胆管癌发病机制一直认识不清，亦缺乏有效的治疗药物。我们前期工作发现鞘氨醇激酶2（Sphk2）高表达于胆管癌细胞和组织中，其小分子抑制剂ABC294640可以抑制多种胆管癌细胞增殖和诱导凋亡，并且可以抑制STAT3的磷酸化，提示Sphk2可能在胆管癌中扮演癌基因的作用。目前对于Sphk2在胆管癌中的生物学功能，及其对IL-6/STAT3通路的调控尚不清楚。本项目拟通过在胆管癌细胞株中沉默和过表达Sphk2，系统探讨Sphk2的生物学功能，明确其参与调控IL-6/STAT3通路的活化作用及相关机制；同时以患者来源的裸鼠移植瘤模型为平台，评估Sphk2的小分子抑制剂ABC294640的体内抗胆管癌作用及其与自噬抑制剂的联合作用。本研究将明确Sphk2在胆管癌恶性表型中的作用，为靶向抑制Sphk2抗胆管癌提供科学依据。

The cholangiocarcinogenesis is largely unknown and there is no effective agent against cholangiocarcinoma (CCA). Our previous work has shown that Sphingosine kinase 2 (Sphk2) was overexpressed in CCA cell lines and tissues. The Sphk2 small molecular inhibitor ABC294640 inhibited cell proliferation and induced apoptosis in six CCA cell lines. In addition, ABC294640 inhibited STAT3 phosphorylation. Therefore, Sphk2 may play an oncogenic role in CCA. Currently, the biologic role of Sphk2 in CCA and the effect of Sphk2 in the regulation of IL-6/STAT3 signaling pathway is largely unkown. The current project is going to investigate the biologic role of Sphk2 in CCA and the regulatory role of Sphk2 in the IL-6/STAT3 signaling pathway through knockdown and overexpression methods. Finally, we will evaluate the in vivo antitumor effect of the ABC294640 alone or in combination with autophagy inhibitors in a patient-derived xenograft mouse model. Our goal is to determine the role of Sphk2 in CCA and provide scientific evidence of targeting Sphk2 for the treatment of CCA.