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KLF15低表达上调HDGF促进膀胱尿路上皮癌侵袭进展的机制研究
结题报告
批准号:
81972391
项目类别:
面上项目
资助金额:
55.0 万元
负责人:
许传亮
学科分类:
肿瘤复发与转移
结题年份:
2023
批准年份:
2019
项目状态:
已结题
项目参与者:
许传亮
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中文摘要
膀胱癌是泌尿系常见且诊疗费用最高的恶性肿瘤。解释其侵袭进展的分子机制,是提高危险分层准确性和开发靶向药物及提高疾病预后的关键。前期研究中:1)KLF15在膀胱癌低表达,与分级、肌层浸润负相关,低表达预后差;2)KLF15过表达抑制膀胱癌细胞迁移和侵袭;3)KLF15下调使HDGF上调,可能是通转录调控,且转录组测序表明HDGF在膀胱癌中上调。由此,我们提出科学假说:KLF15在膀胱癌中表达下调,导致HDGF转录活性增强,表达水平升高,HDGF通过调控下游信号通路,最终促进膀胱癌进展,阻断KLF15/HDGF及通路相关键分子可抑制膀胱癌进展。本项目拟通过转基因动物模型、人源化肿瘤移植模型、肿瘤细胞系及临床标本四个层面,采用ChIP、蛋白质免疫共沉淀、CRISPR/cas9等技术,阐明KLF15通过HDGF对膀胱癌侵袭的调控机制,为膀胱癌危险分层标志物及靶向药物筛选提供理论和实践基础。
英文摘要
Bladder cancer is a common malignancy of the urinary tract which is the most expensive cancer per capita to treat. Unveiling the mechanisms of bladder cancer invasion and progression is crucial for improving prognosis by contributing to risk stratification and therapeutic target discovering. Our previous study yielded three results. First, KLF15 is under-expressed in bladder cancer, its expression was negatively correlated with tumor grading and existence of muscle invasion, and low-expression of KLF15 is associated with poor prognosis. Second, Overexpression of KLF15 inhibits bladder cancer cell migration and invasion. Third, Down-regulation of KLF15 may up-regulates HDGF expression through transcription activation. And our sequencing data indicates that HDGF promotes tumorigenesis of bladder cancer. Therefore, we propose a hypothesis that KLF15 is down-regulated in bladder cancer, resulting in increased transcriptional activity of HDGF and higher expression levels. Ultimately, HDGF promotes progression of bladder cancer by regulating downstream signaling pathways. Blocking KLF15/HDGF pathway associated molecules inhibits bladder cancer progression. This project aims to elaborate the regulation mechanism of KLF15/HDGF on the invasion of bladder cancer by utilizing ChIP, Co-IP and CRISPR/cas9 techniques and through transgenic animal model, patient-derived xenograft (PDX) models, tumor cell lines and clinical specimens. And we plan to provide the theoretical and practical basis for establishing new schemes incorporating KLF15 for risk stratification and targeted therapy of patients with bladder cancer.
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DOI:10.1002/cam4.5932
发表时间:2023-06
期刊:CANCER MEDICINE
影响因子:4
作者:Zhang, Chen;Wang, Maoyu;Ying, Yidie;Meng, Fang;Gao, Hongliang;Zeng, Shuxiong;Zhu, Yasheng;Liu, Anwei;Zhang, Zhensheng;Xu, Chuanliang
通讯作者:Xu, Chuanliang
DOI:10.1002/mc.23643
发表时间:2023-10
期刊:Molecular Carcinogenesis
影响因子:4.6
作者:Maoyu Wang;Chen Zhang;Yidie Ying;Meimian Hua;Fang Meng;Ziwei Wang;Anwei Liu;Shuxiong Zeng
通讯作者:Maoyu Wang;Chen Zhang;Yidie Ying;Meimian Hua;Fang Meng;Ziwei Wang;Anwei Liu;Shuxiong Zeng
DOI:10.1002/btm2.10624
发表时间:2023-12-04
期刊:BIOENGINEERING & TRANSLATIONAL MEDICINE
影响因子:7.4
作者:Xiong,Qiao;Liu,Ting;Xu,Chuanliang
通讯作者:Xu,Chuanliang
DOI:10.21037/tau-23-371
发表时间:2023-11-30
期刊:Translational andrology and urology
影响因子:2
作者:
通讯作者:
DOI:10.3389/fcell.2021.813420
发表时间:2021
期刊:Frontiers in cell and developmental biology
影响因子:5.5
作者:Xu J;Zeng S;Li J;Gao L;Le W;Huang X;Wang G;Chen B;Zhang Z;Xu C
通讯作者:Xu C
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