Premium
Toward the Molecular Identification of Afr2 , A Gene Implicated in Liver Cancer
Author(s) -
Grimes Zach,
SeipeltThiemann Rebecca,
Paterson Martha,
Spear Brett
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.593.9
Subject(s) - carcinogenesis , biology , liver cancer , gene , alpha fetoprotein , regulator , liver regeneration , genetics , microarray analysis techniques , cancer research , cancer , gene expression , microbiology and biotechnology , hepatocellular carcinoma , regeneration (biology)
In humans, liver cancer is the 5 th leading cause of cancer death in men, and the 9 th in women. Alpha‐fetoprotein (AFP) is a fetal protein that is active during liver development and hepatocellular differentiation. After the development stage, AFP is transcriptionally silenced due to the action of alpha‐fetoprotein regulator 1 ( Afr1 ). However, during liver regeneration and tumorigenesis, AFP expression is reactivated by the action of α‐fetoprotein regulator 2 ( Afr2 ). It is this observation that has led to the use of AFP levels as a diagnostic marker for liver cancers. Two strains of mice differ in their ability to develop liver tumors and reactivate expression of AFP. C3H/HeJ mice develop liver tumors and express high AFP levels in the regenerating liver while C57/BL6 do neither. Heterozygote mice express an intermediate level of AFP and show reduced tumorigenesis. Recombination mapping showed that Afr2 is located on chromosome 2. The purpose of this study was to use a refined genetic map and existing gene variation and expression data to identify Afr2 candidate genes. First, genetic variation for the region of interest was compared using genomic data from both the Mouse Genome International and the Sanger Institute. Gene ontology and domain identification databases were used to gain information about the genes that showed variation between strains. Several genes with the potential to regulate gene expression were identified. Second, microarray studies of control and reactivated liver in both strains were compared for genes that were upregulated in C3H/HeJ reactivated liver and found in the select region of chromosome 2. Through the combinatorial analysis of these lists, four genes were identified as candidates. Finally, studies are underway to investigate whether any of these candidate genes is able to activate transcription of a reporter gene cloned near the reported AFR2‐binding region. Identification of Afr2 may lead to better therapeutics for treatment of liver cancer due to its pivotal role in directing liver‐specific gene expression.