lncRNA-BCCR募集WDR5促进膀胱癌化疗耐药的机制研究

Chemoresistance is the main reason of relapse and treatment failure in bladder cancer, but the mechanism is not fully understood. Emerging evidence shows that long non-coding RNA (lncRNAs) play an important regulatory role in cancers by acting as oncogenes or tumor suppressors. However, the roles and mechanism of lncRNAs in chemoresistance of bladder cancer remain elusive. Our previous study found that lncRNA-BCCR is overexpressed in cisplatin resistant bladder cancer cell sublines, and its expression level is correlated with tumor stage, grade and overall survival. Through gain or loss of function, we demonstrated that lncRNA-BCCR significantly enhanced the chemoresistance of bladder cancer cells in vitro and vivo. Furthermore, we identified that lncRNA-BCCR binds to WDR5, the key component of MLL1 complex, by RNA pull down, mass spectrometry and RIP. Knockdown WDR5 attenuates the effect of lncRNA-BCCR overexpression on chemoresistance in bladder cancer cells. Therefore, we propose a new mechanism that lncRNA-BCCR recruits WDR5 to regulate the transcription of a serial chemoresistance related genes，such as DNA repair, to promote the chemoresistance of bladder cancer. To gain the proof of lncRNA-BCCR regulates chemoresistance of bladder cancer by WDR5, we will perform in vitro and vivo functional experiments, co-immunoprecipitation and next generation sequencing analysis. This study is aim to elucidate the function and mechanism of lncRNA-BCCR in bladder cancer and how they modulate the target genes by binding WDR5, to clarify the clinical significance of lncRNA-BCCR in bladder cancer recurrence, therapy resistance and prognosis, identify the new biomarker and target for chemoresistant bladder cancer cells targeting therapy.

化疗耐药是膀胱癌复发和治疗失败的主要原因之一，但其耐药机制未明。长链非编码RNA(lncRNA)在肿瘤发生、发展中起关键调控作用，但lncRNA在调控膀胱癌化疗耐药的作用和机制尚不明确。我们预实验发现lncRNA-BCCR在膀胱癌耐药细胞和癌组织中高表达，与生存预后密切相关，并促进膀胱癌细胞在体内外对顺铂的化疗耐药。免疫共沉淀证明它与WDR5结合，沉默WDR5明显削弱过表达lncRNA-BCCR的促耐药作用。由此我们提出膀胱癌化疗耐药新机制：lncRNA-BCCR通过募集染色质修饰蛋白WDR5在上游激活DNA损伤修复等耐药基因的表达，从而促进膀胱癌的化疗耐药。本研究拟进一步采用体内外实验，免疫共沉淀和高通量测序等技术，获得lncRNA-BCCR通过WDR5调控膀胱癌化疗耐药的可靠证据，明确其临床意义，为作为预测化疗敏感性的标记物和提高化疗疗效的新靶点提供理论基础，为膀胱癌精准诊疗提供新思路

化疗耐药是膀胱癌复发和治疗失败的主要原因之一，但其耐药机制未明。长链非编码RNA(lncRNA)在肿瘤发生、发展中起关键调控作用。我们研究发现lncRNA-BCCR在膀胱癌耐药细胞和癌组织中高表达，与分期，分级成正相关，是生存预后不良的因素。体外和体内功能学实验表明lncRNA-BCCR促进膀胱癌细胞在体内外对顺铂的化疗耐药。机制研究表明lncRNA-BCCR募集WDR5到DNA损伤修复和抗凋亡的基因ERCC1, ERCC4, XRCC1和BIRC5启动子上，介导H3K4me3来促进下游靶基因表达，发挥化疗耐药作用。然而，沉默WDR5明显削弱过表达lncRNA-BCCR的促耐药作用。本研究为作为lncRNA-BCCR预测化疗敏感性的标记物和提高化疗疗效的新靶点提供理论基础，为膀胱癌的精准诊疗提供新思路。在该项目的资助下，本人以第一作者或通讯作者在Journal of Clinical Investigation，Clinical Cancer Research和Molecular Cancer等国际知名杂志上，发表SCI论文11篇，总IF：94.4，其中IF>10分的4篇， 10>IF>5的4篇。获得授权发明专利1项和申请发明专利1项。在项目执行期间获得国家自然科学基金面上项目 1 项。