改邪归正：癌基因HLF在Bmi1驱动肝内胆管癌发生中的抑癌作用研究

肝内胆管癌（ICC）基础研究匮乏，临床治疗手段极其有限。癌基因Bmi1可以驱动多种肿瘤发生，但其在ICC发生中的作用及机制尚不明确。前期研究发现Bmi1在人ICC中高表达，并可以在小鼠体内驱动ICC发生，而沉默Bmi1可以抑制ICC细胞生长。RNA测序发现癌基因HLF可能为其调控靶点，沉默HLF可以促进ICC细胞增殖。据此，我们推断Bmi1通过抑制HLF驱动ICC发生，HLF在ICC中发挥抑癌作用。本研究中，我们尝试回答两个科学问题：1.Bmi1是否通过抑制HLF驱动ICC发生发展？2.HLF抑制ICC发生的细胞生物学机制？我们将利用Bmi1肝脏敲除小鼠结合高压注射转染ICC模型回答第一个问题，并利用细胞模型和分子生物学技术回答第二个问题。本研究将确认Bmi1是否可以作为ICC治疗的靶标，并首次揭示癌基因HLF在肿瘤发生中的抑癌作用，具有很强的创新性和科学意义。

Intrahepatic cholangiocarcinoma (ICC) is a lethal malignancy lacking effective systemic therapy, and even fundamental research about it is very limited. Oncogene Bmi1 can drive tumor initiation and progression in many types of cancers, but its role in the pathogenesis of ICC is not yet clear. Our preliminary data have shown that Bmi1 is highly expressed in human ICC tissues and can drive ICC formation in mice, whereas silencing Bmi1 inhibited the growth of ICC cells. RNA sequencing revealed that HLF is a potential target of Bmi1, and knockdown of HLF promoted ICC cell growth. Hence, we speculate that Bmi1 drives ICC initiation and progression via inhibition of HLF. In this study, we endeavor to answer two scientific questions: whether Bmi1 drives the initiation and development of ICC in mice by repressing HLF, and how does HLF function as a tumor suppressor in ICC? We will answer the first question using Bmi1 and/or HLF liver specific knockout mice together with tail vein hydrodynamic injection modeling, and the second question using in vitro model and molecular biology techniques. This study aims to confirm whether Bmi1 can be used as a target for the treatment of ICC, and to reveal the tumor suppressor role of HLF in cancer development.