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首页> 外文期刊>Hepatology: Official Journal of the American Association for the Study of Liver Diseases >Nrf2, but not -catenin, mutation represents an early event in rat hepatocarcinogenesis
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Nrf2, but not -catenin, mutation represents an early event in rat hepatocarcinogenesis

机译：Nrf2，但不是-catenin突变代表大鼠肝癌发生中的早期事件

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摘要

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 Nrf2/Keap1 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 Nrf2/Keap1 mutations were present in 71% of early preneoplastic lesions and in 78.6% and 59.3% of early and advanced HCCs, respectively. Mutations of Nrf2 were more frequent, missense, and located in the Nrf2-Keap1 binding region. Mutations of Keap1 occurred at a much lower frequency in both preneoplastic lesions and HCCs and were mutually exclusive with those of Nrf2. Functional in vitro and in vivo studies showed that Nrf2 silencing inhibited the ability of tumorigenic rat cells to grow in soft agar and to form tumors. Unlike Nrf2 mutations, those of Ctnnb1, which are frequent in human HCC, were a later event as they appeared only in fully advanced HCCs (18.5%). Conclusion: In the Resistant Hepatocyte model of hepatocarcinogenesis the onset of Nrf2 mutations is a very early event, likely essential for the clonal expansion of preneoplastic hepatocytes to HCC, while Ctnnb1 mutations occur only at very late stages. Moreover, functional experiments demonstrate that Nrf2 is an oncogene critical for HCC progression and development. (Hepatology 2015;62:851-862)
机译：肝细胞癌（HCC）通过多阶段过程发展，但是与不同步骤（尤其是早期步骤）相关的分子变化的性质在很大程度上尚不清楚。最近，在实验性和人类肿瘤中观察到NRF2 / KEAP1通路的失调和这些基因的突变，表明它们可能在癌症发展中发挥作用。为了评估Nrf2 / Keap1突变是HCC发生的早期事件还是晚期事件，我们在大鼠抗性肝细胞模型中研究了它们的频率，该模型包括给予二乙基亚硝胺，然后短暂暴露于2-乙酰氨基芴。该模型能够解剖肝癌发生的所有阶段。我们发现Nrf2 / Keap1突变分别存在于71％的早期肿瘤前病变和78.6％和59.3％的早期和晚期HCC中。 Nrf2的突变是更频繁，错义，并位于Nrf2-Keap1绑定区域。 Keap1突变在肿瘤前病变和肝癌中的发生频率要低得多，并且与Nrf2互斥。体外和体内功能研究表明，Nrf2沉默抑制了致瘤大鼠细胞在软琼脂中生长并形成肿瘤的能力。与Nrf2突变不同，Ctnnb1突变在人类HCC中很常见，是后来发生的事件，因为它们仅出现在完全晚期的HCC中（18.5％）。结论：在肝癌发生的抗性肝细胞模型中，Nrf2突变的发作是一个非常早期的事件，可能对于前肿瘤性肝细胞向HCC的克隆扩增至关重要，而Ctnnb1突变仅在很晚才发生。此外，功能实验表明Nrf2是对HCC进展和发展至关重要的癌基因。 （肝病2015; 62：851-862）

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