Nrf2, but not β‐catenin, mutation represents an early event in rat hepatocarcinogenesis. Issue 3 (22nd April 2015)

• Record Type: Journal Article
• Authors: Zavattari, Patrizia; Perra, Andrea; Menegon, Silvia; Kowalik, Marta Anna; Petrelli, Annalisa; Angioni, Maria Maddalena; Follenzi, Antonia; Quagliata, Luca; Ledda‐Columbano, Giovanna Maria; Terracciano, Luigi; Giordano, Silvia; Columbano, Amedeo
• Is Part Of: Hepatology. Volume 62:Issue 3(2015:Sep.)
• Page Start: 851
• Page End: 862
• Publication Date: 2015-04-22
• Subjects: Heart -- Diseases -- Nursing -- Periodicals; Lungs -- Diseases -- Nursing -- Periodicals; Intensive care nursing -- Periodicals; Foie -- Maladies -- Périodiques; 616.362
• DOI: 10.1002/hep.27790
• Languages: English
• ISSNs: 0270-9139

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>Hepatocellular carcinoma (HCC) develops through a multistage process, but the nature of the molecular changes associated with the different steps, the very early ones in particular, is largely unknown. Recently, dysregulation of the NRF2/KEAP1 pathway and mutations of these genes have been observed in experimental and human tumors, suggesting their possible role in cancer development. To assess whether <italic>Nrf2/Keap1</italic> mutations are early or late events in HCC development, we investigated their frequency in the rat Resistant Hepatocyte model, consisting of the administration of diethylnitrosamine followed by a brief exposure to 2‐acetylaminofluorene. This model enables the dissection of all stages of hepatocarcinogenesis. We found that <italic>Nrf2/Keap1</italic> mutations were present in 71% of early preneoplastic lesions and in 78.6% and 59.3% of early and advanced HCCs, respectively. Mutations of <italic>Nrf2</italic> were more frequent, missense, and located in the Nrf2‐Keap1 binding region. Mutations of <italic>Keap1</italic> occurred at a much lower frequency in both preneoplastic lesions and HCCs and were mutually exclusive with those of <italic>Nrf2</italic>. Functional <italic>in vitro</italic> and <italic>in vivo</italic> studies showed that <italic>Nrf2</italic> silencing inhibited the ability of tumorigenic rat cells to grow in soft agar and to form tumors. Unlike <italic>Nrf2</italic> mutations, those of <italic>Ctnnb1</italic>, which are frequent in human HCC, were a later event as they appeared only in fully advanced HCCs (18.5%). <italic>Conclusion</italic>: In the Resistant Hepatocyte model of hepatocarcinogenesis the onset of <italic>Nrf2</italic> mutations is a very early event, likely essential for the clonal expansion of preneoplastic hepatocytes to HCC, while <italic>Ctnnb1</italic> mutations occur only at very late stages. Moreover, functional experiments demonstrate that <italic>Nrf2</italic> is an oncogene critical for HCC progression and development. (H<sc>epatology</sc> 2015;62:851‐862)</p> </abstract>