lncRNAENST-hnRNPU-GSDMD轴抑制细胞焦亡在乳腺癌化疗耐药中的作用及机制研究

化疗耐药是癌症治疗亟待解决的难题；焦亡是近年提出的一种炎性细胞坏死。ENST00000508435（简称ENST）是我们通过芯片筛选获得的在乳腺癌高表达的lncRNA。实验发现：阿霉素耐药MCF7细胞ENST表达显著升高，亲本MCF-7过表达ENST后焦亡关键分子GSDMD表达下降。提示：ENST在化疗耐药中发挥重要作用并与抑制焦亡相关。前期发现ENST与hnRNPU结合。而hnRNPU与β-TrCP结合抑制NF-κB或与PRC2结合通过染色质重塑调控焦亡基因。设想ENST通过ENST-hnRNPU-GSDMD轴抑制细胞焦亡促进化疗耐药。本项目拟通过体内外实验，明确ENST在化疗耐药中的作用，阐明其机制是ENST介导hnRNPU招募PRC2抑制TRAF-MALT1-caspase 1或抑制NF-κB进而下调GSDMD，抑制细胞焦亡，导致乳腺癌化疗耐药。本研究可为防治化疗耐药提供新思路。

Chemotherapeutic resistance is a difficult problem to be solved in the treatment of cancer and pyroptosis is a kind of inflammatory cell necrosis that has been put forward in recent years. LncRNA ENST00000508435 (ENST) that we have obtained through screening has a high expression level in breast cancer. Our results showed that the expression of ENST was increased significantly in doxorubicin resistant MCF-7 cells, and the expression of GSDMD, the key molecule that leads to pyroptosis, was decreased after overexpression of ENST was overexpressed in MCF-7. It is suggested that ENST plays an important role in chemotherapeutic drug resistance and is related to the inhibition of pyroptosis. Our early data demonstrated the combination of ENST and hnRNPU, and it was reported that hnRNPU can bind to β-TrCP to inhibit NF-κB or combine with PRC2 to regulate the genes related to pyroptosis by chromatin remodeling. We hypothize that ENST inhibits cell pyroptosis through the ENST-hnRNPU-GSDMD axis to promote chemotherapeutic resistance. The aim of this project is to clarify the role of ENST in chemoresistance through in vivo and in vitro experiments. The mechanisms for ENST promotinged breast cancer chemotherapy resistance may involve ENST mediated PRC2 recruitment through hnRNPU to inhibit TRAF-MALT1-caspase 1 or ENST mediated of NF-κB inhibition and down regulation of GSDMD, which results in inhibition of pyroptosis and inducing breast cancer chemotherapy resistance. This study can provide new ideas for the prevention and treatment of chemotherapeutic drug resistance.