Gene expression changes induced by the human carcinogen aristolochic acid I in renal and hepatic tissue of mice.
Aristolochic acid (AA) is the causative agent of urothelial tumors associated with AA nephropathy and is also implicated in the development of Balkan endemic nephropathy-associated urothelial tumors. These tumors contain AA-characteristic TP53 mutations. We examined gene expression changes in Hupki (human TP53 knock-in) mice after treatment with aristolochic acid I (AAI) by gavage (5 mg/kg body weight). After 3, 12 and 21 days of treatment gene expression profiles were investigated using Agilent Whole Mouse 44K Genome Oligo Array. Expression profiles were significantly altered by AAI treatment in both target (kidney) and nontarget (liver) tissue. Renal pathology and DNA adduct analysis confirmed kidney as the target tissue of AAI-induced toxicity. Gene ontology for functional analysis revealed that processes related to apoptosis, cell cycle, stress response, immune system, inflammatory response and kidney development were altered in kidney. Canonical pathway analysis indicated Nfκb, aryl hydrocarbon receptor, Tp53 and cell cycle signaling as the most important pathways modulated in kidney. Expression of Nfκb1 and other Nfκb-target genes was confirmed by quantitative real-time PCR (qRT-PCR) and was consistent with the induction of Nfκb1 protein. Myc oncogene, frequently overexpressed in urothelial tumors, was upregulated by AAI on the microarrays and confirmed by qRT-PCR and protein induction. Collectively we found that microarray gene expression analysis is a useful tool to define tissue-specific responses in AAI-induced toxicity. Several genes identified such as TP53, Rb1, Mdm2, Cdkn2a and Myc are frequently affected in human urothelial cancer, and may be valuable prognostic markers in future clinical studies.
Arlt
Volker M
VM
Section of Molecular Carcinogenesis, Institute of Cancer Research, Sutton, Surrey, United Kingdom. volker.arlt@icr.ac.uk
Zuo
Jie
J
Trenz
Kristina
K
Roufosse
Candice A
CA
Lord
Graham M
GM
Nortier
Joelle L
JL
Schmeiser
Heinz H
HH
Hollstein
Monica
M
Phillips
David H
DH
D000818:Animals; D034341:Aristolochic Acids / Q000633:toxicity*; D015153:Blotting, Western; D002273:Carcinogens / Q000633:toxicity; D002453:Cell Cycle / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D034341:Aristolochic Acids; D002273:Carcinogens; D016328:NF-kappa B; D018336:Receptors, Aryl Hydrocarbon; D016159:Tumor Suppressor Protein p53; C000228:aristolochic acid I