Tanabe K, Campbell S C, Alexander J P, Steinbach F, Edinger M G, Tubbs R R, Novick A C, Klein E A
Department of Urology, Tokyo Women's Medical College, Japan.
Urol Res. 1997;25(4):231-8. doi: 10.1007/BF00942091.
Intercellular adhesion molecule-1 (ICAM-1) mediates two important functional aspects of tumor biology, namely enhancement of tumor metastasis and mediation of host defense mechanisms such as lymphocyte-mediated tumor cytotoxicity. Since ICAM-1 is expressed by most renal cell carcinomas (RCC), the regulation of ICAM-1 expression is important in understanding the biological behavior of RCC. We report an investigation on ICAM-1 expression and molecular regulation by cytokines and protein kinase C activator on RCC cell lines. Of the various cytokines, tumor necrosis factor alpha (TNF alpha), interferon-gamma (IFN gamma), and phorbol myristate acetate (PMA) strongly upregulated ICAM-1 protein expression on RCC. The kinetics of ICAM-1 message induction was studied by Northern analysis of total RNA extracted from RCC and normal kidney proximal tubular (NKPT) cells. Time course studies showed that ICAM-1 mRNA was upregulated by INF gamma, TNF alpha, and PMA, plateaued after 2 h, and remained increased for up to 24 h. Although ICAM-1 mRNA in NKPT cells was upregulated by these cytokines, their messages returned to basal levels after 24 h. ICAM-1 mRNA stability assays showed that both unstimulated and stimulated RCC cells had very stable ICAM-1 mRNA up to 24 h. In order to investigate whether increased gene transcription contributes to ICAM-1 upregulation, RCC cells were treated with TNF alpha, IFN gamma, or PMA with or without simultaneous addition of actinomycin D. ICAM-1 message induction-blocking studies suggested that primary upregulation of ICAM-1 mRNA may be caused by transcriptional upregulation. These results suggest that long-lasting ICAM-1 message upregulation in response to cytokines or PMA may be due to transcriptional upregulation in the early phase and stabilization of ICAM-1 message in the later phase (after 4 h). These observations suggest that RCC may lack the normal downregulatory mechanisms which control ICAM-1 expression and may explain the high frequency of ICAM-1 expression observed on primary human RCC.
细胞间黏附分子-1（ICAM-1）介导肿瘤生物学的两个重要功能方面，即增强肿瘤转移以及介导宿主防御机制，如淋巴细胞介导的肿瘤细胞毒性。由于大多数肾细胞癌（RCC）都表达ICAM-1，因此ICAM-1表达的调控对于理解RCC的生物学行为很重要。我们报告了一项关于细胞因子和蛋白激酶C激活剂对RCC细胞系中ICAM-1表达及分子调控的研究。在各种细胞因子中，肿瘤坏死因子α（TNFα）、干扰素-γ（IFNγ）和佛波酯（PMA）强烈上调RCC上ICAM-1蛋白的表达。通过对从RCC和正常肾近端小管（NKPT）细胞中提取的总RNA进行Northern分析，研究了ICAM-1信息诱导的动力学。时间进程研究表明，ICAM-1 mRNA被INFγ、TNFα和PMA上调，在2小时后达到平台期，并在长达24小时内持续增加。尽管NKPT细胞中的ICAM-1 mRNA被这些细胞因子上调，但其信息在24小时后恢复到基础水平。ICAM-1 mRNA稳定性分析表明，未刺激和刺激的RCC细胞在长达24小时内都具有非常稳定的ICAM-1 mRNA。为了研究基因转录增加是否导致ICAM-1上调，RCC细胞用TNFα、IFNγ或PMA处理，同时添加或不添加放线菌素D。ICAM-1信息诱导阻断研究表明，ICAM-1 mRNA的初始上调可能是由转录上调引起的。这些结果表明，对细胞因子或PMA的持久ICAM-1信息上调可能是由于早期的转录上调和后期（4小时后）ICAM-1信息的稳定。这些观察结果表明，RCC可能缺乏控制ICAM-1表达的正常下调机制，这可能解释了在原发性人类RCC上观察到的ICAM-1高表达频率。
