长链非编码RNA DDX11-AS1在乳腺癌化疗耐药中的作用及机制

The mechanisms of chemoresistance and how to reverse it have been hot themes in cancer therapy research. Recent studies found that long non-coding RNA (lncRNA) is closely related with tumor development and metastasis, however, there are few studies focusing on its role in chemoresistance. We found that lncRNA DDX11-AS1 was significantly up-regulated in chemoresistant breast cancer cells by sequencing technology, and inhibition of DDX11-AS1 partially reversed the chemoresistance. Bioinformatic analysis showed that there were ERα binding signals in DDX11-AS1 promoter; besides, DDX11-AS1 may potentially interact with RNA binding protein LIN28A. This research aimed to further explore the characteristics of DDX11-AS1 expression and its correlation with breast cancer chemoresistance using drug resistant cell lines, mouse model and clinical tissue samples. Subsequently, we will explore whether ERα could regulate DDX11-AS1 expression and whether DDX11-AS1 enhanced chemoresistance through interacting with LIN28A. This research will extend our knowledge about the role of lncRNA in breast cancer chemoresistance and provide a potential target for reversing chemoresistance in breast cancer therapy.

肿瘤耐药产生机制及如何逆转耐药是肿瘤治疗的研究热点。近年来发现长链非编码RNA（lncRNA）与肿瘤的发生、转移密切相关，但其与肿瘤耐药的关系却研究甚少。我们前期通过高通量测序发现 lncRNA DDX11-AS1在乳腺癌化疗耐药细胞中表达显著升高，抑制DDX11-AS1表达可抑制乳腺癌细胞耐药性；生物信息学预测表明DDX11-AS1启动子区存在雌激素核受体ERα结合信号，且DDX11-AS1可能与RNA结合蛋白LIN28A存在互作。本项目计划从乳腺癌耐药细胞、活体动物及临床组织样本三个层面，进一步研究DDX11-AS1的表达水平及其与乳腺癌细胞耐药性的关联，并在此基础上验证DDX11-AS1转录活性是否受到ERα调控，同时探索DDX11-AS1是否通过与LIN28A相互作用来促进乳腺癌化疗耐药，从而全面了解DDX11-AS1在乳腺癌化疗耐药中的作用，为临床逆转耐药治疗提供新的潜在靶点。

化疗耐药目前已成为乳腺癌临床治疗失败的主要原因之一，耐药性产生机制及如何逆转耐药是目前肿瘤治疗的研究热点。近年来研究发现长链非编码RNA (Long non-coding RNAs, lncRNAs)与多种肿瘤耐药有关。LncRNA DDX11-AS在多种肿瘤细胞中表达升高，但在乳腺癌化疗耐药中的作用尚不清楚。本研究发现lncRNA DDX11-AS1可参与乳腺癌化疗耐药，DDX11-AS1在耐药乳腺癌细胞中表达上调，且其高表达与患者不良预后相关。DDX11-AS1的高表达可增强乳腺癌细胞的化疗耐药，DDX11-AS1可与RNA结合蛋白LIN28A相互作用，增强下游基因ATG7和ATG12的mRNA稳定性，从而促进乳腺癌细胞的耐药性。进一步生存曲线分析表明，ATG12的高表达与乳腺癌患者不良预后有关，而ATG7与乳腺癌患者的预后相关性无统计学意义。我们的研究揭示了乳腺癌耐药中一条新的通路即DDX11-AS1/LIN28A/ATG12，可为临床提高乳腺癌化疗效果提供新的途径。