Abstract
Mutations in adenomatous polyposis coli (APC) gene are found in more than 80% of colorectal cancer (CRC) patients. The nuclear transcription factor Nrf2 plays a central role in the regulation of oxidative stress and inflammation. Previously, we have shown that chronic inflammation in Nrf2-/- (Nrf2 knockout; KO) mice resulted in higher expression of inflammatory markers and cytokines, coupled with higher inflammatory damage to the colonic crypt cells, as compared to the Nrf2+/+ (wild type; WT) mice. Induction of mutation in the colon by administration of carcinogen, AOM prior to DSS-induced inflammation resulted in higher tumor incidence and numbers in Nrf2KO mice. These results indicate that Nrf2-dependent inhibition of inflammation appears to be critical in inhibiting mutation-initiated colorectal carcinogenesis. In this study, we aim to investigate if loss of Nrf2 would dose-dependently promote intestinal tumorigenesis in Apcmin/+ mice. To demonstrate the in vivo mechanisms, we constructed both Apc mutated and Nrf2 deficient strain Apcmin/+ mice with C57BL/6 Nrf2KO mice to obtain F1, Apcmin/+;Nrf2+/- and F2, Apcmin/+;Nrf2-/-mice. Nrf2KO decreased the protein expression of antioxidant enzyme NQO1 in Apcmin/+. In contrast, Nrf2KO enhanced the expression of inflammatory markers such as COX-2, cPLA, LTB4 in Apcmin/+. Finally, Nrf2KO resulted in higher level of PCNA and c-Myc expression in intestinal tissue, indicating the deficiency of Nrf2 promotes proliferation of intestinal crypt cells in Apcmin/+. Taken together, our results suggest that Nrf2KO attenuates anti-oxidative stress pathway, induces inflammation, and increases proliferative potential in the intestinal crypts leading to enhanced intestinal carcinogenesis and adenomas in Apcmin/+.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 77-84 |
| Number of pages | 8 |
| Journal | Molecular Carcinogenesis |
| Volume | 53 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 1 2014 |
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All Science Journal Classification (ASJC) codes
- Molecular Biology
- Cancer Research
Keywords
- Apc
- Colon carcinogenesis
- Inflammation
- Nrf2
- Oxidative stress
Cite this
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Nrf2 knockout enhances intestinal tumorigenesis in Apcmin/+ mice due to attenuation of anti-oxidative stress pathway while potentiates inflammation. / Cheung, Ka Lung; Lee, Jong Hun; Khor, Tin Oo; Wu, Tien Yuan; Li, Guang Xun; Chan, Jefferson; Yang, Chung; Kong, Ah-Ng.
In: Molecular Carcinogenesis, Vol. 53, No. 1, 01.01.2014, p. 77-84.Research output: Contribution to journal › Article
TY - JOUR
T1 - Nrf2 knockout enhances intestinal tumorigenesis in Apcmin/+ mice due to attenuation of anti-oxidative stress pathway while potentiates inflammation
AU - Cheung, Ka Lung
AU - Lee, Jong Hun
AU - Khor, Tin Oo
AU - Wu, Tien Yuan
AU - Li, Guang Xun
AU - Chan, Jefferson
AU - Yang, Chung
AU - Kong, Ah-Ng
PY - 2014/1/1
Y1 - 2014/1/1
N2 - Mutations in adenomatous polyposis coli (APC) gene are found in more than 80% of colorectal cancer (CRC) patients. The nuclear transcription factor Nrf2 plays a central role in the regulation of oxidative stress and inflammation. Previously, we have shown that chronic inflammation in Nrf2-/- (Nrf2 knockout; KO) mice resulted in higher expression of inflammatory markers and cytokines, coupled with higher inflammatory damage to the colonic crypt cells, as compared to the Nrf2+/+ (wild type; WT) mice. Induction of mutation in the colon by administration of carcinogen, AOM prior to DSS-induced inflammation resulted in higher tumor incidence and numbers in Nrf2KO mice. These results indicate that Nrf2-dependent inhibition of inflammation appears to be critical in inhibiting mutation-initiated colorectal carcinogenesis. In this study, we aim to investigate if loss of Nrf2 would dose-dependently promote intestinal tumorigenesis in Apcmin/+ mice. To demonstrate the in vivo mechanisms, we constructed both Apc mutated and Nrf2 deficient strain Apcmin/+ mice with C57BL/6 Nrf2KO mice to obtain F1, Apcmin/+;Nrf2+/- and F2, Apcmin/+;Nrf2-/-mice. Nrf2KO decreased the protein expression of antioxidant enzyme NQO1 in Apcmin/+. In contrast, Nrf2KO enhanced the expression of inflammatory markers such as COX-2, cPLA, LTB4 in Apcmin/+. Finally, Nrf2KO resulted in higher level of PCNA and c-Myc expression in intestinal tissue, indicating the deficiency of Nrf2 promotes proliferation of intestinal crypt cells in Apcmin/+. Taken together, our results suggest that Nrf2KO attenuates anti-oxidative stress pathway, induces inflammation, and increases proliferative potential in the intestinal crypts leading to enhanced intestinal carcinogenesis and adenomas in Apcmin/+.
AB - Mutations in adenomatous polyposis coli (APC) gene are found in more than 80% of colorectal cancer (CRC) patients. The nuclear transcription factor Nrf2 plays a central role in the regulation of oxidative stress and inflammation. Previously, we have shown that chronic inflammation in Nrf2-/- (Nrf2 knockout; KO) mice resulted in higher expression of inflammatory markers and cytokines, coupled with higher inflammatory damage to the colonic crypt cells, as compared to the Nrf2+/+ (wild type; WT) mice. Induction of mutation in the colon by administration of carcinogen, AOM prior to DSS-induced inflammation resulted in higher tumor incidence and numbers in Nrf2KO mice. These results indicate that Nrf2-dependent inhibition of inflammation appears to be critical in inhibiting mutation-initiated colorectal carcinogenesis. In this study, we aim to investigate if loss of Nrf2 would dose-dependently promote intestinal tumorigenesis in Apcmin/+ mice. To demonstrate the in vivo mechanisms, we constructed both Apc mutated and Nrf2 deficient strain Apcmin/+ mice with C57BL/6 Nrf2KO mice to obtain F1, Apcmin/+;Nrf2+/- and F2, Apcmin/+;Nrf2-/-mice. Nrf2KO decreased the protein expression of antioxidant enzyme NQO1 in Apcmin/+. In contrast, Nrf2KO enhanced the expression of inflammatory markers such as COX-2, cPLA, LTB4 in Apcmin/+. Finally, Nrf2KO resulted in higher level of PCNA and c-Myc expression in intestinal tissue, indicating the deficiency of Nrf2 promotes proliferation of intestinal crypt cells in Apcmin/+. Taken together, our results suggest that Nrf2KO attenuates anti-oxidative stress pathway, induces inflammation, and increases proliferative potential in the intestinal crypts leading to enhanced intestinal carcinogenesis and adenomas in Apcmin/+.
KW - Apc
KW - Colon carcinogenesis
KW - Inflammation
KW - Nrf2
KW - Oxidative stress
UR - http://www.scopus.com/inward/record.url?scp=84890441806&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84890441806&partnerID=8YFLogxK
U2 - 10.1002/mc.21950
DO - 10.1002/mc.21950
M3 - Article
AN - SCOPUS:84890441806
VL - 53
SP - 77
EP - 84
JO - Molecular Carcinogenesis
JF - Molecular Carcinogenesis
SN - 0899-1987
IS - 1
ER -