Protective role of NRF2 in hepatic carcinogenesis

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  • Kensler Thomas W.
    Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, USA Department of Pharmacology and Chemical Biology, University of Pittsburgh, USA
  • Groopman John D
    Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, USA
  • Taguchi Keiko
    Division of Medical Biochemistry, Tohoku University Graduate School of Medicine, Japan
  • Yamamoto Masayuki
    Division of Medical Biochemistry, Tohoku University Graduate School of Medicine, Japan

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<p>Liver cancer is the second leading cause of cancer mortality worldwide; up to one-fifth have been estimated to be attributed to aflatoxin exposure. Thus, considerable research effort has focused on prevention strategies to reduce the impact of aflatoxin-induced hepatocarcinogenesis. The synthetic oleanane triterpenoid 1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im), a powerful activator of Keap1-Nrf2 signaling, protects F344 rats against aflatoxin B1 (AFB1)-induced acute toxicity and preneoplastic lesion formation. In a lifetime cancer bioassay rats were dosed daily with AFB1 for 4 weeks and received either vehicle or CDDO-Im (thrice weekly), one week prior to and throughout the exposure period. Weekly urine and monthly serum samples were collected for biomarker analyses. The comparative response of a toxicogenomic RNA expression signature for AFB1 was examined as were tumor and serum miRNA levels. CDDO-Im completely protected against AFB1-induced liver cancer compared to a 96% incidence observed in the AFB1-only group and, correspondingly, altered the toxicogenomic signature and miRNA trajectories. To ascertain the role of Nrf2, follow-up studies were conducted with two lines of Nrf2 knockout F344 rats. CDDO-Im failed to induce representative Nrf2 target genes in the livers of these animals, further validating the Nrf2 pathway as a key target of CDDO-Im. Moreover, these knockout rats were exceedingly sensitive to the acute toxicity of AFB1. With CDDO-Im treatment, integrated levels of urinary AFB1-N7-guanine, the primary DNA adduct excised from the liver, were significantly reduced and those of aflatoxin-N-acetylcysteine, a glutathione S-transferase (GST)-derived detoxication product, were consistently elevated 3-fold after the first AFB1 dose. Mice are intrinsically resistant to AFB1 hepatotoxicity; however, sensitivity is greatly enhanced in GSTA3 knockout mice. Collectively, these data indicate a key role for the induction of Nrf2-regulated GSTs in the protective effect. Moreover, strategies to elevate NRF2 signaling in populations at high risk for aflatoxin exposures should be included in public health measures to reduce liver cancer burden. Supported by NIH grant R35 CA197222 and MEXT/JSPS KAKENHI.</p>

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