Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
Clin Cancer Res. 2019 Feb 15;25(4):1389-1403. doi: 10.1158/1078-0432.CCR-18-1656. Epub 2018 Nov 5.
Chemoresistance and tumor relapse are the leading cause of deaths in bladder cancer patients. Bladder cancer stem cells (BCSCs) have been reported to contribute to these pathologic properties. However, the molecular mechanisms underlying their self-renewal and chemoresistance remain largely unknown. In the current study, a novel lncRNA termed Low expressed in Bladder Cancer Stem cells () has been identified and explored in BCSCs.
Firstly, we establish BCSCs model and explore the BCSCs-associated lncRNAs by transcriptome microarray. The expression and clinical features of are analyzed in three independent large-scale cohorts. The functional role and mechanism of are further investigated by gain- and loss-of-function assays and .
is significantly downregulated in BCSCs and cancer tissues, and correlates with tumor grade, chemotherapy response, and prognosis. Moreover, markedly inhibits self-renewal, chemoresistance, and tumor initiation of BCSCs both and . Mechanistically, directly binds to heterogeneous nuclear ribonucleoprotein K (hnRNPK) and enhancer of zeste homolog 2 (EZH2), and serves as a scaffold to induce the formation of this complex to repress SRY-box 2 (SOX2) transcription via mediating histone H3 lysine 27 tri-methylation. SOX2 is essential for self-renewal and chemoresistance of BCSCs, and correlates with the clinical severity and prognosis of bladder cancer patients.
As a novel regulator, plays an important tumor-suppressor role in BCSCs' self-renewal and chemoresistance, contributing to weak tumorigenesis and enhanced chemosensitivity. The -hnRNPK-EZH2-SOX2 regulatory axis may represent a therapeutic target for clinical intervention in chemoresistant bladder cancer.
化疗耐药和肿瘤复发是膀胱癌患者死亡的主要原因。膀胱癌干细胞（BCSCs）已被报道有助于这些病理特性。然而，它们自我更新和化疗耐药的分子机制在很大程度上仍不清楚。在本研究中，鉴定并研究了一种新型长非编码 RNA，称为膀胱癌干细胞中低表达的（）。
首先，我们通过转录组微阵列建立了 BCSCs 模型，并探讨了与 BCSCs 相关的长非编码 RNA。在三个独立的大型队列中分析了的表达和临床特征。通过 gain-和 loss-of-function 测定以及进一步研究了的功能作用和机制。
在 BCSCs 和癌症组织中，显著下调，与肿瘤分级、化疗反应和预后相关。此外，显著抑制 BCSCs 的自我更新、化疗耐药和肿瘤起始能力。机制上，直接与异质核核糖核蛋白 K（hnRNPK）和增强子结合锌指蛋白 2（EZH2）结合，并作为支架诱导该复合物的形成，通过介导组蛋白 H3 赖氨酸 27 三甲基化来抑制 SOX2 转录。SOX2 是 BCSCs 自我更新和化疗耐药所必需的，与膀胱癌患者的临床严重程度和预后相关。
作为一种新型调节剂，在 BCSCs 的自我更新和化疗耐药中发挥重要的肿瘤抑制作用，导致肿瘤生成能力减弱和化疗敏感性增强。-hnRNPK-EZH2-SOX2 调节轴可能代表化疗耐药膀胱癌临床干预的治疗靶点。
