UP-REGULATION OF HOXC6, HOXD1, AND HOXD8 HOMEOBOX GENE-EXPRESSION IN HUMAN NEUROBLASTOMA-CELLS FOLLOWING CHEMICAL INDUCTION OF DIFFERENTIATION

An early event in the pathogenesis of neuroblastoma (NB), a tumor deri ved from embryonal neural crest tissue, appears to be the arrested dif ferentiation of neuroblasts. However, NE cells can be induced to diffe rentiate in vitro with numerous chemicals including retinoic acid (RA) and dibutyryl cyclic AMP (db-cAMP). One family of transcription facto rs, encoded by the homeobox (HOX) genes, plays a crucial role in Droso phila, Xenopus, and mammalian embryonic differentiation and developmen t. We have previously identified six HOX genes (HOXC6, HOXC8, HOXD1, H OXD4, HOXD8, and HOXD9), by a sensitive PCR-based approach, in a cDNA library prepared from the human LA-N-5 NE cell line induced to differe ntiate with RA. In this report, we studied the regulation of these six HOX genes in a series of NE cell lines chemically induced to differen tiate. Untreated NE cells express low or undetectable levels of HOX mR NA, and HOXC8 remains undetectable in the induced cells. However, a si gnificant induction of HOXC6, HOXD1, and HOXD8 expression is seen in t he RA-treated NE cell lines, albeit with different patterns and degree of up-regulation. db-cAMP treatment also induced HOXC6 and HOXD8 expr ession in two of the three NE cell lines analyzed. Low levels of HOXD4 and HOXD9 induction were observed in two and one RA-treated NE cell l ine, respectively. Up-regulation of HOXC6, HOXD1, and HOXD8 expression in human NE cells, chemically induced to differentiate, appears to be associated with maturation toward a differentiated neuronal phenotype .