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High incidence of allelic loss on chromosome 5 and inactivation of p15INK4B and p16INK4A tumor suppressor genes in oxystress-induced renal cell carcinoma of rats

Oncogene volume 18, pages 3793–3797 (1999)Cite this article

Abstract

Ferric nitrilotriacetate induces oxidative damage in renal proximal tubules, a consequence of Fenton-like reaction, that ultimately leads to a high incidence of renal cell carcinoma (RCC) in rats. In order to find common genetic alterations in this oxystress-induced carcinogenesis model, RCCs were produced in F1 hybrid rats between Wistar and Long-Evans strains and genomes were screened for loss of heterozygosity (LOH) with microsatellite polymorphic markers by PCR. Five consecutive markers on chromosome 5 (D5Mgh5, D5Mit9, D5Mgh6, D5Mit11 and D5Mit6) showed LOH in ≥40% of the RCCs. As possible candidate tumor suppressor genes on chromosome 5, p15INK4B and p16INK4A were investigated for genetic alteration and aberrant methylation by Southern blot, PCR/SSCP/sequencing and methylation-specific PCR. Genetic alteration (homozygous or hemizygous deletion with or without point mutation) or aberrant methylation were found in 30.7 and 53.8% of the RCC cases, respectively, which was proportionally associated with the histological nuclear grade and metastatic activity. Our data suggest that inactivation of p15 and p16 genes could be one of the major pathways responsible for oxystress-induced carcinogenesis.

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Abbreviations

Fe-NTA:

ferric nitrilotriacetate

HNE:

4-hydroxy-2-nonenal

LOH:

loss of heterozygosity

MDA:

malondialdehyde

PCR:

polymerase chain reaction

RCC:

renal cell carcinoma

ROS:

reactive oxygen species

SSCP:

single-strand conformation polymorphism

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Acknowledgements

This study was supported in part by a Grant-in-Aid from the Japanese Ministry of Education, Science, Sports and Culture, a grant from the Program for Promotion of Basic Research Activities for Innovative Bioscience (PROBRAIN), and a grant from the Japanese Owner's Association. We thank Ms Noriko Shibata for technical assistance and James E Strickland (NCI, NIH, Bethesda, MD, USA) for critical reading of the manuscript.

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  1. Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Sakyo-ku, 606-8501, Kyoto, Japan

    Tomoyuki Tanaka, Yoko Iwasa, Shohei Kondo, Hiroshi Hiai & Shinya Toyokuni

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  1. Tomoyuki Tanaka
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Tanaka, T., Iwasa, Y., Kondo, S. et al. High incidence of allelic loss on chromosome 5 and inactivation of p15INK4B and p16INK4A tumor suppressor genes in oxystress-induced renal cell carcinoma of rats. Oncogene 18, 3793–3797 (1999). https://doi.org/10.1038/sj.onc.1202707

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