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
结题报告
批准号:
81472413
项目类别:
面上项目
资助金额:
78.0 万元
负责人:
李翀
学科分类:
H1819.肿瘤生物治疗
结题年份:
2018
批准年份:
2014
项目状态:
已结题
项目参与者:
夏朋延、王彦英、杜颖、杨昭、朱平平、李曼、郝璐、黄贯岭、何璐云
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中文摘要
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。
英文摘要
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.
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。
期刊论文列表
专著列表
科研奖励列表
会议论文列表
专利列表
Single-cell Sequencing Reveals Variants in ARID1A, GPRC5A and MLL2 Driving Self-renewal of Human Bladder Cancer Stem Cells
单细胞测序揭示了 ARID1A、GPRC5A 和 MLL2 的变异驱动人类膀胱癌干细胞的自我更新。
DOI:10.1016/j.eururo.2016.06.025
发表时间:2017-01-01
期刊:EUROPEAN UROLOGY
影响因子:23.4
作者:Yang,Zhao;Li,Chong;Wu,Song
通讯作者:Wu,Song
Somatic FGFR3 Mutations Distinguish a Subgroup of Muscle-Invasive Bladder Cancers with Response to Neoadjuvant Chemotherapy.
体细胞 FGFR3 突变可区分肌层浸润性膀胱癌亚组与新辅助化疗的反应
DOI:10.1016/j.ebiom.2018.06.011
发表时间:2018-09
期刊:EBioMedicine
影响因子:11.1
作者:Yang Z;Zhang R;Ge Y;Qin X;Kang X;Wang Y;Zhang X;Song C;Quan X;Wang H;Chen H;Li C
通讯作者:Li C
DOI:10.1016/j.eururo.2016.09.005
发表时间:2017
期刊:European Urology
影响因子:23.4
作者:Yang Z;Wu S;Cai Z;Li C
通讯作者:Li C
GALNT1-Mediated Glycosylation and Activation of Sonic Hedgehog Signaling Maintains the Self-Renewal and Tumor-Initiating Capacity of Bladder Cancer Stem Cells
GALNT1 介导的 Sonic Hedgehog 信号的糖基化和激活维持膀胱癌干细胞的自我更新和肿瘤启动能力
DOI:10.1158/0008-5472.can-15-2309
发表时间:2016-03-01
期刊:CANCER RESEARCH
影响因子:11.2
作者:Li, Chong;Du, Ying;Fan, Zusen
通讯作者:Fan, Zusen
The KMT1A-GATA3-STAT3 Circuit Is a Novel Self-Renewal Signaling of Human Bladder Cancer Stem Cells
KMT1A-GATA3-STAT3 电路是人膀胱癌干细胞的一种新型自我更新信号
DOI:10.1158/1078-0432.ccr-17-0882
发表时间:2017-11-01
期刊:CLINICAL CANCER RESEARCH
影响因子:11.5
作者:Yang, Zhao;He, Luyun;Wen, Tingyi
通讯作者:Wen, Tingyi
膀胱癌新型DNA适配体Apt71的筛选鉴定和致癌机理的研究
CCP6介导的谷氨酸化修饰调控膀胱癌干细胞自我更新及其肿瘤干预的分子机制研究
膀胱癌特异性肿瘤标志物的筛选鉴定和致癌机理的研究
国内基金
海外基金