The long-term objective of this research is to elucidate and characterize the mechanism(s) responsible for expression of the tumor aldehyde dehydrogenase phenotype appearing during rat hepatocarcinogenesis.
The Specific Aims of this proposal are: (1) To clone and characterize a cDNA and genomic segment of DNA encoding the tumor-associated aldehyde dehydrogenase (ALDH). (2) To compare the structure and activity of the tumor ALDH gene in primary hepatocellular carcinomas, hepatoma cell lines, normal rat liver and other rat tissues. (3) To begin evaluating possible physiological roles for tumor aldehyde dehydrogenase in tumor cell metabolism. (4) To continue the characterization of the structural and functional properties of the various purified normal liver and inducible aldehyde dehydrogenases to understand the interrelationships between the various isozymes. (5) To further develop our in vitro system for studying the genesis and regulation of aldehyde dehydrogenase activity. (6) To continue examining the mechanism of tumor aldehyde dehydrogenase expression during hepatocarcinogenesis by evaluating the ability of an additional tumor induction protocol, without exogeneous initiator exposure, to induce the tumor ALDH phenotype. (7) To begin assessing the generality of tumor aldehyde dehydrogenase expression during chemical carcinogenesis by testing a protocol of urinary bladder carcinogenesis for its ability to induce this novel phenotype. By fulfilling the Specific Aims outlined above, we will have completed the first detailed analysis of the genetic and biochemical changes underlying the generation of a transformation-induced enzyme phenotypic modification. In addition, completion of this work will allow us to define the regulatory mechanisms involved in the expression of this poorly understood enzyme system in normal as well as neoplastic cells.
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