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Effect of the tumor promoter phenobarbital on the pattern of global gene expression in liver of connexin32‐wild‐type and connexin32‐deficient mice
Author(s) -
Stahl Sabine,
Ittrich Carina,
MarxStoelting Philip,
Köhle Christoph,
Ott Thomas,
Buchmann Albrecht,
Schwarz Michael
Publication year - 2005
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.20815
Subject(s) - phenobarbital , biology , promoter , connexin , gene expression , gene , wild type , cancer research , microbiology and biotechnology , endocrinology , genetics , gap junction , mutant , intracellular
Abstract The antiepileptic drug phenobarbital (PB) is used frequently as a model tumor promoter in rodent liver. It is believed to increase the probability of cancer by accelerating the clonal expansion of cells transformed during tumor initiation. The molecular mechanism underlying this process is only partly understood but seems to require the function of connexin32 (Cx32), one of the 2 gap junction proteins expressed in hepatocytes. PB mediates transcriptional activation of various genes in liver but which of these are relevant for tumor promotion is unknown. We have used oligonucleotide microarrays to identify genes differentially modulated in expression by PB in liver of Cx32‐wild‐type and Cx32‐null mice. Mice of both strains were kept on PB containing (0.05%) or control diet for 2 weeks. Total liver RNA was isolated from 3 mice per experimental group and reverse transcribed; cDNAs were hybridized to oligonucleotide microarrays and a gene‐by‐gene linear model was used for statistical analysis of data. Five genes were identified as induced or repressed in untreated Cx32‐null as compared to untreated Cx32‐wild‐type mice. PB affected the expression of 53 genes, of which 13 code for members of Phase‐I/II of drug metabolism, and 12 genes were differentially affected in expression by PB in Cx32‐null as compared to Cx32‐wild‐type mice. Among the differentially affected genes that could be verified by quantitative RT‐PCR or Western analysis were the insulin like growth factor binding protein‐1 , retinol dehydrogenase‐6 and the Y‐chromosomally located gene Dby , among which may be a candidate of relevance for PB‐mediated tumor promotion. © 2005 Wiley‐Liss, Inc.