Long Noncoding RNA LBCS Inhibits Self-Renewal and Chemoresistance of Bladder Cancer Stem Cells through Epigenetic Silencing of SOX2
Long Noncoding RNA LBCS Inhibits Self-Renewal and Chemoresistance of Bladder Cancer Stem Cells through Epigenetic Silencing of SOX2
复制标题
长非编码 RNA LBCS 通过 SOX2 表观遗传沉默抑制膀胱癌干细胞的自我更新和化疗耐药性
DOI：
10.1158/1078-0432.ccr-18-1656
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发表时间：
2019-02-15
影响因子：
11.5
通讯作者：
Lin, Tianxin
中科院分区：
文献类型：
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作者：
Chen, Xu;Xie, Ruihui;Lin, Tianxin
目的：化疗耐药和肿瘤复发是膀胱癌患者死亡的主要原因。据报道，膀胱癌干细胞(BCSCs)与这些病理特性有关。然而，它们自我更新和耐药的分子机制在很大程度上仍不清楚。在目前的研究中，一种新的被称为在膀胱癌干细胞中低表达的LncRNA(Lnc-LBCs)已经在BCSCs中被发现和探索。实验设计：首先建立BCSCs模型，利用转录芯片技术筛选BCSCs相关的LncRNAs。在三个独立的大规模队列中分析LNC-LBC的表达和临床特征。通过体内外功能获得和功能丧失实验，进一步研究LNC-LBCs的功能作用和机制。结果：LNC-LBCs在BCSCs和癌组织中表达显著下调，并与肿瘤分级、化疗疗效及预后相关。此外，在体内外，LNC-LBCs均能显著抑制BCSCs的自我更新、化疗耐药和肿瘤起始。在机制上，lnc-LBCs直接与异质性核糖核蛋白K(HnRNPK)和Zust同源增强子2(EZH2)结合，通过介导组蛋白H3赖氨酸27的三甲基化，诱导该复合体的形成，抑制SRY-box 2(SOX2)的转录。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密切相关。结论：作为一种新的调控因子，lnc-LBCs在BCSCs的自我更新和化疗耐药中发挥着重要的肿瘤抑制作用，有助于BCSCs的弱致瘤性和化疗敏感性的增强。Lnc-LBCs-hnRNPK-EZH2-SOX2调控轴可能是化疗耐药膀胱癌临床干预的治疗靶点。
Purpose: 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 (lnc-LBCS) has been identified and explored in BCSCs. Experimental Design: Firstly, we establish BCSCs model and explore the BCSCs-associated lncRNAs by transcriptome microarray. The expression and clinical features of lnc-LBCS are analyzed in three independent large-scale cohorts. The functional role and mechanism of lnc-LBCS are further investigated by gain- and loss-of-function assays in vitro and in vivo. Results: Lnc-LBCS is significantly downregulated in BCSCs and cancer tissues, and correlates with tumor grade, chemotherapy response, and prognosis. Moreover, lnc-LBCS markedly inhibits self-renewal, chemoresistance, and tumor initiation of BCSCs both in vitro and in vivo. Mechanistically, lnc-LBCS 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. Conclusions: As a novel regulator, lnc-LBCS plays an important tumor-suppressor role in BCSCs’ self-renewal and chemoresistance, contributing to weak tumorigenesis and enhanced chemosensitivity. The lnc-LBCS–hnRNPK–EZH2–SOX2 regulatory axis may represent a therapeutic target for clinical intervention in chemoresistant bladder cancer.