化疗增敏对于提升肝癌总体治疗效果、改善预后具有十分重要的意义。肿瘤干细胞（CSCs）样特性增强是肝癌产生化疗抵抗的关键因素。本课题根据前期积累，结合国内外报道，提出三氧化二砷（ATO）增加肝癌化疗敏感性的分子机制假说如下：当顺铂诱导肿瘤坏死过程中，肿瘤组织释放多种细胞因子，其中GDF15作为关键信号分子之一，通过上调GRP75继而激活Nanog，诱导肝癌细胞CSCs样特性显著增强，进而产生化疗抵抗；而ATO则可通过直接与GDF15的半胱氨酸残基结合，诱导其发生泛素化降解，进而阻滞其下游GRP75/Nanog信号通路，抑制肝癌细胞CSCs样特性，最终增加肝癌对顺铂化疗的敏感性。本项目拟从细胞、动物及人群水平系统探讨我们提出的科学假说，同时阐明血清GDF15和GRP75在肝癌化疗产生抵抗以及化疗预后评估中的意义，为寻找有效的肝癌化疗增敏途径提供新思路。

Improving the efficiency of chemotherapy on hepatocellular carcinoma (HCC) plays a key role in enhancing the overall therapeutic effect and the improvement of the prognosis of HCC patients. The elevation of cancer stem cells (CSCs)-like properties, is the root cause of HCC chemotherapy resistance. Here, based on our previous studies and on the researches worldwide, we suggest a new mechanism underlying the effects of arsenic trioxide (ATO) on the improvement of the efficiency of chemotherapy on HCC. Tumor tissues release a lot of cytokine when cisplatin causes tumor necrosis. Of all, GDF15 plays a key role in the induction of chemotherapy resistance. That is GDF15 improves the CSCs-like properties via up-regulating the GRP75/Nanog signal pathway. However, ATO can inhibit the expression of GDF15 by directly binding to this protein, which causes the ubiquitination of GDF15 and then blocks the GRP75/Nanog signal pathway. This process leads to an attenuation of CSCs-like properties, which finally improves the efficiency of chemotherapy on HCC. This project intends to perform the work in the cell model, animal model, as well as in the population. Meanwhile, we will also clarify the significance of the serum GDF15 and GRP75 in the HCC chemotherapy resistance and prognosis. By understanding a new mechanism by which ATO improves the efficiency of chemotherapy on HCC, this project will expand our knowledge in the discovering of the new ways to increase the sensitive of HCC chemotherapy.