肿瘤干细胞（CSC）是肿瘤转移复发的根源，研究发现CSC可来源于特定肿瘤微环境作用下分化型癌细胞的去分化。我们在前期肝癌干细胞无血清体外培养模型的研究中证实，培养液中FGF10和IGF1能协同介导癌细胞去分化成为CSC，然而其分子调控机制不明。进一步实验发现FGF10和IGF1上调Nanog表达过程中存在Erk1/2抑制而STAT3激活的现象，猜测肿瘤微环境中FGF10和IGF1可协同调控Erk1/2与STAT3信号通路的转换，上调Nanog表达，进而驱动肝癌细胞去分化成为CSC。本课题通过对非干性肝癌细胞诱导去分化转化为肝癌干细胞的再生机制进行体内外实验研究，阐明肿瘤微环境中参与肝癌细胞去分化的关键调控分子和信号通路，探索建立阻断相关靶标分子和信号通路的靶向治疗方法及其对肝癌的抑制作用，从而加深对肿瘤生物学特性以及肿瘤与肿瘤微环境关系的理解，为制定针对CSC的预防和治疗措施提供实验依据。

Cancer stem cells (CSCs) are thought to be responsible for tumor metastasis and recurrence. Recent studies have shown that CSCs might originate from the dedifferentiation of differentiated tumor cells in special microenvironment. We previously established a serum-free system model for hepatocellular carcinoma (HCC) CSC culture in vitro, and found that FGF10 and IGF1 might synergistically mediate the differentiated tumor cells to dedifferentiate to CSCs. However, the molecular mechanisms of such dedifferentiation have not been elucidated. Further study found that the Erk1/2 was inhibited and STAT3 was activated in the process of upregulation of Nanog by FGF10 and IGF1, suggesting FGF10 and IGF1 in tumor microenvironments may synergistically regulate the transition of Erk1/2 and STAT3 signal pathways, FGF10 may act synergistically with IGF1 to drive the dedifferentiation, then upregulate the expression of Nanog and promote HCC cells to dedifferentiate to CSCs. In this project, the in vitro and in vivo experiments are carried out to study the regeneration mechanisms of induced dedifferentiation of non-stem HCC cells to tranform to CSCs, for the purpose of clarifying the key regulatory molecules and signaling pathways involved in the dedifferentiation of HCC cells in tumor microenvironments, exploring to establish the target therapy to block the relative target molecules and signaling and to test the inhibitory effect of this target therapy on HCC, thus deepening the understanding about tumor biological characteristics and the relationship between tumors and tumor microenvironment. The project will provide the experimental basis for developing the prevention and treatment measures targeting CSCs.