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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA023226-17
Application #
3166055
Study Section
Pathology B Study Section (PTHB)
Project Start
1977-08-01
Project End
1991-01-31
Budget Start
1988-02-01
Budget End
1989-01-31
Support Year
17
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Brown University
Department
Type
Schools of Medicine
DUNS #
001785542
City
Providence
State
RI
Country
United States
Zip Code
02912
Wright, Jocelyn H; Johnson, Melissa M; Shimizu-Albergine, Masami et al. (2014) Paracrine activation of hepatic stellate cells in platelet-derived growth factor C transgenic mice: evidence for stromal induction of hepatocellular carcinoma. Int J Cancer 134:778-88
Riehle, Kimberly J; Johnson, Melissa M; Johansson, Fredrik et al. (2014) Tissue-type plasminogen activator is not necessary for platelet-derived growth factor-c activation. Biochim Biophys Acta 1842:318-25
Obayashi, Yoko; Campbell, Jean S; Fausto, Nelson et al. (2013) Impaired lipid accumulation in the liver of Tsc2-heterozygous mice during liver regeneration. Biochem Biophys Res Commun 437:146-50
Riehle, Kimberly J; Haque, Jamil; McMahan, Ryan S et al. (2013) Sustained Glutathione Deficiency Interferes with the Liver Response to TNF-? and Liver Regeneration after Partial Hepatectomy in Mice. J Liver Disease Transplant 1:
McMahan, Ryan S; Riehle, Kimberly J; Fausto, Nelson et al. (2013) A disintegrin and metalloproteinase 17 regulates TNF and TNFR1 levels in inflammation and liver regeneration in mice. Am J Physiol Gastrointest Liver Physiol 305:G25-34
Okada, Hikari; Honda, Masao; Campbell, Jean S et al. (2012) Acyclic retinoid targets platelet-derived growth factor signaling in the prevention of hepatic fibrosis and hepatocellular carcinoma development. Cancer Res 72:4459-71
Riehle, Kimberly J; Dan, Yock Y; Campbell, Jean S et al. (2011) New concepts in liver regeneration. J Gastroenterol Hepatol 26 Suppl 1:203-12
Vaquero, Javier; Campbell, Jean S; Haque, Jamil et al. (2011) Toll-like receptor 4 and myeloid differentiation factor 88 provide mechanistic insights into the cause and effects of interleukin-6 activation in mouse liver regeneration. Hepatology 54:597-608
Campbell, Jean S; Argast, Gretchen M; Yuen, Sebastian Y et al. (2011) Inactivation of p38 MAPK during liver regeneration. Int J Biochem Cell Biol 43:180-8
Wright, Jocelyn H; Modjeski, Kristina L; Bielas, Jason H et al. (2011) A random mutation capture assay to detect genomic point mutations in mouse tissue. Nucleic Acids Res 39:e73

Showing the most recent 10 out of 80 publications