The goals of this work are divided into three interrelated parts: a) the analysis of proto-oncogene expression during liver regeneration and its relationships with the triggering and progression of the growth response; b) analysis of the regulation of proto-oncogene expression in liver epithelial cells obtained from preneoplastic livers and an assessment of the tumorigenic and developmental potential of these cells; c) studies of the cellular distribution and oncodevelopmental regulation of multiple alphafetoprotein (AFP) RNA sequences which may serve as markers for the identification of cell lineages in liver carcinogenesis. Our work has shown that the expression of c-myc, c-Ha-ras, c-Ki-ras and p53 proto-oncogenes occurs in a transient and regulated manner during liver regeneration. We now propose to study in detail the regulation of the biphasic expression of c-myc during liver regeneration in rats and attempt to determine the relationships between c-myc expression and other events which take place almost immediately after partial hepatectomy. To guide these studies, we present a working hypothesis in which hepatocyte replication during liver regeneration is divided into competence and progression phases, each associated with specific proto-oncogenes and growth factors. We suggest further that the progression phase of liver regeneration might be regulated by autocrine mechanisms and that the growth factors which may participate in these self-regulatory mechanisms might be synthesized by the regenerating liver and by liver cells in culture which are adapted to grow and multiply in low serum media. We also propose to investigate the tumorigenic and developmental potential of cultured liver epithelial cells in which the expression of some proto-oncogenes is no longer linked to the cell cycle and to determine the relevance of these in vitro findings for certain models of hepatocarcinogenesis. The third goal of the proposal is based on our recent studies of multiple alphafetoprotein (AFP) RNA sequences in rat liver which indicate that a subpopulation of nonparenchymal cells in normal rat liver contains the mature AFP mRNA transcript. We suggest that this subpopulation of nonparenchymal cells might be the source for the small amounts of AFP synthesized in normal adult rat liver and constitute the proposed but as yet uncharacterized facultative stem cell compartment.
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