Mild inflammation accelerates colon carcinogenesis in Mlh1-deficient mice.
OBJECTIVE
Inflammatory bowel disease, which frequently accompanies silencing of Mlh1, plays a key role in the pathogenesis of colorectal cancer. The interaction between inflammation and mismatch repair deficiency, however, remains unclear. The aim of this study was to determine the effect of inflammation on colorectal carcinogenesis in Mlh1-deficient mice.


METHODS
Inflammatory colitis was induced by treatment with 1% dextran sodium sulfate (DSS) in drinking water for 1 week in Mlh1 knockout (Mlh1(-/-)), Mlh1 heterozygous (Mlh1(+/-)) and wild-type (Mlh1(+/+)) mice at 10 weeks of age. The development of colon tumors was followed for a subsequent 15 weeks and the tumors were analyzed immunohistochemically for the expression and localization of iNOS, beta-catenin and p53.


RESULTS
Male and female Mlh1(-/-) mice with DSS showed a 63 and 44% incidence of tumors, respectively, whereas no tumors were observed in Mlh1(+/-) and Mlh1(+/+) mice. The mice without DSS treatment did not develop any tumors regardless of the genotype. While aberrant expression of beta-catenin was not detected in colonic neoplasms, p53 and iNOS expression was increased in 100 and 77%, respectively. These immunohistochemical changes were consistent with those of human colon cancers associated with ulcerative colitis.


CONCLUSIONS
Our results indicate that Mlh1 deficiency strongly accelerates colon carcinogenesis when combined with inflammation. Thus the cells with Mlh1 deficiency, either inherently or colitis associated, may be at an increased risk of cancer under inflammatory conditions.
Taniguchi
Kazuki
K
Surgical Oncology, Tokyo Medical and Dental University, Tokyo, Japan.
Kakinuma
Shizuko
S
Tokairin
Yutaka
Y
Arai
Masami
M
Kohno
Hiroyuki
H
Wakabayashi
Keiji
K
Imaoka
Tatsuhiko
T
Ito
Eisaku
E
Koike
Morio
M
Uetake
Hiroyuki
H
Nishimura
Mayumi
M
Yamauchi
Kazumi
K
Sugihara
Ken-ichi
K
Shimada
Yoshiya
Y
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000925:Anticoagulants / Q000633:toxicity; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D003092:Colitis / Q000139:chemically induced / Q000150:complications*; D003110:Colonic Neoplasms / Q000209:etiology* / Q000378:metabolism; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D005260:Female; D015994:Incidence; D007249:Inflammation / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D000925:Anticoagulants; D002352:Carrier Proteins; C501485:Mlh1 protein, mouse; D009687:Nuclear Proteins; D016264:Dextran Sulfate; D000070957:MutL Protein Homolog 1