The broad, long term objective of this proposal is to understand the potential role of retinoic acid (RA) in the treatment of hepatoma.
The specific aims of the proposed experiments are to: 1) study how RA regulates the phenotype of hepatoma cells, 2) determine the manner in which alpha-fetoprotein (AFP) and albumin (A1b) genes are regulated during the phenotypical change, 3) assess the regulatory mechanisms, and 4) elucidate the roles of retinoic acid receptor (RAR) in the regulatory process, and during hepatocarcinogenesis. Our preliminary data indicated that in Morris hepatoma McA-RH 8994 cell line, RA enhanced the expression of AFP and A1b genes which are characteristic of hepatocyte differentiation. To understand the involved regulatory mechanism, the AFP mRNA half life and transcriptional rate of AFP gene will be examined by pulse chase analysis of 3H uridine incorporation and nuclear run off assay in RA treated or untreated McA-RH 8994 cells. The functional elements of AFP gene will be examined by transient transfection assay using various kinds of AFP-chloramphenicol acetyltransferase (AFP-CAT) constructs. The 5'-flanking rat AFP genomic elements implicating RA responsiveness will be determined. Gel shift assay will be employed to examine the in vitro binding property of the element and the presence of binding proteins. RARbeta gene was inactivated and resistant to RA in Morris hepatoma McA-RH 8994 and 7777 cell lines. This aberrant expression of a normal gene may relate to carcinogenesis and provides a model system for studying the role of RARbeta in transformation. The cis-acting element within the promoter region of RARbeta gene will be isolated from genomic libraries of normal rat liver and hepatoma cells. The RARbeta gene sequence will be examined and the presence of mutation will be identified. The trans-acting factors which are putatively involved in control of RARbeta gene expression will also be studied by gel shift assay. The results of this study will help us in understanding the roles of RAR in regulating liver specific gene expression and in hepatocarcinogenesis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29CA053596-04
Application #
2095426
Study Section
Metabolic Pathology Study Section (MEP)
Project Start
1991-08-15
Project End
1996-05-31
Budget Start
1994-06-01
Budget End
1995-05-31
Support Year
4
Fiscal Year
1994
Total Cost
Indirect Cost
City
Torrance
State
CA
Country
United States
Zip Code
90502
Liu, Hui-Xin; Rocha, Clarissa Santos; Dandekar, Satya et al. (2016) Functional analysis of the relationship between intestinal microbiota and the expression of hepatic genes and pathways during the course of liver regeneration. J Hepatol 64:641-50
Liu, Hui-Xin; Hu, Ying; Wan, Yu-Jui Yvonne (2016) Microbiota and bile acid profiles in retinoic acid-primed mice that exhibit accelerated liver regeneration. Oncotarget 7:1096-106
Hu, Ying; Chau, Thinh; Liu, Hui-Xin et al. (2015) Bile acids regulate nuclear receptor (Nur77) expression and intracellular location to control proliferation and apoptosis. Mol Cancer Res 13:281-92
Liu, Hui-Xin; Keane, Ryan; Sheng, Lili et al. (2015) Implications of microbiota and bile acid in liver injury and regeneration. J Hepatol 63:1502-10
Liu, Hui-Xin; Hu, Ying; French, Samuel W et al. (2015) Forced expression of fibroblast growth factor 21 reverses the sustained impairment of liver regeneration in hPPAR?(PAC) mice due to dysregulated bile acid synthesis. Oncotarget 6:9686-700
Yang, Fan; Hu, Ying; Liu, Hui-Xin et al. (2015) MiR-22-silenced cyclin A expression in colon and liver cancer cells is regulated by bile acid receptor. J Biol Chem 290:6507-15
Yang, Fan; He, Yuqi; Liu, Hui-Xin et al. (2014) All-trans retinoic acid regulates hepatic bile acid homeostasis. Biochem Pharmacol 91:483-9
Liu, Hui-Xin; Ly, Irene; Hu, Ying et al. (2014) Retinoic acid regulates cell cycle genes and accelerates normal mouse liver regeneration. Biochem Pharmacol 91:256-65
Tsuei, Jessica; Chau, Thinh; Mills, David et al. (2014) Bile acid dysregulation, gut dysbiosis, and gastrointestinal cancer. Exp Biol Med (Maywood) 239:1489-504
He, Yuqi; Tsuei, Jessica; Wan, Yu-Jui Yvonne (2014) Biological functional annotation of retinoic acid alpha and beta in mouse liver based on genome-wide binding. Am J Physiol Gastrointest Liver Physiol 307:G205-18

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