GPS2负调控CIP2A表达而促进三阴乳腺癌铁自噬的作用及机制研究

三阴乳腺癌(TNBC)尚无明确的治疗靶点，发病机制有待深入阐明。癌基因CIP2A在TNBC中高表达。预实验发现其表达与铁自噬负相关；TNBC细胞敲减CIP2A能促进铁自噬活化。推测CIP2A通过抑制铁自噬促进TNBC癌进展。同时，预实验鉴定发现GPS2与CIP2A表达负相关，与铁自噬正相关，在TNBC中低表达。分析力学预测发现GPS2结合CIP2A启动子，并在ChIP中证实；TNBC细胞过表达GPS2能下调CIP2A表达并活化铁自噬，提示GPS2负调控CIP2A转录表达而促进TNBC铁自噬。本研究拟通过临床标本，细胞、动物实验等层面探索GPS2与预后、CIP2A、铁自噬的相关性及调控；利用Luciferase/ChIP/MST等分子手段明确GPS2负调控CIP2A表达、CIP2A负调控铁自噬的作用方式。构建GPS2/CIP2A/铁自噬调控轴，为发现TNBC新型治疗靶点提供理论依据。

There is no clear therapeutic target for triple-negative breast cancer (TNBC), and the mechanism of its occurrence and progression needs to be further elucidated. The oncogene cancerous inhibitor of protein phosphatase 2A (CIP2A) is highly expressed in TNBC. In our preliminary experiment, we found that the expression of CIP2A was negatively correlated with ferritinophagy; knockdown of CIP2A promoted the activation of ferritinophagy. It is speculated that CIP2A participates in the occurrence and progression of TNBC by inhibiting ferritinophagy. Moreover, prexperimental identification found that the G protein pathway suppressor 2 (GPS2) was low-expressed in TNBC, negatively correlated with CIP2A expression, and positively correlated with ferritinophagy. Analysis of mechanical prediction revealed that GPS2 binds to the promoter of CIP2A and was confirmed in Chromatin IP. Overexpression of GPS2 in TNBC cells downregulated CIP2A expression and activated ferritinophagy, suggesting that GPS2 negatively regulates CIP2A transcription and then promotes TNBC ferritinophagy. In the present project, we are aimed to explore the relationship between GPS2, CIP2A, ferritinophagy and its regulatory mechanism in vitro and in vivo using clinical specimens, cell lines and animal experiments. To clarify the mode of action of GPS2 negatively regulating CIP2A transcription and CIP2A negatively regulating ferritinophagy by molecular methods such as Luciferase, Chromatin IP, and microscale thermophoresis (MST), and to construct the signal axis of GPS2 decreases the expression of CIP2A and promotes ferritinophagy. The expected results of this project will provides a theoretical basis for discovering new therapeutic targets of TNBC.