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. Itis expressed in fetal bladder, down-regulated postnatally and is re-expressed in human bladder carcinoma. This study was designed toinvestigate the dynamics of the expression of H19 in the mouse bladdercarcinoma induced by N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) and itsrelation to stages of neoplastic transformation. BBN was administered tomice in the drinking water for 26-28 weeks. The bladders were removed at5-10 week intervals for histopathological examination and for in situhybridization for H19 RNA, using a 35S- labeled probe. Following BBNadministration expression of H19 first appeared after 5 weeks in the laminapropria adjacent to the basement membrane, concomitant with mucosalhyperplasia. At 11 weeks focal expression was noted in epithelial cells.Invasive carcinomas, of the transitional and squamous sub-types, were seenafter 20 weeks and more of BBN administration. At this stage H19 expressionwas observed in scattered tumor cells, in the connective tissue stroma ofthe tumor and in the lamina propria underlying the remaininghyperplastic/dysplastic mucosa. Abundant expression of H19 was evident infetal bladder but was absent in normal adult bladder. We conclude that,similar to humans, the H19 gene product is an oncofetal RNA molecule in theexperimental mouse model of bladder carcinoma. In this model H19 isexpressed in the connective tissue of the lamina propria prior to itsexpression in epithelial cells, concurrent with preneoplastic changes inthe transitional epithelium of the bladder.