Cullin1-FBXL18通过降解E2F7促进肝癌发展的机制研究

FBXL18 is one of F-box proteins of SCF E3 ligase, which regulates multiple biological processes through ubiquitination degradation of substrates.To date, it is elusive whether FBXL18 regulates cellular senescence. We found that knockdown of FBXL18 through RNAi library screening induced cellular senescence, which significantly suppressed the malignancies of human liver cancer cells. Meanwhile, FBXL18 silencing induced the accumulation of p27 and transcription down-regulation of SKP2, the ubiquitin E3 ligase which is responsible for p27 degradation. Moreover, FBXL18 can form Cullin1-FBXL18 complex, which interacted with and down-regulated the expression of transcription factor E2F7. In addition, FBXL18 was up-regulated in human liver cancer tissues comparing to adjacent normal tissues, suggesting FBXL18 is a potential novel liver cancer therapeutic target.Thus, we make a hypothesis that FBXL18 silencing induces the accumulation of E2F7, which in turn down-regulates the transcription of SKP2, resulting in the accumulation of p27 and subsequent cellular senescence of liver cancer. Here, we aim to investigate the effect and mechansim of FBXL18 targeting in human liver cancer both in vitro and in vivo, which may be beneficial to identify FBXL18 as a novel therapeutic liver cancer target.

FBXL18是SCF E3泛素连接酶底物识别亚基F-box蛋白家族一员，通过泛素化介导降解底物，调控生命活动过程。迄今，FBXL18是否调控细胞衰老过程未见报道。我们前期研究发现：下调经RNAi文库筛选的FBXL18既可诱导肝癌细胞衰老，显著抑制肝癌细胞恶性表型，又可诱导p27蛋白积聚和介导其降解的泛素连接酶SKP2的转录下调。同时FBXL18可形成Cullin1-FBXL18复合物，结合并下调转录因子E2F7。此外FBXL18在人肝癌组织中高表达，提示FBXL18是一个潜在的新型肝癌治疗靶标。据此，我们提出假说：靶向FBXL18可诱导E2F7的积聚，进而下调SKP2的转录，SKP2的表达下调引起p27的积聚，进而诱导肝癌细胞衰老。本项目拟研究体内外靶向FBXL18治疗人肝癌的效果及分子机制，为鉴定FBXL18成肝癌治疗靶标提供理论依据。

F-box蛋白是SCF(Skp1-Cullin1-F-box protein)多亚基泛素连接酶底物识别亚基，而FBXL18作为F-box蛋白其中一员，通过泛素化底物，调控生长及免疫等生物活动过程，但其在肿瘤如肝癌发生发展过程中的作用仍未阐释清楚。本项目中，我们通过生物信息学结合临床肝癌组织的蛋白表达分析，首次发现FBXL18在肝癌组织中高表达，且与肝癌病人的预后呈负相关，首次确定FBXL18是一个潜在肝癌新靶标。其次，通过体内外的模型研究发现，靶向FBXL18可诱导肝癌细胞衰老。在机制上，FBXL18可通过调节SKP2-p27信号轴调控细胞衰老，但其底物仍在进一步探索鉴定中。

内容获取失败，请点击重试