Carcinogenesis Advance Access originally published online on January 10, 2006
Carcinogenesis 2006 27(5):1068-1073; doi:10.1093/carcin/bgi327
© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
IL-10 deficiency leads to somatic mutations in a model of IBD
Yuichirou Sato *,
Seiichi Takahashi,
Yoshitaka Kinouchi,
Manabu Shiraki,
Katsuya Endo,
Yoshifumi Matsumura,
Yoichi Kakuta,
Masaki Tosa,
Atsuhiro Motida,
Hiroko Abe,
Go Imai,
Hiroshi Yokoyama,
Eiki Nomura,
Kenichi Negoro,
Sho Takagi,
Hiroyuki Aihara,
Ken-ichi Masumura 1,
Takehiko Nohmi 1 and
Tooru Shimosegawa
Department of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan and 1 Division of Genetics and Mutagenesis, National Institute of Health Sciences, Tokyo, Japan
* To whom correspondence should be addressed. E-mail: ysatou{at}int3.med.tohoku.ac.jp
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Abstract
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Individuals with inflammatory bowel disease (IBD) are at increased
risk of developing gastrointestinal cancer. Here, we have tested
the possibility that chronic inflammation could trigger mutations.
For this, we have used IL-10-deficient (
IL-10–/–)
mice, which spontaneously develop intestinal inflammation, in
combination with a transgenic gpt gene and
red/
gam gene (
gpt+IL-10–/–),
which is a well-characterized mutation reporter locus. The total
mutation frequency in the colon of
gpt+IL-10–/– mice was about five times higher than that in normal
gpt+IL-10+/+ mice. In the particular case of G:C to A:T transitions, the
frequency of mutations in
gpt+IL-10–/– mice was
4.1 times higher than that in control mice. Interestingly, the
frequency of small deletions and insertions was also strikingly
increased (
10 times). The majority of the deletion or insertion
mutations were observed in the monotonous base runs or adjacent
repeats of short tandem sequences. In contrast, the frequency
of large deletions, detected by loss of the Spi marker present
in the
red/
gam transgene, was similar among the mouse strains.
Finally, as a control, the mutation frequency in non-inflamed
tissues, such as the liver, were similar between
gpt+IL-10–/– mice and
gpt+IL-10+/+ mice. Our data demonstrate that the chronic
inflammatory environment in the colon promotes the generation
of mutations.
Abbreviations: FAP, familial adenomatous polyposis; Spi, sensitive to P2 interference; 6-TG, 6-thioguanine; TGF-ß1, transforming growth factor-ß1; UC, ulcerative colitis
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Introduction
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Ulcerative colitis (UC) and Crohn's disease are chronic inflammatory
bowel diseases (IBD) associated with a high risk of gastrointestinal
cancer. This risk begins to increase
10 years after the onset
of the disease and increases with the extent and duration of
the inflammatory process (
1). Gastrointestinal cancer in individuals
with IBD appears to develop through a multistep process involving
genomic instability and the progressive accumulation of genomic
alterations (
2–
4). However, it has not been fully elucidated
what kinds of genomic mutations are critical for tumorigenesis.
It has been reported that interleukin-10 knockout (IL-10–/–) mice spontaneously develop intestinal inflammation characterized by discontinuous transmural lesions affecting the small and large intestine and by the dysregulated production of proinflammatory cytokines (5). Inflammatory changes first appear in the cecum and ascending and transverse colon of such 3-weeks-old mice, and thereafter spread to the remainder of the colon and rectum (5). Prolonged disease with transmural lesions and a high incidence of colorectal adenocarcinomas are also observed. However, in germ-free conditions, IL-10–/– mice never develop inflammation nor adenocarcinomas (5).
Recently, a new transgenic mouse line, gpt delta (gpt+), was established to facilitate the detection and analysis of mutations in vivo (6). The striking feature of gpt+ mice is their ability to reveal deletions and point mutations. About 80 copies of lambda EG10 shuttle vector DNA carrying the red/gam gene of lambda phage and the gpt gene of Escherichia coli are integrated in chromosome 17. Relatively large deletions in the red/gam gene are individually identified by sensitive to P2 interference (Spi)– selection, and base substitutions or small frameshifts in the gpt gene are individually identified by 6-thioguanine (6-TG) selection, respectively (6,7).
IL-10–/– mice and gpt+ mice are of C57BL/6J background, although the vendors of these mice were each different. Therefore, the recombinant mice, gpt+IL-10–/–, are much like IL-10–/– mice or gpt+ mice. In this paper, to elucidate the role of inflammation on the accumulation of mutations in colonic DNA, we analyzed gpt+IL-10–/– and gpt+IL-10+/+ mice by 6-TG selection, Spi– selection and direct sequencing method. Then we compared the patterns and frequencies of mutations in colonic DNA.
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Materials and methods
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Mice
The experimental protocol was approved by the committee of animal
research of the Tohoku University School of Medicine, Sendai,
Japan.
IL-10–/– mice were obtained from Jackson
Laboratories (Bar Harbor, ME) and
gpt+ mice were obtained from
SLC (Hamamatsu, Japan). To investigate the role of inflammation
in the mutagenicity, the recombinant mice,
gpt+IL-10–/–,
were established by crossing
gpt+ with
IL-10–/– mice. Mice were housed in plastic cages in an environmentally
controlled room (24°C, 12 h/12 h light/dark cycle). Chow
(Nippon Nosan, Yokohama, Japan) and tap water were given
ad libitum during the experiment. At 15 weeks or 40 weeks of age,
eight
gpt+IL-10–/– mice and eight
gpt+IL-10+/+ mice
(four 15-weeks mice and four 40-weeks mice, for each type, all
siblings) were weighed and killed by cervical dislocation. The
colon was removed and divided into proximal and distal portions.
DNA isolation and in vitro packaging
Genomic DNA was extracted from the colon using RecoverEaseTM DNA Isolation Kit (Stratagene, La Jolla, CA) according to the manufacture's recommendations. Lambda EG10 phages were rescued from genomic DNA by the in vitro packaging method using Transpack® Packaging Extract (Stratagene) following the instructions.
Mutation assay and sequencing analysis
The 6-TG selection was carried out as described previously (6). DNA sequencing of the gpt gene was performed with BigDye® Terminator v3.1 Cycle Sequencing Kit (Applied Biosystems, Foster City, CA). The PCR primers of the gpt gene were primer-1 (5'-TACCACTTTATCCCGCGTCAGG-3') and primer-2 (5'-ACAGGGTTTCGCTCAGGTTTGC-3') (6).
The sequencing primers were primer-A (5'-GAGGCAGTGCGTAAAAAGAC-3') and primer-B (5'-CTATTGTAACCCGCCTGAAG-3').
The Spi– selection was performed as described previously (7). Phage lysates of the recovered Spi– mutants were used as templates for PCR analysis. The PCR primers were primer-001 (5'-CTCTCCTTTGATGCGAATGCCAGC-3'), primer-002 (5'-GGAGTAATTATGCGGAACAGAATCATGCCAGC-3'), primer-005 (5'-CGTGGTCTGAGTGTGTTACAGAGG-3'), primer-006 (5'-GTTATGCGTTGTTCCATACAACCTCC-3') and primer-012 (5'-CGGTCGAGGGACCTAATAACTTCG-3'). The appropriate primers for DNA sequencing were selected on the basis of the results of the aforementioned PCR analysis (7).
Statistical analysis
Data were expressed as mean ± standard error (SE). Differences between two groups were tested for statistical significance using Student's t-test. A P-value < 0.05 denoted the presence of a statistically significant difference.
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Results
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At 15 weeks of age, the average weight of the
gpt+IL-10–/– mice was 23.7 ± 3.1 g, and that of the
gpt+IL-10+/+ mice
was 28.1 ± 2.1 g (
P < 0.05). Two of the four
gpt+IL-10–/– mice and none of the
gpt+IL-10+/+ mice showed bloody stools
or prolapse of the anus. At 40 weeks of age, the average weight
of the
gpt+IL-10–/– mice was 26.2 ± 4.7 g,
and that of the
gpt+IL-10+/+ mice was 30.6 ± 3.0 g (
P < 0.05). One of the four
gpt+IL-10–/– mice and
none of the
gpt+IL-10+/+ mice showed bloody stools or prolapse
of the anus. The excised colons from the
gpt+IL-10–/– mice were slightly thick and edematous compared with those of
the
gpt+IL-10+/+ mice. As reported previously (
5), the
gpt+IL-10–/– mice developed inflammation in SPF conditions.
The 6-TG mutant frequency in the total colon of the gpt+IL-10–/– mice was 13.4x 10–6, which was about five times higher than that of the gpt+IL-10+/+ mice (2.8 x 10–6) (Figure 1). In both the proximal and distal colon of the gpt+IL-10–/– mice, the 6-TG mutant frequencies were significantly higher than those of the gpt+IL-10+/+ mice (11.8 x 10–6 versus 3.3 x 10–6, P = 0.004, 15.0 x 10–6 versus 2.3 x 10–6, P = 0.01, respectively).
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Fig. 1. Mutation frequency of 6-TG selection in the total colon of gpt+IL-10–/– mice (filled square) and gpt+IL-10+/+ mice (unfilled square). The mutation frequencies of 6-TG selection in the total colon of gpt+IL-10–/– mice were significantly higher than those in the total colon of gpt+IL-10+/+ mice. P < 0.05, statistically significant difference versus gpt+IL-10+/+. Bars represent mean values and SE.
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At 15 weeks of age, the 6-TG mutant frequency of the total colon
in the
gpt+IL-10–/– mice was 11.6
x 10
–6,
which was about five times higher than that of the
gpt+IL-10+/+ mice (2.3
x 10
–6) (
Figure 2). In the sequencing analysis
of the
gpt+IL-10–/– mice, 51.5% of the mutants were
single base substitutions (G:C to A:T transition, 14.7%; A:T
to G:C transition, 1.5%; G:C to T:A transversion, 7.4%; G:C
to C:G transversion, 14.7%; A:T to T:A transversion, 8.8%; A:T
to C:G transversion, 4.4%), 35.3% were 1 bp deletions and 13.2%
were 1–3 bp insertions. In contrast, 91.6% of the mutants
in the
gpt+IL-10+/+ mice were single base substitutions (G:C
to A:T transition, 33.3%; A:T to G:C transition, 16.7%; G:C
to T:A transversion, 33.3%; G:C to C:G transversion, 8.3%),
8.3% were 1 bp deletions and none were insertions or complex
mutants (
Table I). The frequency of transition mutations in
the colitis mice was 1.7 times higher than that of the control
mice, the transversion was 4.4 times higher and the 1 bp deletion
was 21.6 times higher (
Table I). Furthermore, 13.2% of the mutants
in the colitis mice were insertions, in marked contrast with
the result that insertions were not observed in the control
mice. In the
gpt+IL-10–/– mice, 93.8% of the 1 bp
deletions and insertions occurred in the monotonous base runs
or adjacent repeats of short tandem sequences (
Table II). In
both the proximal and distal colon of the
gpt+IL-10–/– mice, the 6-TG mutant frequencies were higher than those of
the
gpt+IL-10+/+ mice (11.1
x 10
–6 versus 2.8
x 10
–6,
12.1
x 10
–6 versus 1.7
x 10
–6, respectively), but
the differences did not reach significance.
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Fig. 2. Mutation frequency of 6-TG selection in the total colon of gpt+IL-10–/– mice and gpt+IL-10+/+ mice (filled square, 15 weeks; unfilled square, 40 weeks). The mutation frequencies of 6-TG selection in the total colon of gpt+IL-10–/– mice were significantly higher than those in the total colon of gpt+IL-10+/+ mice, at 15 weeks or 40 weeks of age. The mutation frequencies of 6-TG selection in the total colon of 40 weeks gpt+IL-10–/– mice were not significantly higher than those in the total colon of 15 weeks gpt+IL-10–/– mice. P < 0.05, statistically significant difference versus gpt+IL-10+/+. Bars represent mean values and SE.
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At 40 weeks of age, the 6-TG mutant frequency of the total colon
in the
gpt+IL-10–/– mice was 15.2
x 10
–6,
which was about five times higher than that of the
gpt+IL-10+/+ mice (3.3
x 10
–6) (
Figure 2). In the sequencing analysis
of the
gpt+IL-10–/– mice, 84.1% of the mutants were
single base substitutions (G:C to A:T transition, 46%; A:T to
G:C transition, 11.1%; G:C to T:A transversion, 19%; G:C to
C:G transversion, 1.6%; A:T to T:A transversion, 3.2%; A:T to
C:G transversion, 3.2%), 9.5% were 1–3 bp deletions and
6.4% were 1–2 bp insertions. In contrast, 93.4% of the
mutants in the
gpt+IL-10+/+ mice were single base substitutions
(G:C to A:T transition, 52.2%; A:T to G:C transition, 2.2%;
G:C to T:A transversion, 32.6%; G:C to C:G transversion, 6.5%),
4.3% were 1 bp deletions and 2.2% were 2 bp insertions (
Table III).
The frequency of transition mutations in the colitis mice was
1.8 times higher than that of the control mice; the transversions
were 1.3 times higher. In the transitions, the frequency of
G:C to A:T in the
gpt+IL-10–/– mice was 4.1 times
higher than that of the control mice, and 4.1 times higher than
that of the 15-weeks
gpt+IL-10–/– mice. Furthermore,
the small deletions of the
gpt+IL-10–/– mice were
10.3 times higher (
Table III), and the small insertions were
13.4 times higher than those of the control mice. In the
gpt+IL-10–/– mice, 90% of the deletions and insertions occurred in the monotonous
base runs or adjacent repeats of short tandem sequences (
Table IV).
In both the proximal and distal colon of the
gpt+IL-10–/– mice, the 6-TG mutant frequencies were higher than those of
the
gpt+IL-10+/+ mice (12.4
x 10
–6 versus 3.9
x 10
–6,
17.9
x 10
–6 versus 2.8
x 10
–6, respectively), but
the differences did not reach significance.
The Spi
– mutant frequency of the total colon in the
gpt+IL10–/– mice was not significantly different from the
gpt+IL10+/+ mice
(15 and 40 weeks; 1.5
x 10
–6 versus 1.4
x 10
–6,
P = 0.9, 15 weeks; 1.1
x 10
–6 versus 0.8
x 10
–6,
P = 0.4, 40 weeks; 1.8
x 10
–6 versus 2.0
x 10
–6,
P = 0.8) (
Figures 3 and
4). In sequencing analysis, the pattern
of the mutations was identical in both types of mice (
Table V,
VI).
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Fig. 3. Mutation frequency of Spi– selection in the colon of gpt+IL-10–/– mice (filled square) and gpt+IL-10+/+ mice (unfilled square). The mutation frequencies of Spi– selection in the total colon of gpt+IL-10–/– mice were not significantly higher than those in the total colon of gpt+IL-10+/+ mice. P < 0.05, statistically significant difference versus gpt+IL-10+/+. Bars represent mean values and SE.
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Fig. 4. Mutation frequency of Spi– selection in the total colon of gpt+IL-10–/– mice and gpt+IL-10+/+ mice (filled square, 15 weeks; unfilled square, 40 weeks). The mutation frequencies of Spi– selection in the total colon of gpt+IL-10–/– mice were not significantly higher than those in the total colon of gpt+IL-10+/+ mice, at 15 weeks or 40 weeks of age. The mutation frequencies of Spi– selection in the total colon of 40-weeks gpt+IL-10–/– mice were not significantly higher than those in the total colon of 15-weeks gpt+IL-10–/– mice. P < 0.05, statistically significant difference versus gpt+IL-10+/+. Bars represent mean values and SE.
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Discussion
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Assaying mutations using transgenic mice is a powerful tool
for obtaining information about the pattern and frequency of
inflammation-induced mutations. A feature of the assay using
gpt+ mice is the incorporation of two distinct selections for
detecting different types of mutations: Spi
– selection
for relatively large deletions and 6-TG selection for base substitutions
and small frameshifts (
6,
7). In this study, we examined the
in vivo mutation spectrum induced by chronic inflammation by
comparing
gpt+IL-10–/– mice with
gpt+IL-10+/+ mice.
The APC gene is a tumor suppressor gene, and carcinomas from familial adenomatous polyposis (FAP) patients or non-FAP patients exhibit a high frequency of mutations in the APC gene. In FAP tumors or sporadic tumors, small deletions and insertions of the APC gene are most frequent (8). In the present study, small deletions and insertions strikingly increased in the gpt+IL-10–/– mice. Regarding the point mutations of the APC gene in FAP tumors or sporadic tumors, G:C to A:T transitions were most prevalent (8), which was similar to the gpt+IL-10–/– mice. The frequency of G:C to A:T transitions in the 40-weeks gpt+IL-10–/– mice was 4.1 times higher than that of the 40-weeks control mice, and 4.1 times higher than that of the 15-weeks gpt+IL-10–/– mice. It is suggested that G:C to A:T transitions in the inflamed colon accumulate with time. Furthermore, point mutations and allelic loss of the APC gene have been reported in UC-related dysplasia and cancer, although there is a controversy about the frequencies (9). In that report, five of the seven APC mutations were frameshifts and two were point mutations. Of the five frameshifts, four were deletions, and three of these occurred within homocopolymer tracts and one was a 4 bp direct repeat (AAGA). On this point, the mutation spectrum of our result was similar to that of APC mutations.
The p53 gene is a member of a family of tumor suppressor genes, and inactivation of this protein plays a crucial role in the emergence and further progression of a multitude of human malignancies, including carcinoma of the colon and rectum. It was reported that the p53 mutation can be detected in early colitic cancer and dysplasia of UC patients' colon, in contrast to sporadic colon cancer (10). Previous studies demonstrated that over 50% of UC samples had increased frequency of G:C to A:T transition mutations of the p53 gene (10–14). In our study, it is suggested that G:C to A:T transitions in the inflamed colon accumulate with time. Therefore, our data may reflect some mechanisms responsible for the p53 mutations of UC.
Microsatellite instability (MI) has been reported not only in colitic cancers but also in dysplasias and even in non-dysplastic inflamed mucosa, though the frequencies were not so great (4). It seems that MI is related to insufficient repair of replication errors. Transforming growth factor (TGF)-ß1 inhibits the differentiation of some cells of mesodermal origin and potently inhibits the proliferation of epithelial cells. Conversely, cells that lose responsiveness to TGF-ß1 may show uncontrolled growth and become tumorigenic. Previous studies showed that mutational inactivation of the polydeoxyadenine (poly A) microsatellite tract within TGF-ß1 receptor type II (TGF-ß1RII) occurs early and in a subset of UC neoplasms, and that the majority of reported mutations were 1- or 2-base deletions or insertions (15). In our study, small deletions and insertions had greatly increased, and 90% of the 1 bp deletions and insertions occurred, just like microsatellite sequences and poly A tract, in the monotonous base runs or adjacent repeats of short tandem sequences. In a previous study on DNA polymerase 
, Fortune et al. (16) suggested that strand slippage during replication may be a primary source of insertion and deletion mutagenesis in eukaryotic genomes. Therefore, it may be suggested that the 1 bp deletions and insertions in the gpt+IL-10–/– mice increased because of a replication error following repeated mucosal injury and regeneration in the chronic inflammation.
Shin reported that the predominant spontaneous events observed in a mouse kidney epithelial cell line (K435) were G:C to C:G transversion mutations and small events observed in mutant cells isolated from the hydrogen peroxide and ionizing radiation exposed cells were also predominantly G:C to C:G transversions. They suggested that the mechanism did not include a classical deficiency in mismatch repair and the initial formation of C:C or G:G mispairs provided the most plausible explanation (17). At 15 weeks of age, the frequency of G:C to C:G in the colitis mice was most frequent and nine times higher than that of the control mice. The mutation mechanism, which did not include a classical deficiency in mismatch repair in the report on K435, may partially contribute to our data in gpt+IL-10–/– mice.
UC is a chronic inflammatory disease that produces reactive oxygen and nitrogen species and increases the risk of colorectal cancer. Reactive oxygen and nitrogen species produced by inflammatory cells can interact with key genes involved in carcinogenic pathways such as p53, DNA mismatch repair genes and even DNA base excision-repair genes (18,19). In previous studies, a positive correlation was observed between higher inducible nitric oxide synthase (iNOS) activity and increased p53 G:C to A:T transitions in inflamed colon and colon cancer (11,14). The deamination of 5-methylcytosine has been argued to be a major mechanism for the induction of G:C to A:T transitions at CpG dinucleotides in DNA (20). Nitric oxide produced during inflammation may cause both deamination and oxidative damage to DNA. It has been reported that IL-10–/– mice had increased damage scores and granulocyte infiltration concurrent with increased mRNA and protein synthesis for iNOS in intestinal tissues (21). These data suggest that oxidative stress and DNA adducts may drive the accumulation of mutations in the colon of the gpt+IL10–/– mice. In a previous paper on chronic Helicobacter pylori infections, it was suggested that the Helicobacter-infected mice exhibited severe gastritis and a high level of iNOS messenger RNA expression and A:T to C:G and G:C to T:A transversions had greatly increased (22). In our study, the frequency of G:C to T:A transversions in the 40-weeks gpt+IL-10–/– mice was 2.6 times higher than that of the 40-weeks control mice, and 3.3 times higher than that of the 15-weeks gpt+IL-10–/– mice. On this point, the mutation spectrum of our result was similar to that of the paper on chronic Helicobacter pylori infections. On the contrary, our data suggested that G:C to A:T transitions in the inflamed colon accumulate with time unlike that suggested in the paper on chronic Helicobacter pylori infections. We think that the difference between our result and the paper on chronic Helicobacter pylori infections is due to differences of organs, duration of inflammation or methods of mutation assay.
It was necessary to confirm that the mutant frequency in non-inflamed organs of IL10–/– mice did not increase. We analyzed livers in the 40-weeks mice as non-inflamed organ in order to clear whether the effect observed is associated to inflammation or IL-10 deficiency. At 40 weeks of age, the 6-TG mutant frequency in the liver of the gpt+IL10–/– mice was 2.4 x 10–6, which was not significantly different from the gpt+IL10+/+ mice (1.7 x 10–6). The livers of the gpt+IL10–/– mice were not inflamed, macroscopically. In consequence, it was suggested that the effect observed was associated to inflammation.
In our data, several types of mutations increased, and it is suggested that multiple mechanisms have a role in carcinogenesis of inflamed colon. In the mutations of the gpt+IL10–/– mice, short deletions or insertions in the monotonous base runs or adjacent repeats of short tandem sequences and G:C to A:T transitions were striking mutations. Therefore, biochemical support may be useful for proving that replication error and oxidative stress mainly play a role in carcinogenesis in the inflamed colon.
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Acknowledgments
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We are deeply grateful to Prof. Tetsuya Ono for his appropriate
advices on mouse experiments. This work was supported in part
by a grant-in-aid from the Japan Society for the Promotion of
Science, and by the Kurokawa Cancer Foundation.
Conflict of Interest Statement: None declared.
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Received July 29, 2005;
revised September 5, 2005;
accepted December 20, 2005.
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Abstract
Introduction