The dynamics of the imprinted H19 gene expression in the mouse model of bladder carcinoma induced by N-butyl-N-(4-hydroxybutyl)nitrosamine

The imprinted H19 gene product is an oncofetal RNA molecule in humans. It i s expressed in fetal bladder, downregulated postnatally and is re-expressed in human bladder carcinoma. This study was designed to investigate the dyn amics of the expression of H19 in the mouse bladder carcinoma induced by N- butyl-N-(4-hydroxybutyl)nitrosamine (BBN) and its relation to stages of neo plastic transformation. BBN was administered to mice in the drinking water for 26-28 weeks. The bladders were removed at 5-10 week intervals for histo pathological examination and for in situ hybridization for H19 RNA, using a S-35-labeled probe. Following BBN administration expression of H19 first a ppeared after 5 weeks in the lamina propria adjacent to the basement membra ne, concomitant with mucosal hyperplasia, At 11 weeks focal expression was noted in epithelial cells. Invasive carcinomas, of the transitional and squ amous sub-types, were seen after 20 weeks and more of BBN administration. A t this stage H19 expression was observed in scattered tumor cells, in the c onnective tissue stroma of the tumor and in the lamina propria underlying t he remaining hyperplastic/dysplastic mucosa, Abundant expression of H19 was evident in fetal bladder but was absent in normal adult bladder. We conclu de that, similar to humans, the H19 gene product is an oncofetal RNA molecu le in the experimental mouse model of bladder carcinoma. In this model H19 is expressed in the connective tissue of the lamina propria prior to its ex pression in epithelial cells, concurrent with preneoplastic changes in the transitional epithelium of the bladder.