我国乙肝病毒感染者众多导致新增肝癌病例数及死亡病例数均居全球之首。Sorafenib是首个FDA批准的晚期肝癌的治疗药物，但包括脂代谢异常在内的多种原因导致的Sorafenib耐药严重限制其疗效。ZHX2是新近发现的肝癌抑癌基因，在多发性骨髓瘤和肝癌耐药中发挥重要作用，并且调控血清脂质水平。实验室最新结果表明ZHX2抑制肝癌细胞Sorafenib耐药性，并降低细胞内脂质水平，表达谱分析显示ZHX2下调脂代谢关键调控基因SIRT1表达。由此申请者提出：ZHX2调控肝癌细胞脂代谢重编程抑制Sorafenib耐药。本课题拟通过体内外实验阐明ZHX2调控SIRT1影响脂代谢重编程的分子机制及其在抑制肝癌细胞Sorafenib耐药中的作用。课题的开展与完成对肝癌治疗具有重大的临床应用价值。

HBV infection is the major cause of HCC in China, which leads to most of new cases and death of HCC in the world. Sorafenib is the first FDA-approved drug for advanced HCC, but abnormal expression of lipid metabolism genes lead to Sorafenib resistance limiting its efficacy. ZHX2 is a newly identified HCC suppressor gene that plays an important role in MM and HCC chemo-resistance, and regulates serum lipid levels. Recently, our lab found that ZHX2 inhibits Sorafenib resistance in HCC cells, reduces intracellular lipid levels, and down-regulates SIRT1 expression. So, we propose that ZHX2 regulates the reprogramming of HCC cell lipid metabolism and inhibits Sorafenib resistance. This study aims to clarify the molecular mechanism of ZHX2 regulating SIRT1 affecting lipid metabolism reprogramming and its role in inhibiting Sorafenib resistance in HCC cells by in vitro and in vivo experiments. This study is important for the treatment of HCC.