Cytoglobin联合5-FU策略靶向肿瘤干细胞治疗肝细胞癌的研究

人Cytoglobin（CYGB）是六配位单体携氧蛋白，具有过氧化物酶活性，是体内天然的活性氧清除剂。肿瘤干细胞（CSCs）决定了肿瘤的自我更新、异质性及治疗耐受等。前期研究发现CYGB调控胞内异常氧化应激（OS），显著抑制了肝细胞癌（HCC）的干细胞性，而缺氧诱导肝癌细胞对5-氟脲嘧啶（5-FU）的治疗耐受。因此，本课题提出CYGB靶向OS及CSCs致敏肝癌细胞对5-FU治疗的新策略。拟开展的研究内容包括：1）不同氧浓度CYGB联合5-FU的联合效应；2）缺氧时CYGB联合5-FU对肿瘤干细胞性及亚群分布的作用；3）CYGB联合5-FU靶向NRF2及HIF1a缺氧信号的作用；4）体内实验评估CYGB联合5-FU的疗效及安全性；5）体内实验论证CYGB联合5-FU靶向调控OS-CSCs治疗肿瘤的联合机制。通过联合用药拮抗氧化应激及肿瘤干细胞诱导的药物耐受，为临床治疗进展期HCC提供新策略。

Human cytoglobin (CYGB), an ubiquitously expressed hexacoordinate haemoglobin, functions as a peroxidase or nitric oxide dioxygenase (NOD). It is a dynamic mediator in maintenance of intracellular redox homeostasis. Cancer stem cells (CSCs) are a crucial subpopulation and determine tumor self-renewal, plasticity and heterogeneity, which contribute to tumorigenesis, progression and resistance to chemoradiotherapies. Targeting CSCs may provide a curative approach to overcome therapy resistance and prevent tumor progression. We reported that CYGB ameliorates the stemness of hepatocellular carcinoma (HCC) via controlling oxidative-nitrosative stress signals. 5-fluorouracil (5-FU) is the backbone in the treatment of digestive tumors. We reported that hypoxia significantly induces the resistance of colorectal cancer to 5-FU monotherapy. Therefore, we hypothesized that CYGB may synergize with 5-FU to overcome drug resistance and prevent tumor progression through interdicting the undesirable interaction of oxidative stress with CSCs. The project is planned to implement as followed: 1) The combination index of CYGB plus 5-FU under normoxia and hypoxia; 2) The effect of CYGB in combination with 5-FU on HCC stemness and CSCs subpopulation; 3) The regulation of CYGB in combination with 5-FU on NRF2 and HIF1a of the hypoxic signals; 4) To assess the therapeutic effect and toxicity of CYGB in combination with 5-FU therapies in vivo; 5) To demonstrate the mechanism of CYGB in combination with 5-FU disrupting the interaction of OS with CSCs in vivo. Collectively, the study aims to provide the promising therapy strategies to overcome the progression of advanced HCC via targeting abnormal oxidative stress and cancer stem cells.