国内外研究和本课题组均发现HOX家族与多种恶性肿瘤有关，前期我们发现胃癌中HOXA13表达上调，HOXA13阳性表达患者预后不良，对5-Fu治疗不敏感，DHRS2、MDM2作为下游分子参与HOXA13高表达引起的胃癌耐药。文献提示MDM2活化后破坏P53稳定性引起耐药。根据前期研究及文献，推测：HOXA13作为转录因子负调控DHRS2，活化MDM2，破坏P53稳定性，促进ABCB1表达，导致化疗耐药。本项目将利用P53工具细胞验证HOXA13通过P53通路发挥耐药和促癌作用；正负向调控技术证实HOXA13对DHRS2、MDM2的调控关系；通过ChIP-Seq、CoIP技术探讨HOXA13、DHRS2与MDM2是否存在内源性相互作用；通过生存分析、PDTX模型研究HOXA13表达水平与化疗药物敏感性的关系。本项目可能发现新的胃癌化疗敏感判断标志物，有利于进一步阐明胃癌的耐药机制。

The other researchers and our group all found that HOX gene family is associated with a variety of malignant tumors. In the previous study, we found that the expression of HOXA13 is up-regulated in gastric cancer and HOXA13-positive patients had a poor prognosis and were resistant to chemotherapy. As downstream molecules of HOXA13, DHRS2 and MDM2 take part in the resistance of 5-Fu in the HOXA13 up-regulated gastric cancer cell. The recent studies suggests the activated MDM2 decreases the stability of P53 and then induces drug-resistance. According to our previous study and relative published results, we speculate that HOXA13 serves as a negative regulator of DHRS2, down-regulated DHRS2 elevates the activity of Mdm2, decreases the stability of P53, promotes the expression of ABCB1, and then leads to the resistance to chemotherapy. The project will use P53 tools cells to verify HOXA13 plays a role in drug-resistance and tumor promotion via P53 pathway and adopt the positive and negative control technology to verify that HOXA13 regulates DHRS2 and MDM2.We will investigate whether there exists endogenous interaction between HOXA13、DHRS2 and MDM2 by utilizing ChIP-Seq and CoIP technology and we will study the relationship of HOXA13 expression level and chemosensitivity through survival analysis and PDTX models. This project may discover new biomarkers for gastric cancer chemosensitivity and help to further clarify the mechanism of chemoresistance in gastric cancer.