基于肝素酶对化疗性外泌体摄入的ARF6/PIPK/PIP2/syndecan通路影响探讨固本抑瘤II号干预三阴性乳腺癌化疗抵抗的作用机制

化疗抵抗CR是三阴性乳腺癌TNBC治疗难点，外泌体是耐药载体。肝素酶Hpa促进肿瘤增殖转移及外泌体分泌。最新报道Hpa切割肿瘤细胞膜表面硫酸肝素HS，暴露HS上负电荷，易于和带正电荷的外泌体结合，增强外泌体摄入，促进耐药。课题组基因测序发现，高Hpa细胞在内吞作用、Ras通路和Fcγ介导的吞噬方面与对照组有明显差异，提示Hpa促进外泌体摄入。基于前期证实的固本抑瘤II号(GY)化疗增效和抑制Hpa作用，提出假说：GY通过抑制Hpa，影响未耐药肿瘤细胞对化疗性外泌体的摄入，通过ARF6/PIPK/PIP2途径调节细胞中Syndecan循环，影响化疗耐药信号的胞间传递，增强TNBC化疗疗效。本研究以不同Hpa水平人TNBC细胞为工具，从ARF6/PIPK/PIP2/syndecan通路诠释GY干预化疗抵抗作用及机理，为临床更合理地应用中药干预肿瘤和化疗耐药提供理论指导和实验证据支持。

Although anti-tumor research has been progressing, chemotherapy resistance is still the main difficult problem for triple-negative breast cancer. Exosome is the carrier for chemotherapy resistance and the main bridge of cells cross talking. The latest research found that the expression of heparanase (Hpa) can affect the cell membrane surface structure and the uptake of exosomes by tumor cells and affect the interaction between cells, but no effect on TNBC has been reported. Together with our previous foundation that GUBENYILIU II (GY) which under YIQIHUOXUEJIEDU Traditional Chinese Medicine theory can both reduce chemotherapy resistance and heparanase level, we come to our hypothesis: (1) Chemotherapy stimulates high Hpa expression in triple-negative breast cancer, accelerates tumor cell uptaking of chemotherapeutic exosomes, transmits chemotherapy resistance signals, and accelerates tumor cell survival and malignancy after chemotherapy (2) By regulating ARF6/PIPK/PIP2/syndecan, GY affects tumor cells' uptake of chemotherapeutic exosomes and intervenes chemotherapy resistance. Focus on the ARF6/PIPK/PIP2/syndecan, with different heparanase expression levels of human triple negative breast cancer cell lines, we propose this project. The research will help to understand the new roles of GY, and the exploration will improve our knowledge on cheoexosomes, cross talking, and chemotherapy resistance. Published articles will be the direct outcome of this project.