MOLECULAR REGULATION OF INTERCELLULAR-ADHESION MOLECULE-1 (ICAM-1) EXPRESSION IN RENAL-CELL CARCINOMA

Intercellular adhesion molecule-1 (ICAM-1) mediates two important func tional aspects of tumor biology, namely enhancement of tumor metastasi s and mediation of host defense mechanisms such as lymphocyte-mediated tumor cytotoxicity. Since ICAM-1 is expressed by most renal cell carc inomas (RCC), the regulation of ICAM-1 expression is important in unde rstanding the biological behavior of RCC. We report an investigation o n 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 p horbol myristate acetate (PMA) strongly upregulated ICAM-1 protein exp ression on RCC. The kinetics of ICAM-1 message induction was studied b y 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 N KPT cells was upregulated by these cytokines, their messages returned to basal levels after 24 h. ICAM-1 mRNA stability assays showed that b oth unstimulated and stimulated RCC cells had very stable ICAM-1 mRNA up to 24 h. In order to investigate whether increased gene transcripti on contributes to ICAM-1 upregulation, RCC cells were treated with TNF alpha, IFN gamma, or PMA with or without simultaneous addition of act inomycin D. ICAM-1 message induction-blocking studies suggested that p rimary upregulation of ICAM-1 mRNA may be caused by transcriptional up regulation. These results suggest that long-lasting ICAM-1 message upr egulation in response to cytokines or PMA may be due to transcriptiona l upregulation in the early phase and stabilization of ICAM-1 message in the later phase (after 4 h). These observations suggest that RCC ma y lack the normal downregulatory mechanisms which control ICAM-1 expre ssion and may explain the high frequency of ICAM-1 expression observed on primary human RCC.