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Tumor and Stem Cell Biology

Nrf2 Prevents Initiation but Accelerates Progression through the Kras Signaling Pathway during Lung Carcinogenesis

Hironori Satoh, Takashi Moriguchi, Jun Takai, Masahito Ebina and Masayuki Yamamoto
Hironori Satoh
Authors' Affiliations: Departments of Medical Biochemistry and Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, JapanAuthors' Affiliations: Departments of Medical Biochemistry and Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
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Takashi Moriguchi
Authors' Affiliations: Departments of Medical Biochemistry and Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
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Jun Takai
Authors' Affiliations: Departments of Medical Biochemistry and Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
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Masahito Ebina
Authors' Affiliations: Departments of Medical Biochemistry and Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
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Masayuki Yamamoto
Authors' Affiliations: Departments of Medical Biochemistry and Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
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DOI: 10.1158/0008-5472.CAN-12-4499
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Abstract

Nrf2 (Nfe2l2) governs cellular defenses against oxidative and electrophilic stresses and protects against chemical carcinogenesis. However, many cancers have been found to accumulate NRF2 protein, raising questions of precisely how Nrf2 contributes to carcinogenesis. In this report, we explored such questions in an established urethane-induced multistep model of lung carcinogenesis. Consistent with earlier observations, Nrf2-deficient (Nrf2−/−) mice exhibited a relative increase in tumor foci by 8 weeks after urethane administration. However, after 16 weeks, we observed a relative reduction in the number of tumors with more malignant characteristics in Nrf2−/− mice. Furthermore, all Nrf2+/+ tumors harbored activated mutations in Kras, whereas Nrf2−/− tumors were rarely associated with similar Kras mutations. Overall, our results established that Nrf2 has two roles during carcinogenesis, one of which is preventive during tumor initiation and the second that promotes malignant progression. These findings establish Nrf2 inhibitors as rational tools to prevent malignant progression in lung cancer, whereas Nrf2 activators are more suited for lung cancer prevention. Cancer Res; 73(13); 1–11. ©2013 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).

  • Received December 9, 2012.
  • Revision received March 14, 2013.
  • Accepted April 1, 2013.
  • ©2013 American Association for Cancer Research.
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Published OnlineFirst June 21, 2013
doi: 10.1158/0008-5472.CAN-12-4499

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Nrf2 Prevents Initiation but Accelerates Progression through the Kras Signaling Pathway during Lung Carcinogenesis
Hironori Satoh, Takashi Moriguchi, Jun Takai, Masahito Ebina and Masayuki Yamamoto
Cancer Res June 21 2013 DOI: 10.1158/0008-5472.CAN-12-4499

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Nrf2 Prevents Initiation but Accelerates Progression through the Kras Signaling Pathway during Lung Carcinogenesis
Hironori Satoh, Takashi Moriguchi, Jun Takai, Masahito Ebina and Masayuki Yamamoto
Cancer Res June 21 2013 DOI: 10.1158/0008-5472.CAN-12-4499
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Cancer Research Online ISSN: 1538-7445
Cancer Research Print ISSN: 0008-5472
Journal of Cancer Research ISSN: 0099-7013
American Journal of Cancer ISSN: 0099-7374

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