Nrf2 knockout enhances intestinal tumorigenesis in Apcmin/+ mice due to attenuation of anti-oxidative stress pathway while potentiates inflammation

Ka Lung Cheung, Jong Hun Lee, Tin Oo Khor, Tien Yuan Wu, Guang Xun Li, Jefferson Chan, Chung Yang, Ah-Ng Kong

Research output: Contribution to journalArticle

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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 languageEnglish (US)
Pages (from-to)77-84
Number of pages8
JournalMolecular Carcinogenesis
Volume53
Issue number1
DOIs
StatePublished - Jan 1 2014

Fingerprint

Carcinogenesis
Oxidative Stress
Inflammation
Mutation
APC Genes
Leukotriene B4
Proliferating Cell Nuclear Antigen
Inbred C57BL Mouse
Knockout Mice
Carcinogens
Adenoma
Colorectal Neoplasms
Colon
Transcription Factors
Antioxidants
Cytokines
Incidence
Enzymes
Neoplasms
Proteins

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cancer Research

Keywords

  • Apc
  • Colon carcinogenesis
  • Inflammation
  • Nrf2
  • Oxidative stress

Cite this

Cheung, Ka Lung ; Lee, Jong Hun ; Khor, Tin Oo ; Wu, Tien Yuan ; Li, Guang Xun ; Chan, Jefferson ; Yang, Chung ; Kong, Ah-Ng. / Nrf2 knockout enhances intestinal tumorigenesis in Apcmin/+ mice due to attenuation of anti-oxidative stress pathway while potentiates inflammation. In: Molecular Carcinogenesis. 2014 ; Vol. 53, No. 1. pp. 77-84.
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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 journalArticle

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

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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/+.

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