Fenton reaction-induced renal carcinogenesis in Mutyh-deficient mice exhibits less chromosomal aberrations than the rat model.
Guang Hua LiShinya AkatsukaShan Hwu ChewLi JiangTakahiro NishiyamaAkihiko SakamotoTakashi TakahashiMitsuru FutakuchiHiromu SuzukiKunihiko SakumiYusaku NakabeppuShinya ToyokuniPublished in: Pathology international (2017)
Oxidative stress including iron excess has been associated with carcinogenesis. The level of 8-oxoguanine, a major oxidatively modified base in DNA, is maintained very low by three distinct enzymes, encoded by OGG1, MUTYH and MTH1. Germline biallelic inactivation of MUTYH represents a familial cancer syndrome called MUTYH-associated polyposis. Here, we used Mutyh-deficient mice to evaluate renal carcinogenesis induced by ferric nitrilotriacetate (Fe-NTA). Although the C57BL/6 background is cancer-resistant, a repeated intraperitoneal administration of Fe-NTA induced a high incidence of renal cell carcinoma (RCC; 26.7%) in Mutyh-deficient mice in comparison to wild-type mice (7.1%). Fe-NTA treatment also induced renal malignant lymphoma, which did not occur without the Fe-NTA treatment in both the genotypes. Renal tumor-free survival after Fe-NTA treatment was marginally different (P = 0.157) between the two genotypes. Array-based comparative genome hybridization analyses revealed, in RCC, the loss of heterozygosity in chromosomes 4 and 12 without p16INKA inactivation; these results were confirmed by a methylation analysis and showed no significant difference between the genotypes. Lymphomas showed a preference for genomic amplifications. Dlk1 inactivation by promoter methylation may be involved in carcinogenesis in both tumors. Fe-NTA-induced murine RCCs revealed significantly less genomic aberrations than those in rats, demonstrating a marked species difference.
Keyphrases
- diabetic rats
- high glucose
- renal cell carcinoma
- oxidative stress
- copy number
- dna methylation
- drug induced
- wild type
- gene expression
- papillary thyroid
- type diabetes
- single molecule
- squamous cell carcinoma
- dna damage
- combination therapy
- endothelial cells
- hydrogen peroxide
- single cell
- aqueous solution
- skeletal muscle
- autism spectrum disorder
- intellectual disability
- young adults
- insulin resistance
- stress induced
- heat shock
- lymph node metastasis
- circulating tumor
- circulating tumor cells