双氢青蒿素通过自噬依赖性gankyrin降解抑制胆管癌生长与转移及机制研究

The abnormal expression of gankyrin is closely related to tumorigenesis. Our previous study found that gankyrin can promote tumor growth and metastasis through activating IL-6/STAT3 in cholangiocarcinoma, suggesting gankyrin might be an ideal target for the treatment of cholangiocarcinoma. However, too few drugs currently target gankyrin, making the treatment in trouble. Dihydroartemisinin (DHA) is one of the traditional Chinese medicine extracts of artemisinin, which has good anti-tumor application prospect. Our preliminary experiments showed that DHA inhibits the growth and metastasis of cholangiocarcinoma with gankyrin downregulation. Importantly, the downregulation could be reversed by autophagy inhibitor, suggesting autophagy dependent degradation might be involved. Since the mechanism by which DHA degrades gankyrin is not yet clear, we will further explore the mechanism of gankyrin degradation by DHA and elucidate the relationship between gankyrin and autophagy. Therefore, we propose the scientific hypothesis that "DHA inhibits the growth and metastasis of cholangiocarcinoma by autophagy-dependent degradation of gankyrin." We will use different cells, animal models and tissue samples through a variety of experimental methods such as IHC, lenti-virus, PCR, etc. to verify the above scientific hypothesis and elucidate the mechanism for the prevention and treatment of cholangiocarcinoma provides a new theoretical basis and therapeutic targets.

Gankyrin的异常表达与肿瘤的发生发展密切相关。我们前期发现胆管癌中gankyrin可以激活IL-6/STAT3信号通路促进肿瘤生长和转移，提示其可能是胆管癌治疗的新靶点，但目前靶向gankyrin的抑制剂研发尚处于起步阶段，亟待继续探索。我们预实验结果发现传统中药青蒿的提取物双氢青蒿素（DHA）可以明显抑制胆管癌细胞增殖，同时伴随gankyin蛋白表达降低，进一步研究发现DHA对gankyrin的下调可以被自噬抑制剂扭转，提示自噬性降解可能是其降低gankyrin表达的关键机制。基于此，我们提出“DHA通过自噬依赖性gankyrin降解抑制胆管癌生长与转移”的科学假设，拟进一步通过免疫组化、病毒转染、PCR及自噬检测等实验来验证上述假设。本研究的成功有望为胆管癌，尤其是gankyrin高表达的胆管癌患者提供新的治疗策略，从gankyrin角度出发为肿瘤的个体化治疗奠定理论基础。

Gankyrin的异常表达与肿瘤的发生发展密切相关。我们前期发现胆管癌中Gankyrin可以激活IL-6/STAT3信号通路促进肿瘤生长和转移，提示其可能是胆管癌治疗的新靶点，但目前靶向Gankyrin的抑制剂研发尚处于起步阶段，亟待继续探索。我们预实验结果发现传统中药青蒿的提取物双氢青蒿素（DHA）可以明显抑制胆管癌细胞增殖，同时伴随gankyin蛋白表达降低，进一步研究发现DHA对Gankyrin的下调可以被自噬抑制剂扭转，提示自噬性降解可能是其降低Gankyrin表达的关键机制。基于此，我们提出“DHA通过自噬依赖Gankyrin降解抑制胆管癌生长与转移”的科学假设，并进一步通过免疫组化、病毒转染、PCR及自噬检测等实验来验证了上述假设。本研究的成功有望为胆管癌，尤其是Gankyrin高表达的胆管癌患者提供新的治疗策略，从Gankyrin角度出发为肿瘤的个体化治疗奠定理论基础。