Genetic inactivation of Nrf2 prevents clonal expansion of initiated cells in a nutritional model of rat hepatocarcinogenesis

Journal of Hepatology
Claudia OrrùAmedeo Columbano

Abstract

Dysregulation of the Keap1-Nrf2 pathway has been observed in experimental and human tumors, suggesting possible roles of the pathway in cancer development. Herein, we examined whether Nrf2 (Nfe2l2) activation occurs at early steps of rat hepatocarcinogenesis, to assess critical contributions of Nrf2 to the onset of hepatocellular carcinoma (HCC). We used wild-type (WT) and Nrf2 knockout (Nrf2KO) rats treated with a single injection of diethylnitrosamine (DENA) followed by choline-devoid methionine-deficient (CMD) diet. This experimental model causes massive fatty liver and steatohepatitis with fibrosis and enables identification of early stages of hepatocarcinogenesis. We found that Nrf2 activation takes place in early preneoplastic lesions identified by the marker glutathione S-transferase placental form (GSTP). Nrf2 missense mutations, known to disrupt the Keap1-Nrf2 binding, were present in 65.7% of GSTP-positive foci. Nrf2KO rats were used to directly investigate whether Nrf2 is critical for initiation and/or clonal expansion of DENA-damaged hepatocytes. While Nrf2 genetic inactivation did not alter DENA-induced initiation, it led to increased liver injury and chronic compensatory hepatocyte regeneration when rats were fed ...Continue Reading

Citations

Nov 30, 2019·Archives of Pharmacal Research·Keiko Taguchi, Thomas W Kensler
Nov 20, 2019·Cancers·Ram C ShankaraiahMassimo Negrini
Jun 3, 2021·International Journal of Molecular Sciences·Effi HaqueHiroaki Taniguchi
Jul 11, 2020·Cancer Cell·John D HayesKenneth D Tew
Feb 21, 2019·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Mohammed M H Al-GayyarReem Diri
Sep 17, 2021·Cellular and Molecular Gastroenterology and Hepatology·Sandra MattuAmedeo Columbano

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