The H19-IGF2 Role in Bladder Cancer Biology and DNA-Based Therapy

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Abstract

The H19-IGF2 locus within the imprinted cluster of the human chromosome 11, has been implicated in a variety of disorders and cancer pre-disposition including bladder cancer. BBN induced bladder cancer model in rats has identified both H19 and IGF2 among differentially expressed genes that are induced in response to carcinogen exposure. In this chapter, the role of both H19 and IGF2 genes in cancer will be handled in general with special focus on bladder cancer. Although IGF2 role in human cancers is relatively well established, recent data from our laboratory and others have just revealed a critical role for H19 RNA in the process of tumorigenicity including that of the bladder. H19 functions as a stress modulator, being induced by hypoxia, and a survival factor that is involved in several fundamental processes of tumorigenesis. Furthermore, we uncovered a molecular mechanism that integrates H19, p53 and HIF1-┙ to hypoxic stress response. Placing the H19 gene product in this deadly circuit undoubtedly will have major impacts in its utility as a target for cancer gene therapy. Regulatory sequences of both H19 and IGF2 have already been used to successfully target expression of a toxic protein, diphtheria toxin A (DT-A), in carcinoma cells in culture, in several xenograft, orthotopic animal models, and in chemically induced BBN model of bladder cancer. In case of H19, it is successfully used in patients with bladder carcinoma for a period of over 5 years and recently a clinical trial phase I/IIa using this therapeutic approach has been successfully completed. It is also successfully used in other types of human cancers but will not be handled in the current chapter. We will discuss also novel approaches, to create a new family of plasmids. In one approach a cytotoxic gene is driven by two different regulatory sequences, selected from the cancerspecific promoters H19, IGF2-P3 and IGF2-P4 carried on a single construct. In a second

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