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A detailed molecular description of human bladder carcinogenesis is lacking. Only a limited set of genes and potential tumor markers have been analyzed in this tumor type. Hence, additional markers which would permit accurate prediction of the invasive potential of bladder tumors would have considerable clinical significance and might provide new insights into the cascade of events leading to bladder carcinoma. Our recent studies have suggested that a special "regulatory RNA" (that is, an RNA lacking a definable protein product) named H19 indeed constitutes such a marker. Of interest, the H19 gene, which encodes the H19 RNA, is one of a small group of imprinted genes; some imprinted genes are thought to have a decisive role in embryonal human cancers. H19 RNA was originally defined as a fetal murine liver messenger-like RNA with no protein product and without a known function. Our group subsequently showed that H19 mRNA is also expressed in various organs of the human fetus, as well as in the placenta. We also demonstrated that H19 RNA is absent from adult human tissues, but intriguingly, reappears in a selected set of human tumors; hence, H19 RNA is an oncofetal RNA. Of particular note, H19 RNA is strikingly abundant, constituting between 5-10% of the total mRNA of the cells in which it appears. This proposal seeks to build upon these observations with the following specific aims: 1) to quantitate H19 and IGF2 mRNA levels in a large number of human bladder carcinoma biopsy specimens using a novel computerized in situ hybridization method in order to correlate H19 and IGF2 RNA levels with clinical stages of the tumor; 2) to determine whether there is monoallelic versus biallelic expression of H19 and IGF2 in the same human bladder carcinoma biopsy specimens, and to assess their methylation status; 3) to assess the functions of the H19 and IGF2 gene products in human bladder carcinoma cell lines and primary cultures via sense and antisense H19 gene transfer experiments; and 4) to establish a murine in vivo model for bladder carcinoma in which the dynamics of H19 and IGF2 expression and tumor progression can be correlated. These studies will shed light on the hypotheses that: (i) H19 is an oncofetal gene which is a marker of the tumorigenic and especially invasive potential of bladder carcinoma; and (ii) H19 provides a novel and clinically useful diagnostic marker for prognosticating human bladder carcinoma.
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