E2F1-ASPM-cyclinE1正反馈轴促进肺腺癌恶性增殖的研究

批准号:
82002421
项目类别:
青年科学基金项目
资助金额:
24.0 万元
负责人:
熊延路
依托单位:
学科分类:
肿瘤细胞命运
结题年份:
2023
批准年份:
2020
项目状态:
已结题
项目参与者:
熊延路
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中文摘要
新致病基因及其作用机制是肺腺癌防治的重要推动因素。通过转录组学筛选及实验验证,我们发现肺腺癌中异常纺锤体样小头畸形相关蛋白(ASPM)显著高表达,且是新的独立预后危险因素。进而发现,ASPM可能通过阻碍GSK3作用cyclinE1,维持cyclinE1稳定,促进肺腺癌增殖。而转录预测和初步实验表明,E2F1很可能是ASPM的新转录激活因子。结合文献我们提出:肺腺癌中,ASPM通过阻碍GSK3磷酸化cyclinE1(Thr380),抑制cyclinE1泛素化降解,从而激活重要的cyclinE1/CDK2-pRb-E2Fs通路,促进恶性增殖。而活化的E2Fs家族中E2F1又转录上调ASPM,进而正反馈活化该信号轴。本项目拟通过细胞学、分子生物学、动物学等方法从体内体外水平探究E2F1-ASPM-cyclinE1正反馈轴调控肺腺癌恶性增殖的机制,为探索肺腺癌的致病机理乃至研究防治策略提供新思路。
英文摘要
Novel pathogenic genes and underlying mechanisms improve notably the prevention and treatment of lung adenocarcinoma (LUAD). Through transcriptomic screening and experimental validation, we have found LUAD possessed high expression of abnormal spindle-like microcephaly-associated (ASPM), which functioned as a novel independent prognostic risk factor. Furthermore, we found ASPM might inhibit interaction of GSK3 and cyclin E1, maintaining cyclin E1 stability, which promoted LUAD proliferation. Besides, we found that E2F1 probably functioned as a novel transcription activator of ASPM via transcription prediction and preliminary experiments. Combining with the literature, we propose that, in LUAD, ASPM inhibits GSK3-mediated phosphorylation of cyclin E1(Thr380), thus preventing ubiquitin-dependent degradation of cyclin E1. Thereby activated cyclin E1/CDK2-pRb-E2Fs pathway significantly potentiates malignant proliferation, while activated E2F1 in E2Fs family would also upregulate ASPM expression by transcriptional activation, causing positive feedback for this signal axis. This project intends to explore the mechanism of E2F1-ASPM-cyclin E1 positive feedback axis regulating the malignant proliferation of LUAD in vivo and in vitro through cytology, molecular biology, zoology and other methods, in order to provide new ideas for exploring the pathogenic mechanisms and therapeutic strategies of LUAD.
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
DOI:10.1038/s12276-022-00896-9
发表时间:2022-11
期刊:EXPERIMENTAL AND MOLECULAR MEDICINE
影响因子:12.8
作者:Zhu, Jianfei;Fan, Yue;Xiong, Yanlu;Wang, Wenchen;Chen, Jiakuan;Xia, Yanmin;Lei, Jie;Gong, Li;Sun, Shiquan;Jiang, Tao
通讯作者:Jiang, Tao
DOI:10.3389/fimmu.2023.1095388
发表时间:2023
期刊:FRONTIERS IN IMMUNOLOGY
影响因子:7.3
作者:Zhou, Yinxi;Xia, Jinghua;Xu, Shuonan;She, Tao;Zhang, Yanning;Sun, Ying;Wen, Miaomiao;Jiang, Tao;Xiong, Yanlu;Lei, Jie
通讯作者:Lei, Jie
DOI:--
发表时间:2023
期刊:国际检验医学杂志
影响因子:--
作者:吉晓鸿;熊延路;贾建博
通讯作者:贾建博
TFAP2A potentiates lung adenocarcinoma metastasis by a novel miR-16 family/TFAP2A/PSG9/TGF-β signaling pathway.
TFAP2A 通过新型 miR-16 家族/TFAP2A/PSG9/TGF-β 信号通路增强肺腺癌转移
DOI:10.1038/s41419-021-03606-x
发表时间:2021-04-06
期刊:Cell death & disease
影响因子:9
作者:Xiong Y;Feng Y;Zhao J;Lei J;Qiao T;Zhou Y;Lu Q;Jiang T;Jia L;Han Y
通讯作者:Han Y
DOI:10.7507/1007-4848.202102010
发表时间:2023
期刊:中国胸心血管外科临床杂志
影响因子:--
作者:冯杨波;熊延路;赵晋波;雷杰;辛少伟;乔天运;周永生;张晓;姜涛;韩勇
通讯作者:韩勇
国内基金
海外基金
