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Cancer Research 67, 6599, July 15, 2007. doi: 10.1158/0008-5472.CAN-06-4802
© 2007 American Association for Cancer Research
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Molecular Biology, Pathobiology, and Genetics

MUTYH-Null Mice Are Susceptible to Spontaneous and Oxidative Stress–Induced Intestinal Tumorigenesis

Katsumi Sakamoto1,2, Yohei Tominaga4, Kazumi Yamauchi1, Yoshimichi Nakatsu1, Kunihiko Sakumi4, Kaoru Yoshiyama5, Akinori Egashira1, Shinobu Kura1, Takashi Yao3, Masazumi Tsuneyoshi3, Hisaji Maki5, Yusaku Nakabeppu4 and Teruhisa Tsuzuki1

1 Departments of Medical Biophysics and Radiation Biology, 2 Clinical Radiology, and 3 Anatomic Pathology, Graduate School of Medical Sciences, and 4 Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Maidashi Higashi-ku, Fukuoka, Japan; and 5 Department of Molecular Biology, Graduate School of Biological Sciences, Nara Institute of Science and Technology, Takayama, Ikoma, Nara, Japan

Requests for reprints: Yusaku Nakabeppu, Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. Phone: 81-92-642-6800; Fax: 81-92-642-6791; E-mail: yusaku{at}bioreg.kyushu-u.ac.jp.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
MUTYH is a mammalian DNA glycosylase that initiates base excision repair by excising adenine opposite 8-oxoguanine and 2-hydroxyadenine opposite guanine, thereby preventing G:C to T:A transversion caused by oxidative stress. Recently, biallelic germ-line mutations of MUTYH have been found in patients predisposed to a recessive form of hereditary multiple colorectal adenoma and carcinoma with an increased incidence of G:C to T:A somatic mutations in the APC gene. In the present study, a systematic histologic examination revealed that more spontaneous tumors had developed in MUTYH-null mice (72 of 121; 59.5%) than in the wild type (38 of 109; 34.9%). The increased incidence of intestinal tumors in MUTYH-null mice (11 tumors in 10 of 121 mice) was statistically significant compared with the wild type (no intestinal tumors in 109 mice). Two adenomas and seven adenocarcinomas were observed in the small intestines, and two adenomas but no carcinomas were found in the colons. In MUTYH-null mice treated with KBrO3, the occurrence of small intestinal tumors dramatically increased. The mean number of polyps induced in the small intestines of these mice was 61.88 (males, 72.75; females, 51.00), whereas it was 0.85 (males, 0.50; females, 1.00) in wild-type mice. The tumors developed predominantly in the duodenum and in the upper region of the (jejunum) small intestines. We conclude that MUTYH suppresses spontaneous tumorigenesis in mammals, thus providing experimental evidence for the association between biallelic germ-line MUTYH mutations and a recessive form of human hereditary colorectal adenoma and carcinoma. [Cancer Res 2007;67(14):6599–604]


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Cellular DNA and its precursor nucleotides are at high risk of being oxidized by reactive oxygen species, which are inevitably generated by normal metabolic functions, such as mitochondrial respiration, or by exposure to environmental agents. Among the various types of oxidative lesions found in DNA, 8-oxoguanine (8-oxoG) and 2-hydroxyadenine are highly mutagenic if not repaired. During DNA replication, 8-oxoG can form a pair with adenine or cytosine, whereas 2-hydroxyadenine can pair with guanine or thymine, causing a G:C to T:A transversion in the next round of replication (1, 2). Three enzymes, MTH1, OGG1, and MUTYH, have been shown to play important roles in counteracting the buildup of 8-oxoG in cellular genomes of human and rodent cells. MTH1 hydrolyzes 8-oxo-dGTP and 2-OH-dATP to their monophosphate forms and pyrophosphates, thereby preventing the incorporation of 8-oxo-dGTP and 2-OH-dATP into DNA during replication (3). OGG1, an 8-oxoG DNA glycosylase, excises 8-oxoG opposite cytosine in DNA (4–6), which minimizes the formation of a premutagenic base pair, A:8-oxoG. MUTYH (also known as MYH), a mammalian homologue of Escherichia coli MutY, is a DNA glycosylase which has been shown to excise 2-hydroxyadenine incorporated opposite guanine and adenine incorporated opposite 8-oxoG (7–10). As a result, MUTYH is considered to play an important role in preventing G:C to T:A transversion in mammalian cells.

Recently, biallelic germ-line mutations of MUTYH have been identified in patients with an autosomal recessive form of hereditary multiple colorectal adenoma and carcinoma (11–14). Classic familial adenomatous polyposis is an autosomal dominant inherited genetic disease associated with an increased predisposition to multiple colorectal adenomatous polyps and colorectal cancers. Familial adenomatous polyposis is caused by germ-line mutations in the adenomatous polyposis coli (APC) gene, and somatic APC mutations are found in most sporadic colorectal adenomas and carcinomas. Tumors from patients carrying biallelic germ-line mutations of MUTYH exhibit a significantly increased incidence of G:C to T:A somatic mutations in the APC gene (11, 12).

Mutant mouse lines defective in any one of the Mth1, Ogg1, and Mutyh genes have been generated (15–19). MTH1-null mice were found to have increased susceptibility to spontaneous tumorigenesis in comparison with wild-type mice (19). Overall spontaneous mutation frequencies in MTH1-null mice were not significantly higher than those of the wild-type mice; however, in mice with a mismatch repair–deficient background, a significant increase in the frequency of G:C to T:A transversions was observed (20). OGG1-null mice showed a greater accumulation of 8-oxoG in genomic DNA and an elevated frequency of spontaneous mutations (16–18). Using the gpt transgene to analyze spontaneous mutations, it was found that, compared with wild-type mice, the mutation frequency in livers of OGG1-null mice showed a 2.3-fold increase at the age of 16 to 20 weeks, and G:C to T:A transversions were predominantly detected (17). We previously revealed that OGG1 deficiency predisposed mice to spontaneous lung adenoma and carcinoma (18). We also showed that MUTYH-null embryonic stem cells exhibit a 2-fold increase in spontaneous mutation rates as compared with parental cell lines, indicating that a defect in MUTYH causes an increased frequency of spontaneous mutation in mammals (15). Xie et al. (21) generated MUTYH-null mice and reported observing no significant difference in the tumor incidence in these mice, as compared with the control littermates, in a study using a relatively small number of animals. They also showed that deficiencies in both Mutyh and Ogg1 genes predispose these mice to develop tumors, predominantly lung and ovarian types, as well as lymphomas, and, to a lesser extent, gastrointestinal tract tumors.

These studies of mutant mice showed that MTH1, OGG1, and MUTYH are involved in the avoidance of oxidative DNA damage–related mutagenesis as well as in the prevention of tumor development. However, it remained unclear whether harboring a MUTYH defect is in itself sufficient to predispose animals to develop tumors. To evaluate the role of MUTYH in tumorigenesis, we generated MUTYH-null mice and carried out spontaneous tumorigenesis experiments with a large cohort of animals. We found that the MUTYH-null mice do indeed have an increased susceptibility to spontaneous tumorigenesis, which is especially evident in the intestine. Furthermore, administration of KBrO3, a strong oxidative reagent, dramatically induced small intestinal tumors in the MUTYH-null mice.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
MUTYH-null mice. Generation of a heterozygous Mutyh+/– mouse embryonic stem cell line has previously been described (14). Mutant embryonic stem cells were injected into C57BL/6J blastocysts, and the resulting germ-line chimeras were bred with C57BL/6J mice to generate heterozygous mutant F1 mice. Germ-line transmission of mutant Mutyh alleles to F1 mice was confirmed by Southern blot analyses. F1 mice were backcrossed with C57BL/6J mice for two generations to generate N3 Mutyh+/– mice. All mice used in the spontaneous tumorigenesis experiments were obtained by intercrossing of the N3 mice. The genotyping of offspring was done using a PCR-based method. Primer pairs used to detect wild-type and mutant alleles were as follows: 5'-CCTGGTGCAAAGGCCTGA-3' as the forward Mutyh primer and 5'-GCAGTAGACACAGCTGCAT-3' as the reverse Mutyh primer for the wild-type allele, and the reverse primer and 5'-CTACGCATCGGTAATGAAGG-3' as the forward neo primer for the mutated allele. All animals were maintained in an air-conditioned specific pathogen-free (SPF) room with a time-controlled lighting system. The handling and sacrificing of all animals were carried out in accordance with nationally prescribed guidelines, and ethical approval for the studies was granted by the Animal Care and Use Committee of Kyushu University.

Analysis of spontaneous tumorigenesis. Intercrossing N3 heterozygotes (Mutyh+/–) yielded 602 progeny: 146 (24.3%) wild-type, 301 (50.0%) heterozygous, and 155 (25.7%) MUTYH-null mice. Transmission of the MUTYH-null allele was according to a ratio expected for a Mendelian distribution, suggesting that having a MUTYH deficiency does not lead to any deleterious effect in mammalian development. Wild-type and MUTYH-null mice were kept under SPF conditions for 18 months and then sacrificed. All organs and tissues were removed and fixed in 4% formaldehyde fixative. Portions of the tumors and tumor-suspicious tissues were processed for paraffin embedding. The prepared sections were stained with H&E and then pathologically diagnosed. Statistical analyses were done using Fisher's exact probability test.

Analysis of oxidative stress–induced tumorigenesis. Mutyh+/– heterozygous mice were backcrossed with C57BL/6J for more than 10 generations to establish a congenic line with a C57BL/6J background. The congenic Mutyh+/– mice were inbred to generate congenic wild-type and MUTYH-null mice. To analyze oxidative stress–induced tumorigenesis, KBrO3 was given to 4-week-old wild-type and MUTYH-null mice in their drinking water at a concentration of 2 g/L for 16 weeks. Body weights and water consumption were monitored weekly. At 20 weeks of age, all mice were sacrificed and intestines were removed and fixed in 4% formaldehyde fixative. Tumor formation in the intestines was analyzed under a dissecting microscope.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Spontaneous tumorigenesis in MUTYH-null mice. To examine whether MUTYH deficiency alone results in increased tumorigenesis in mammals, we investigated a large cohort of wild-type and MUTYH-null mice maintained under SPF conditions for an extended period to identify any spontaneous tumor development. We did not observe any increased mortality in MUTYH-null mice during this period. At the age of 18 months, 109 wild-type (61 males, 48 females) and 121 MUTYH-null (62 males, 59 females) littermates were sacrificed and tissue specimens were examined. A systematic histologic examination revealed that more tumors had developed in the MUTYH-null mice (72 of 121; 59.5%) than in the wild type [38 of 109 (34.9%); Table 1 ; P < 0.001, Fisher's exact test].


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  		Table 1. Tumor spectra

 
The spectrum of tumor types observed in the MUTYH-null mice was distinctly different from that seen in the wild type (Table 1). The most striking difference was an increased incidence in intestinal tumors in the MUTYH-null mice, with a frequency that was five times greater than in the wild type. In addition, four adenomas and seven carcinomas were detected in the intestines of the MUTYH-null mice, whereas no intestinal tumors of these types were found in the 109 wild-type mice. The increased incidence of the tumors in MUTYH-null mice (11 tumors in 10 of 121 mice) was statistically significant compared with the wild-type (P < 0.001, Fisher's exact test; Table 1; Fig. 1 ). Two adenomas and seven carcinomas were observed in the small intestines, and two adenomas but no carcinomas were found in the colons (Fig. 1; Table 2 ). The carcinoma in mouse no. 106 had developed from an adenoma (Fig. 1D). Interestingly, one MUTYH-null mouse (no. 255) developed two carcinomas in the small intestine, indicating that a multiple formation of carcinomas can develop in the intestine of a MUTYH-null mouse.


Figure 1
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  		Figure 1. Disruption of the Mutyh gene predisposes mice to intestinal adenoma and carcinoma. A, adenoma in the small intestine of no. 66 mouse: a tiny flat lesion with a central depression composed of adenomatous tubules with high-grade dysplasia. Macroscopic (right) and microscopic (left) views are shown. Bar, 1 mm (left); 500 µm (right). B, adenoma in the large intestine of no. 287 mouse: a tiny polypoid lesion composed of adenomatous tubules with low-grade dysplasia. Macroscopic (right) and microscopic (left) views are shown. No stromal invasion is evident. Bar, 0.5 cm (left); 1 mm (right). C, adenocarcinoma in the small intestine of no. 223 mouse: the erosive tumor involves the entire thickness of the intestinal wall and protrudes from it. A low-power view (left) and a high-power view (right) of the boxed area indicated on the left are shown. The tumor is a well to moderately differentiated adenocarcinoma. Bar, 1 mm (left); 100 µm (right). D, adenocarcinoma in adenoma in the small intestine of no. 106 mouse: the polypoid tumor protrudes into the intestinal lumen and is restricted to the mucosa. A low-power view (left) and a high-power view (right) of the boxed area on the left are shown. The tumor is mostly composed of adenomatous tubules with severe nuclear atypia but also contains a focal solid component. No stromal invasion can be seen. The tumor can be diagnosed as an adenocarcinoma arising in a tubular adenoma. Bar, 1 mm (left); 100 µm (right).

 

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  		Table 2. Intestinal epithelial neoplasms in MUTYH-null mice

 
As shown in Table 1, more angiogenic tumors were formed in MUTYH-null mice than in the wild type. The incidence of hepatic hemangiomas and splenic angiosarcomas in the MUTYH-null mice was significantly increased compared with the wild type [Table 1: P < 0.01, 15 versus 3; P < 0.02, 7 versus 0 (Fisher's exact test)]. Our present data clearly indicated that the presence of a MUTYH deficiency is in itself sufficient to predispose mice to develop adenomas/carcinomas in their intestines as well as other types of tumors, consistent with the association between an inherited human MUTYH gene defect and the formation of colorectal tumors.

Oxidative stress–induced tumorigenesis. Potassium bromate (KBrO3) is known to induce the oxidation of DNA in rats and mice (22, 23) and it has been recognized as a renal carcinogen in rats (24, 25). Mutation analyses of mice with the rpsL transgene as a reporter gene revealed that a 4-week administration of KBrO3 at a dose of 2 g/L in drinking water dramatically increased the incidence of G:C to T:A transversions in the small intestines of MUTYH-null mice.6 These observations indicated that the administration of KBrO3 to mice through their drinking water is a useful method for eliciting oxidative stress in the small intestine.

To examine whether oxidative stress increases intestinal tumorigenesis in MUTYH-null mice, congenic wild-type [15 (6 males, 9 females)] and MUTYH-null [16 (8 males, 8 females)] mice were given drinking water containing KBrO3 (2 g/L) for 16 weeks. KBrO3 treatment seemed to cause a similar slowdown in the rate of body weight increase in both groups of animals during the experimental period (data not shown). In the MUTYH-null mice treated with KBrO3, the occurrence of small intestinal tumors dramatically increased (Fig. 2 ; Table 3 ). The mean number of polyps induced in the small intestines of these mice was 61.88 (males, 72.75; females, 51.00), whereas it was 0.85 (males, 0.50; females, 1.00) in wild-type mice. The tumors developed predominantly in the duodenum and in the upper region of the (jejunum) small intestines (Fig. 2A and B). Figure 2C shows a section of one of these tumors formed in MUTYH-null mice. No polyps were observed in the intestines of untreated wild-type or MUTYH-null mice. We thus confirmed that MUTYH-null mice are highly susceptible to oxidative stress–induced tumorigenesis in the intestine compared with wild-type mice. It is noteworthy that Mutyh+/– heterozygous mice treated with KBrO3 in the same protocol exhibited a very low number of polyps in the intestines (11 polyps per 4 female mice; mean, 2.75), confirming that MUTYH deficiency is recessive.


Figure 2
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  		Figure 2. KBrO3-induced tumors in the small intestine of MUTYH-null mice. A, proximal regions of the small intestines of KBrO3-treated mice. +/+, wild type; –/–, MUTYH-null mice. Multiple polyp formations can be observed in the KBrO3-treated MUTYH-null mice. B, a high-power view of the polyps in a KBrO3-treated MUTYH-null female mouse. C, a section of the KBrO3-induced polyp stained with H&E. Bars, 1 cm (A); 1 mm (B); 100 µm (C).

 

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  		Table 3. KBrO3-induced intestinal tumors

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In the present study, we showed that MUTYH-null mice develop various types of spontaneous tumors, including intestinal adenomas and carcinomas, and that oxidative stress further enhances tumor formation in the small intestines of these animals. We conclude that MUTYH suppresses spontaneous tumorigenesis in mammals, thereby providing experimental evidence for the association between biallelic germ-line mutations of MUTYH and a recessive form of hereditary colorectal adenoma and carcinoma in humans.

It has been reported that there was no significant difference in the tumor incidence between wild-type and MUTYH-null mice based on pathologic examinations of littermates sacrificed between 15 and 17 months [19.2% (5 of 26 Mutyh+/+ and Mutyh+/– mice); 18.8% (3 of 16 Mutyh–/– mice); ref. 21]. Thus, the authors concluded that solely having a MUTYH deficiency is not sufficient to predispose mice to tumors within 17 months, similar to having an OGG1 deficiency (21). In the present study, we examined 121 MUTYH-null mice at the age of 18 months and found that 59.5% (72 of 121) of these mice had developed certain types of tumors, including 10 mice with a total of 4 adenomas and 7 adenocarcinomas in their intestinal tracts, whereas 34.9% (38 of 109) of the wild-type mice had developed similar tumors but no adenomas or carcinomas in their intestines. The total tumor incidence in the wild-type mice was 1.8-fold higher in this study than in the previous study, suggesting that there may be a difference in the genetic background of these mice or in their environment, in addition to that due to the larger size of cohort. Moreover, the age of mice examined would also contribute to the difference because we found no histologic abnormalities in 12-month-old mice but a significant number of tumors in 18-month-old mice (19).

It has been reported that the incidence of G:C to T:A transversions increases significantly in the intestines of older mice compared with younger mice (26, 27). Because this transversion is mainly caused by oxidative DNA damage such as 8-oxoG lesions, these observations indicate that the mutations caused by this damage would tend to accumulate in the intestines during the course of aging. Xie et al. (21) showed that MUTYH/OGG1 double-deficient mice predominantly developed lung and ovarian tumors as well as lymphomas. They also showed that 8.6% of MUTYH/OGG1 double-deficient mice exhibited adenomas/carcinomas in their gastrointestinal tracts, which were never observed in wild-type mice. We and others previously reported that there was little difference in the number of intestinal tumors in wild-type and OGG1-null mice, although an OGG1 deficiency resulted in 8-oxoG buildup in genomic DNA and an elevated mutation frequency in the latter (16–18). Thus, the development of intestinal tumors in MUTYH/OGG1 double-deficient mice supports the notion that having a MUTYH deficiency does indeed increase susceptibility to intestinal tumorigenesis regardless of the genetic background or environmental factors.

We previously reported that OGG1-deficient mice developed more skin tumors than wild-type or heterozygous littermates after chronic UVB exposure, indicating that increased oxidative stress significantly enhances their susceptibility to tumorigenesis compared with wild-type mice. To examine whether increased oxidative stress also elevates the intestinal tumor susceptibility of MUTYH-null mice, MUTYH-null and wild-type mice were treated with KBrO3, a known oxidative renal carcinogen associated with 8-oxoG accumulation (24, 25). P.o. administration of KBrO3 at a dose of 2 g/L in drinking water dramatically increased the formation of intestinal polyps in MUTYH-null mice. The number of polyps formed in MUTYH-null mice reached 23 to 111 per animal, similar to the malignant capacity of multiple colorectal adenomatous polyposis in MUTYH-deficient patients. These results clearly indicate that the inherited defect in MUTYH, combined with the oxidative stress elicited in the gastrointestinal tract, leads to tumor development in this tissue.

In 16 weeks of KBrO3 administration to MUTYH-null mice, we did not observe any tumors other than in tissues of the intestinal tract, indicating that a MUTYH deficiency causes a selective increase in susceptibility to intestinal tumors. Moreover, it has been reported that OGG1-null mice chronically exposed to KBrO3 developed no tumor in kidney, lung, liver, spleen, thymus, stomach, or intestine despite an extensive accumulation of 8-oxoG in kidney DNA (28). It has been established that KBrO3 is carcinogenic in rat kidney, thyroid, and mesothelium and is a renal carcinogen in the male mouse (24, 25); however, tumor formation in these animals requires continuous p.o. administration of KBrO3 for periods longer than 100 weeks. We propose here that p.o. administration of KBrO3 to MUTYH-null mice is a most useful experimental model for examining multiple colorectal adenomatous polyposis in MUTYH-deficient patients because it requires the shortest experimental period and has the advantage of specificity with respect to various genetic defects.

We recently found that a massive buildup of 8-oxoG in nuclear or mitochondrial genomes resulted in cell death, with the accumulation in either genome of single-strand breaks, and that this outcome was suppressed by MUTYH knockdown by small interfering RNA, indicating that repair initiated by MUTYH led to the accumulation of single-strand breaks, and induced cell death.7 Taken together with the findings of the present study, these observations indicate that a loss in MUTYH function may result in avoidance of cell death under oxidative stress and may simultaneously increase mutations in proto-oncogenes or tumor suppressor genes due to the accumulation of 8-oxoG, thereby promoting tumorigenesis.

Our present data showed for the first time that having a MUTYH deficiency statistically increases susceptibility to intestinal adenoma/carcinoma in mice, and this susceptibility is further enhanced by oxidative stress, thereby experimentally confirming the association between biallelic germ-line mutations of MUTYH and a recessive form of hereditary colorectal adenoma and carcinoma in humans. In view of these results, MUTYH-null mice are considered to be a useful animal model for examining MUTYH deficiency–related hereditary colorectal adenoma and carcinoma in humans as well as for studies on the prevention of intestinal tumors.


   Acknowledgments
 
Grant support: CREST; the Japan Science and Technology Agency; the Ministry of Education, Culture, Sports, Science, and Technology; the Ministry of Health, Labor and Welfare of Japan; the Japan Society for the Promotion of Science; and Kyushu University Interdisciplinary Programs in Education and Projects in Research Development.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

We thank Drs. Ping Xu, Daisuke Tsuchimoto, and Ayumi Asaeda for their helpful discussions; Setsuko Kitamura, Naomi Adachi, Akemi Matsuyama, and Keiko Aiura for their technical assistance; and Dr. William Campbell for comments on the manuscript.


   Footnotes
 
Note: Current address for K. Yamauchi: Low Dose Radiation Effect Research Project, National Institute of Radiological Sciences, Chiba 263-8555, Japan. Current address for K. Yoshiyama: Section of Plant Biology, UC Davis, 1 Shield Avenue, Davis, CA 95616. Current address for A. Egashira: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.

6 K. Yamauchi et al, submitted. Back

7 Oka et al.,submitted. Back

Received 1/ 2/07. Revised 4/ 4/07. Accepted 5/ 4/07.


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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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