节律分子BMAL1在NASH相关肝癌发生中的作用及机制研究

In the pathogenesis of nonalcoholic steatohepatitis (NASH) associated hepatocellular carcinoma (HCC), the abnormal lipid metabolism and inflammatory reaction of liver cells lead to insulin resistance and necrotic inflammation, leading to the occurrence of NASH-HCC. Numerous studies and our recently published literature have confirmed that the circadian gene plays a key effect on tumorigenesis, but the mechanism is not fully understood. Recently, we found that the expression of BMAL1 in NASH-HCC tissues was significantly lower than that in the adjacent tissues, and the expression of BMAL1 in NASH liver cells was significantly lower than that in the normal liver cells. In addition, the levels of triglyceride and inflammatory cytokines were elevated in liver-specific BMAL1 knockout mice. These results suggest that the loss of BMAL1 can lead to abnormal lipid metabolism and enhance the inflammatory response, and thus promote the occurrence of NASH-HCC. Based on this, this project intends to use the liver-specific BMAL1 knockout mice model, in-depth analysis the effect of BMAL1 inhibit lipid synthesis and inflammatory response and the molecular signal pathway, finally clarify the mechanism of BMAL1 deletion promote the occurrence of NASH-HCC. This project will not only provide a new perspective for understanding the pathogenesis of NASH-HCC, but also provide a new target for the prevention and treatment of HCC.

在非酒精性脂肪性肝炎（NASH）相关肝癌的发生中，由于肝细胞脂代谢及炎症反应异常引发胰岛素抵抗、坏死性炎症等，最终导致肝癌发生。大量文献和我们最近发表的研究证实，生物节律基因在肿瘤发生中发挥关键作用，但具体作用机制尚不清楚。我们最近在NASH相关肝癌组织中发现节律分子BMAL1表达显著低于癌旁组织，同时NASH肝细胞中BMAL1表达也显著低于正常肝细胞。另外，肝特异性敲除BMAL1小鼠中，其甘油三酯和炎症因子水平升高。上述结果提示该分子的功能缺失可导致脂代谢异常并增强炎症反应，进而促进NASH相关肝癌发生。基于此，本项目拟利用肝特异性敲除BMAL1基因小鼠模型，深入分析BMAL1分子抑制脂质合成和炎症反应的生物学作用，探讨分子信号作用通路，最终阐明BMAL1分子缺失促进NASH相关肝癌发生的分子调控机制。本项目将为理解NASH相关肝癌发生机制提供新的视角，也为肝癌防治提供潜在新靶点。

在非酒精性脂肪性肝炎（NASH）相关肝癌的发生中，由于肝细胞脂代谢及炎症反应异常引发胰岛素抵抗、坏死性炎症等，最终导致肝癌发生。大量文献和我们最近发表的研究证实，生物节律基因在肿瘤发生中发挥关键作用，但具体作用机制尚不清楚。本项目拟利用以动物模型和临床样本为研究对象，在多层面多系统探讨BMAL1分子抑制肝癌细胞脂质合成和炎症反应的功能及分子基础，取得如下进展：1）BMAL1分子下调促进肝癌细胞甘油脂质生物合成和肝癌细胞进展；2）BMAL1分子下调可以通过调控甘油脂质生物合成促进肝癌细胞增殖、迁移及侵袭；3）BMAL1可以与表观遗传调控因子EZH2形成复合体转录抑制甘油脂质合成的关键酶GPAM的表达，从而参与BMAL1调控肝癌细胞脂质代谢过程；4）体内外水平验证靶向BMAL1的小分子抑制剂和激动剂对于肝癌细胞的甘油脂质合成过程及肝癌细胞恶性进展具有药理学作用。本项目以生物节律分子BMAL1为核心为肝癌发生机制提供新的视角，也为肝癌防治提供潜在新靶点。