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Of FACT complex and oxidative stress response: a KEAP1/NRF2-dependent novel mechanism sustaining hepatocellular carcinoma progression
Gut ( IF 23.0 ) Pub Date : 2019-10-15 , DOI: 10.1136/gutjnl-2019-319609
Beatrice Foglia 1 , Maurizio Parola 2
Affiliation  

Hepatocellular carcinoma (HCC) is the most common primary liver cancer that usually develops in cirrhotic patients, except for progressive non-alcoholic fatty liver disease (where the tumour may develop also in non-cirrhotic liver).1 HCC is currently the leading cause of mortality in cirrhotic patients, representing the fifth most common cancer and the second leading cause of cancer mortality worldwide.1 Although screening programmes can allow to identify HCC at an earlier stage in patients at risks, still a minority of patients can survive at 5 years from diagnosis, despite treatment. Current treatment options have limitations and first-line drugs approved for systemic therapy, like sorafenib and lenvatinib, can at best offer additional 3 months of survival to HCC patients, emphasising the urgent need to identify novel molecular targets to develop more effective therapies.1 Chronic liver disease progression towards HCC development as well as HCC progression are highly affected by microenvironmental cues in a very complex scenario involving inter-relationships between cells (cancer cells, tumour-associated macrophages or fibroblasts and cancer stem cells) as well as processes or events like inflammatory response, fibrogenic progression, autophagy, hypoxic conditions and oxidative stress.2 In particular, an increase in intracellular levels of reactive oxygen species (ROS) represents a common feature of cancer cells which is usually counterbalanced by an upregulation of antioxidant defenses, particularly through the relevant Kelch-like ECH-associated protein 1 (KEAP1) and nuclear factor erythroid 2-related factor 2 (NRF2) pathway.3 In this pathway, KEAP1, a E2-ligase which is normally negatively regulating NRF2 protein stability via ubiquitin–proteasome degradation, is inactivated under oxidative stress; this preserves NRF2 from degradation and allows its nuclear translocation and binding to antioxidant response element (ARE) sequences in the promoter of antioxidant genes, displacing BTB domain and CNC homolog 1 (BACH1, the selective …

中文翻译:

FACT 复合物和氧化应激反应:维持肝细胞癌进展的 KEAP1/NRF2 依赖性新机制

肝细胞癌 (HCC) 是最常见的原发性肝癌,通常发生在肝硬化患者中,但进行性非酒精性脂肪肝(其中肿瘤也可能发生在非肝硬化中)除外。 1 HCC 目前是导致肝硬化的主要原因肝硬化患者的死亡率,代表全球第五大最常见癌症和第二大癌症死亡原因。 1 虽然筛查计划可以让有风险的患者在早期阶段发现 HCC,但仍有少数患者可以存活 5 年。诊断,尽管治疗。目前的治疗选择有局限性,批准用于全身治疗的一线药物,如索拉非尼和乐伐替尼,最多只能为 HCC 患者提供额外 3 个月的生存期,特别是通过相关的 Kelch 样 ECH 相关蛋白 1 (KEAP1) 和核因子红细胞 2 相关因子 2 (NRF2) 途径。 3 在该途径中,KEAP1,一种 E2 连接酶,通常通过泛素负调节 NRF2 蛋白稳定性–蛋白酶体降解,在氧化应激下失活;这可以防止 NRF2 降解,并允许其核易位并与抗氧化基因启动子中的抗氧化反应元件 (ARE) 序列结合,取代 BTB 结构域和 CNC 同源物 1(BACH1,选择性……
更新日期:2019-10-15
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