长链非编码RNA lncAC1调控膀胱癌干细胞自我更新的分子机制研究

Bladder cancer is still a major epidemiological problem whose incidence continues to rise each year. Increasing evidence showed tumorigenesis of bladder cancer contributes to alterations in molecular pathways that modulate cellular homeostasis. Major cellular processes are comprised of five intrinsic processes that respond to external carcinogenic signals or become internally deregulated owing to genetic changes, including cell cycle regulation, cell death, cell growth, signal transduction and gene regulation. Tumor maintenance and progression also depend on two extrinsic processes that interact with stromal elements and adjoining cells, harboring angiogenesis and tumor cell invasion. Cancer stem cell (CSC) and long non-coding RNA (lncRNA) are the current research fields for bladder cancer. CSC and lncRNA research in bladder cancer can not only reveal the mechanisms of tumorigenesis, but also provide a new type of candidate marker for cancer diagnosis, therapy and molecular typing. In our project, we expect to find a lncRNA as a novel tumor marker of bladder cancer stem cells and to explore the effect of the lncRNA in bladder cancer tumorigenesis, including biological characteristics of bladder cancer stem cells, single cell exons and transcriptome sequencing, and establishing bladder cancer stem cell lncRNA database. Next, we want to confirm lncAC1 and its interacting protein BRE positions in bladder cancer stem cells, and to prove that lncAC1 can promote tumorigenesis, tumor invasion and drug resistance. Last, we also want to clarify signaling pathways of stemness maintenance by lncAC1 mediated in bladder cancer stem cells and evaluate lncAC1 as a potential therapeutic target used to guide clinical intervention on bladder cancer.

发掘新型肿瘤标志物作为诊断与治疗的靶点一直是膀胱癌研究的热点。长链非编码RNA（lncRNA）是近来新发现的一类具有调控基因表达功能的非编码RNA。LncRNA在生命活动及肿瘤发病中具有重要调节作用，但lncRNA对肿瘤干细胞的自我更新的维持知之甚少。我们前期成功分离了膀胱癌干细胞（BCSCs）,通过 RNA表达谱差异分析，鉴定了一批与BCSCs干性密切相关的lncRNA。其中， lncAC1能够显著促进BCSCs的自我更新，增强BCSCs对顺铂等化疗药物的耐受性。我们还发现lncAC1能够上调BRE蛋白的表达，BRE的表达与BCSCs的干性相关。在此基础上，我们将探究lncAC1调控BRE表达的分子机制，揭示lncAC1调控BCSCs干性维持的分子机理，从而明确lncAC1作为膀胱癌干细胞干预新靶点的临床意义，为膀胱癌的临床治疗和药物研发提供理论基础。

肿瘤干细胞和长链非编码RNA（lncRNA）是膀胱癌研究的前沿领域。不仅能够解释膀胱癌的发生发展机制，而且作为肿瘤诊断、病理分型、预后判断和治疗靶点的新的候选分子，展示了良好的应用前景。本项目瞄准lncRNA作为膀胱癌干细胞新靶标的鉴定，（1）确定膀胱癌干细胞生物学特征，对膀胱癌干细胞进行单细胞外显子和转录组测序，建立膀胱癌干细胞特征的lncRNA数据库，探讨核心lncRNA在膀胱癌干细胞起源中的重要调控作用。（2）明确lncRNA-AC1与其相互作用蛋白BRE在膀胱癌干细胞中的定位，探明lncRNA-AC1通过BRE调控膀胱癌干细胞干性维持的分子机制，确定lncRNA-AC1介导的BRE对膀胱癌干细胞高致瘤性、侵袭性和耐药性是必须的。（3）阐明lncRNA-AC1促进膀胱癌干细胞干性维持的信号通路，评价lncRNA-AC1作为潜在的治疗靶点，在生理状态下对膀胱癌干细胞干预的临床应用价值。