Abnormality in Wnt Signaling is Causatively Associated with Oxidative Stress-Induced Intestinal Tumorigenesis in MUTYH-Null Mice

Isoda, Takuro; Nakatsu, Yoshimichi; Yamauchi, K.; Piao, Jingshu; Yao, Takashi; Honda, Hiroshi; Nakabeppu, Yusaku; Tsuzuki, Teruhisa

doi:10.7150/ijbs.9241

Cited by 18 publications

(22 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In most of these lesions, accumulation of βcatenin and cyclin D1 in the nuclei of atypical epithelial cells was observed. These features were consistent with the characteristics of the small intestinal tumors observed in experimental models of human hereditary colorectal cancer using Mutyh −/− or Msh2 −/− mice treated with KBrO 3 [8][9][10]. Thus, the neoplastic proliferative lesions observed in this study may have arisen from oxidative stress-related mechanisms.…”

Section: Discussionsupporting

confidence: 89%

“…Because neither preneoplastic nor neoplastic lesions were observed at all doses of KBrO 3 in Nrf2 +/+ mice, it is likely that the lack of Nrf2 was involved in the development of oxidative stress-associated neoplastic proliferative lesions in the small intestine. However, the incidences and multiplicities of tumors in the small intestine have been reported to be dramatically increased in Mutyh −/− or Msh2 −/− mice treated with KBrO 3 for 16 weeks [8][9][10]. KBrO 3 is able to increase 8-OHdG in DNA at the carcinogenic target site [22].…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, G:C-A:T and A:T-G:C transition mutations and G:C-C:G and G:C-T:A transversion mutations at glycogen synthase kinase 3β (GSK3β)-mediated phosphorylation sites in Ctnnb1 were found in the induced-tumors in Msh2deficient mice treated with KBrO 3 , consistent with the mutation sites and their spectra found in patient with HNPCC. Therefore, Mutyh −/− and Msh2 −/− mice treated with KBrO 3 are useful experimental models for investigation of human hereditary colorectal cancer, despite the differences in the target organs [8][9][10]. Likewise, these data indicate that examination of small intestinal tumors using oxidative stress-related gene-deficient mice administered KBrO 3 will provide valuable information concerning the role of the target gene in colorectal tumorigenesis in humans.…”

Section: Introductionmentioning

confidence: 98%

See 2 more Smart Citations

Effects of Nrf2 silencing on oxidative stress‐associated intestinal carcinogenesis in mice

et al. 2016

View full text Add to dashboard Cite

To assess the risk of colorectal cancer in humans with inactivation of NRF2, Nrf2‐proficient (Nrf2 +/+) and ‐deficient (Nrf2 −/−) mice were exposed to potassium bromate (KBrO3) at concentrations of 750 or 1500 ppm for 52 weeks. Neoplastic proliferative lesions were observed in the small intestine and exhibited accumulations of β‐catenin and cyclin D1. The lesions had characteristics similar to those in experimental models of human hereditary colorectal cancer. An additional 13‐week study was performed to examine the role of Nrf2 in the effects of oxidative stress. Significant increase in combined incidences of preneoplastic and neoplastic lesions in Nrf2 −/− mice administered high‐dose KBrO3. In the short‐term study, although 8‐hydroxydeoxyguanosine (8‐OHdG) levels in the epithelial DNA of Nrf2 −/− mice at the high dose were significantly lower than those of the corresponding Nrf2 +/+ mice, the difference was very small. mRNA levels of Nrf2‐regulated genes were increased in Nrf2 +/+ mice. Overexpression of cyclooxygenase 2 (COX2) and increased numbers of proliferating cell nuclear antigen (PCNA)‐positive cells in the jejunal crypts were observed in Nrf2 −/− mice administered high‐dose KBrO3. Overall, these data suggested that individuals having single‐nucleotide polymorphisms in NRF2 may have a risk of colorectal cancer to some extent.

show abstract

Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

See 1 more Smart Citation

Effects of Nrf2 silencing on oxidative stress‐associated intestinal carcinogenesis in mice

et al. 2016

View full text Add to dashboard Cite

show abstract

“…We showed that chronic oxidative stress experimentally induced by KBrO 3 resulted in multiple tumour formation in the small intestines of Mutyh-null mice (16,17). We also reported that mismatch repair-deficient mice show a susceptibility to KBrO 3 -induced intestinal carcinogenesis (18).…”

mentioning

confidence: 81%

BUBR1 Insufficiency in Mice Increases Their Sensitivity to Oxidative Stress

Matsuda

Matsumoto

Honma

et al. 2016

Self Cite

View full text Add to dashboard Cite

Abstract. Background Budding uninhibited by benzimidazole-related 1 (BUBR1) is a core component of the spindle assembly checkpoint, which monitors whether or not sister chromatids are correctly separated during mitosis. Dysfunction of BUBR1 provokes chromosomal instability, thus leading to aneuploidy (1). Baker et al. generated mice with BubR1 gene mutation with various decreased expression levels of BubR1 due to combinations of wild-type, null, and hypomorphic BubR1 alleles (2-4). The mice that were homogeneous for the hypomorphic allele showed an early onset of aging phenotypes, such as short lifespan, cachectic dwarfism, lordokyphosis, cataracts, loss of subcutaneous fat, impaired wound healing, and decreased vascular wall elasticity (2,4). Chromosomal instability, such as aneuploidy, frequently occurred in the cells derived from hypomorphic BubR1 mice, but few mice spontaneously died of cancer under normal conditions (2). Notably, Dai et al. reported that mice with the wild-type allele and null allele were susceptible to carcinogen-induced adenocarcinoma in the lungs and intestines (5), suggesting that aneuploidy caused by the decreased expression of BUBR1 might enhance carcinogeninduced tumorigenesis in mammals.We recently generated a new strain of hypomorphic BubR1 mice in which the expression of BUBR1 is reduced to 20% of the normal level. These low BUBR1-expressing mutant mice (termed BubR1 L/L mice) do not display apparent abnormalities, such as progeria, infertility, shortened lifespan, or structural anomaly in the tissue during growth and development, under normal conditions. Therefore, BubR1 L/L mice are particularly suitable for investigating the precise roles of BUBR1 in age-related diseases, including cancer. Using these mice, we previously demonstrated that decreased expression of BUBR1 completely inhibits intimal hyperplasia after carotid ligation by suppressing the 769 Τhis article is freely accessible online.

show abstract

“…First, we compared the antitumor effects of celecoxib and DM‐celecoxib on the human colon cancer cell lines HCT‐116 and DLD‐1, in which the Wnt/β‐catenin signaling pathway is constitutively active, and analyzed downstream mediators of the aforementioned pathway. Subsequently, we examined the effect of these compounds on intestinal cancer development in Mutyh ‐deficient ( Mutyh −/− ) mice, which lack the mammalian DNA glycosylase MutY homolog (MUTYH) and develop multiple intestinal cancers in the presence of oxidative stress (likely caused by over‐activation of the Wnt/β‐catenin signaling pathway) …”

mentioning

confidence: 99%

Celecoxib and 2,5‐dimethylcelecoxib inhibit intestinal cancer growth by suppressing the Wnt/β‐catenin signaling pathway

et al. 2016

Self Cite

View full text Add to dashboard Cite

We previously reported that celecoxib, a selective COX‐2 inhibitor, strongly inhibited human colon cancer cell proliferation by suppressing the Wnt/β‐catenin signaling pathway. 2,5‐Dimethylcelecoxib (DM‐celecoxib), a celecoxib analog that does not inhibit COX‐2, has also been reported to have an antitumor effect. In the present study, we elucidated whether DM‐celecoxib inhibits intestinal cancer growth, and its underlying mechanism of action. First, we compared the effect of DM‐celecoxib with that of celecoxib on the human colon cancer cell lines HCT‐116 and DLD‐1. 2,5‐Dimethylcelecoxib suppressed cell proliferation and inhibited T‐cell factor 7‐like 2 expression with almost the same strength as celecoxib. 2,5‐Dimethylcelecoxib also inhibited the T‐cell factor‐dependent transcription activity and suppressed the expression of Wnt/β‐catenin target gene products cyclin D1 and survivin. Subsequently, we compared the in vivo effects of celecoxib and DM‐celecoxib using the Mutyh −/− mouse model, in which oxidative stress induces multiple intestinal carcinomas. Serum concentrations of orally administered celecoxib and DM‐celecoxib elevated to the levels enough to suppress cancer cell proliferation. Repeated treatment with celecoxib and DM‐celecoxib markedly reduced the number and size of the carcinomas without showing toxicity. These results suggest that the central mechanism for the anticancer effect of celecoxib derivatives is the suppression of the Wnt/β‐catenin signaling pathway but not the inhibition of COX‐2, and that DM‐celecoxib might be a better lead compound candidate than celecoxib for the development of novel anticancer drugs.

show abstract

Abnormality in Wnt Signaling is Causatively Associated with Oxidative Stress-Induced Intestinal Tumorigenesis in MUTYH-Null Mice

Cited by 18 publications

References 36 publications

Effects of Nrf2 silencing on oxidative stress‐associated intestinal carcinogenesis in mice

Effects of Nrf2 silencing on oxidative stress‐associated intestinal carcinogenesis in mice

BUBR1 Insufficiency in Mice Increases Their Sensitivity to Oxidative Stress

Celecoxib and 2,5‐dimethylcelecoxib inhibit intestinal cancer growth by suppressing the Wnt/β‐catenin signaling pathway

Contact Info

Product

Resources

About