) promoted their in vitro growth. To unveil the mechanism of action of CAR, we showed that the extracellular domain of CAR facilitated intercellular adhesion. Furthermore, interrupting intercellular adhesion of CAR by a specific antibody alleviates the growth-inhibitory effect of CAR. We also demonstrated that both the transmembrane and intracellular domains of CAR were critical for its growth-inhibitory activity. These data indicate that the cell-cell contact initiated by membrane-bound CAR can elicit a negative signal cascade to modulate cell cycle regulators inside the nucleus of bladder cancer cells. Therefore, the presence of CAR cannot only facilitate viral uptake of adenovirus but also inhibit cell growth. These results can be integrated to formulate a new strategy for bladder cancer therapy.