LncRNA DUBR通过Notch通路调控肝癌细胞干性及化疗耐药的机制研究

肝癌对系统性化疗普遍耐药，是难以回避的一个临床难题。在前期工作中，我们证明了经肝动脉给药进行局部化疗可部分克服肝癌的化疗耐药。进一步探究发现：lncRNA DUBR在部分肝癌组织中上调，且与局部化疗效果显著负相关。体外实验表明：敲除DUBR可下调CD47的表达，并显著增加奥沙利铂诱导的肝癌细胞凋亡。综合前期数据和生物信息学分析，我们推测lncRNA DUBR可通过调控邻近基因CD47，激活Notch通路，从而促进肝癌细胞干性维持及化疗耐药，最终导致化疗失败。综上，本课题拟：1）阐明lncRNA DUBR对肝癌细胞干性及化疗耐药的影响。2）逐一论证转录调控、转录后调控、表观遗传学调控、竞争性结合内源性RNA这四种途径，阐明lncRNA DUBR调控CD47的具体分子机制。3）证实DUBR反义寡核苷酸类药物是否有潜力克服肝癌化疗耐药。预期本课题可为肝癌治疗提供新思路，为逆转化疗耐药提供新靶点。

Hepatocellular carcinoma (HCC) is one of the most prevalent malignant neoplasms with an increasing incidence and mortality worldwide, which is generally resistant to systemic chemotherapy. We have demonstrated that HAIC (hepatic arterial infusion chemotherapy) can partially overcome chemotherapy resistance of HCC. And our previous studies showed that long non-coding RNA DUBR is up-regulated in HCC tissues and significantly related to the prognosis of hepatocellular carcinoma and chemotherapy effect. Knocking down DUBR reduces CD47 expression and increases the apoptosis induced by oxaliplatin in vitro. Based on these findings, we hypothesis that DUBR regulates downstream gene CD47 expression in cis to maintain the stemness feature and drug-resistance of HCC via Notch signal pathway. In this project, We will combine the clinical sample analysis and experimental studies to explore the mechanism of DUBR in promoting stemness and chemotherapy resistance of HCC, especially in regulating CD47 expression, to provide innovative ideas and intervention targets to improve and renew the concept and treatment regimen of HCC.