Growth inhibition of cervical cancer cells by the human retinoic acid receptor beta gene.
Transcription of the retinoic receptor beta (RARbeta) gene is activated in a ligand-dependent manner by the retinoic acid receptor alpha. Reduced RARbeta gene expression and loss of ligand inducibility are frequently observed in human carcinoma cells indicating that such alterations might contribute to carcinogenesis. In this study we have analyzed the influence of RARbeta on cervical cancer cell growth. Transfection of HeLa cells with RARbeta expression plasmids resulted in reduced clonal cell growth in the presence of retinoic acid (RA). RA-induced growth inhibition in HeLa x fibroblast hybrid cells was partially relieved by a dominant-negative RARbeta mutant. HeLa clones stably expressing a RARbeta transgene under control of the human beta-actin promoter [HeLa(RARbeta)] were established and analyzed for transgene-mediated growth alterations in vitro and in vivo. Anchorage-independent growth of the HeLa(RARbeta) lines was indistinguishable from that of control cells in the absence of RA, but strongly impaired after RA treatment. Reduced tumor growth of HeLa(RARbeta) clones was associated with high RARbeta protein levels. Somatic cell fusion experiments revealed that the loss of ligand inducibility of RARbeta gene expression in HeLa cells cannot be complemented by fusion with other cervical cancer cell lines. Our data indicate, firstly, that RARbeta is a negative regulator of tumor cell growth and, secondly, that cancer-associated defects in RARbeta gene expression are caused by stable, non-complementable silencing mechanisms.
Geisen
C
C
Deutsches Krebsforschungszentrum, Angewandte Tumorvirologie, Heidelberg, Germany.
Denk
C
C
Küpper
J H
JH
Schwarz
E
E
D000818:Animals; D002455:Cell Division / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006367:HeLa Cells; D006801:Humans; D006822:Hybrid Cells; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D018168:Receptors, Retinoic Acid / Q000096:biosynthesis / Q000235:genetics*; D014162:Transfection; D002583:Uterine Cervical Neoplasms / Q000628:therapy*
D018168:Receptors, Retinoic Acid; C082925:retinoic acid receptor beta