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Mutations of Nrf2 are an early and frequent event in the development of rat hepatocellular carcinoma
Author(s) -
Columbano Amedeo,
Giordano Silvia,
Perra Andrea,
Kowalik Marta,
LeddaColumbano Giovanna,
Petrelli Annalisa,
Menegon Silvia,
Quagliata Luca,
Terracciano Luigi,
Zavattari Patrizia
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.147.10
Subject(s) - hccs , hepatocellular carcinoma , cancer research , biology , gclc , mutation , population , gene , keap1 , genetics , medicine , downregulation and upregulation , transcription factor , environmental health
Hepatocellular carcinoma (HCC) is a multistage process, but the nature of the molecular changes associated to the different steps, particularly the very early ones, is unknown. The Nrf2–Keap1 pathway is now recognized as a major cellular defense mechanism against oxidative and electrophilic stresses; however, its exact role in cancer development is unclear. To unveil the role of Nrf2 in HCC, we used the Resistant‐Hepatocyte (R‐H) rat model, which identifies distinct lesions (preneoplastic foci, dysplastic nodules, early and advanced HCCs) at well‐defined timings. The results showed that mutations of Nrf2 are very frequent in early preneoplastic lesions positive for the putative progenitor cell marker cytokeratin‐19 (KRT‐19), which are considered to be the precursor cell population of HCC in this model. All the mutations were missense, involved the Nrf2‐Keap1‐ binding regions and were associated with a strong increase of expression of the Nrf2 ‐target genes ( Nqo1, Gclc,Gst4) , in both pre‐ and neoplastic lesions. KRT‐19 positive HCCs arising 10 and 14 months later also showed a high percentage of Nrf2 mutations (70 and 56%, respectively), suggesting that mutation of this gene is critical for HCC development. Nrf2 silencing inhibited the ability of rat tumorigenic cells to grow in soft agar and to develop HCC when injected into syngeneic rats. Conclusion This study demonstrates that Nrf2 mutation is a very early and frequent event, suggesting that dysregulation of the Nrf2‐Keap1 pathway is likely essential for the clonal expansion of KRT‐19+ preneoplastic hepatocytes to HCC.