mPRα介导孕激素抑制肺腺癌细胞生长的快速非基因组作用机制

批准号:
81572284
项目类别:
面上项目
资助金额:
55.0 万元
负责人:
陈琼
依托单位:
学科分类:
H1801.肿瘤病因
结题年份:
2019
批准年份:
2015
项目状态:
已结题
项目参与者:
游绍进、谢明萱、顾其华、周东波、肖锏、方霞、邹勇、邓荃文、卢晓晓
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中文摘要
肺腺癌生物学特性与女性激素密切相关。我们前期研究发现孕激素膜受体mPRα介导孕激素(P4)能抑制肺腺癌细胞生长,但分子机制不清。我们提出mPRα介导P4通过影响细胞膜离子通道功能、下调cAMP/PKA活性,抑制PKA调控的新陈代谢途径呈现快速非基因组抑癌效应。拟采用核外酵母双杂交、活细胞成像术等筛选及鉴定mPRα的相互作用蛋白质和调控网络;用CRISPR/Cas9基因敲除术、蛋白质磷酸化芯片、激光共聚焦及流式细胞术等研究孕激素处理前后、mPRα基因敲除前后肺腺癌细胞内依赖PKA的新陈代谢酶及功能蛋白的磷酸化水平差异及质膜上离子通道功能变化;肺腺癌动物模型观察P4/Org单独或联合吉非替尼、PP1等对肺腺癌移植瘤生长的抑制情况。以期阐明或发现新的由mPRα介导孕激素启动的抑制肺腺癌细胞生长的快速非基因组作用机制,同时为寻找肺腺癌治疗新靶点和减缓EGFR-TKIs耐药提供新思路。
英文摘要
The biological characteristics of lung adenocarcinoma are closely related to female hormones. Our previous studies have found that progesterone inhibits the growth of lung adenocarcinoma cells through membrane progesterone receptor α (mPRα) mediated pathway. However, the detailed molecular mechanisms are still unknown. We hypothesize that progesterone mediated by mPRα may activate the rapid non-genomic action with decreasing intracellular cAMP/PKA levels and inhibiting cell metabolism. By utilizing the cutting-age technologies such as yeast two-hybrid, laser co-focus microscopy, CRISPR/Cas9 gene knockout system, protein phosphorylation chip and lung cancer animal models, we plan to screen and identify the key proteins of mPRα associated signal transducing network. We will investigate the changes in the PKA-related metabolic enzymes, phosphorylation levels of various functional proteins and/or functional alternations of ion channels in plasma membrane, prior to vs. postior to mPRα gene knockout. We establish nude mouse model of human lung adenocarcinoma, and then study the inhibitory effect of P4/Org alone or with gefitinib or PP1on the growth of lung adenocarcinoma xenografts . The objectives of this study are to identify or clarify the non-genomic mechanisms of inhibitory effect of progesterone/mPRα in lung adenocarcinoma cancer cells, to perfect and discover a new mechanism of non-genomic tumor-inhibition by progesterone which is mediated by mPRα, in the meanwhile to provide clues for new treatment targets for lung adenocarcinoma and retard EGFR-TKIs resistance.
肺腺癌生物学特性与女性激素密切相关。我们前期研究发现孕激素膜受体mPRα介导孕激素(P4)能快速抑制肺腺癌细胞生长,但具体的分子机制不清。本项目在前期研究基础上,利用细胞、动物和临床标本阐明了mPRα通过EGFR-SRC-ERK1/2途径介导P4抑制肺腺癌细胞生长,改善肺腺癌对EGFR-TKI的敏感性的机制;并通过膜酵母双杂交技术以及免疫共沉淀技术筛选和鉴定了与mPRα具有相互作用的靶蛋白。同时利用细胞实验证明了PTEN通过下调PI3K/AKT/hTERT通路诱导肺腺癌A549细胞细胞周期阻滞;Twist1、RhoC在肺腺癌的EMT过程中起着重要作用。此外在临床水平阐明了mPRα、孕激素水平与患者临床病理特征的关系。我们的研究阐明了mPRα介导孕激素启动的抑制肺腺癌细胞生长的潜在的快速非基因组作用机制,为寻找肺腺癌治疗新靶点和减缓EGFR-TKIs耐药提供新思路。
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
Prognostic significance of TCF21 mRNA expression in patients with lung adenocarcinoma.
TCF21 mRNA表达在肺腺癌患者中的预后意义
DOI:10.1038/s41598-017-02290-2
发表时间:2017-05-17
期刊:Scientific reports
影响因子:4.6
作者:Xiao J;Liu A;Lu X;Chen X;Li W;He S;He B;Chen Q
通讯作者:Chen Q
Eight potential biomarkers for distinguishing between lung adenocarcinoma and squamous cell carcinoma.
区分肺腺癌和鳞状细胞癌的八种潜在生物标志物
DOI:10.18632/oncotarget.17606
发表时间:2017-09-22
期刊:Oncotarget
影响因子:--
作者:Xiao J;Lu X;Chen X;Zou Y;Liu A;Li W;He B;He S;Chen Q
通讯作者:Chen Q
mPRalpha mediates P4/Org OD02-0 to improve the sensitivity of lung adenocarcinoma to EGFR-TKIs via the EGFR-SRC-ERK1/2 pathway
mPRalpha介导P4/Org OD02-0通过EGFR-SRC-ERK1/2通路提高肺腺癌对EGFR-TKIs的敏感性
DOI:10.1002/mc.23139
发表时间:2020
期刊:Molecular Carcinogenesis
影响因子:4.6
作者:Lu Xiaoxiao;Guan Anqi;Chen Xi;Xiao Jian;Xie Mingxuan;Yang Baishuang;He Shuya;You Shaojin;Li Wei;Chen Qiong
通讯作者:Chen Qiong
Systematic review and meta-analysis of the utility of long non-coding RNA GAS5 as a diagnostic and prognostic cancer biomarker.
长链非编码 RNA GAS5 作为诊断和预后癌症生物标志物用途的系统回顾和荟萃分析
DOI:10.18632/oncotarget.19040
发表时间:2017-09-12
期刊:Oncotarget
影响因子:--
作者:Li W;Li N;Shi K;Chen Q
通讯作者:Chen Q
Neutrophil extracellular traps promote lipopolysaccharide-induced airway inflammation and mucus hypersecretion in mice.
中性粒细胞胞外陷阱促进脂多糖诱导的小鼠气道炎症和粘液分泌过多
DOI:10.18632/oncotarget.24022
发表时间:2018-03-02
期刊:Oncotarget
影响因子:--
作者:Zou Y;Chen X;Xiao J;Bo Zhou D;Xiao Lu X;Li W;Xie B;Kuang X;Chen Q
通讯作者:Chen Q
衰老中性粒细胞NOD2棕榈酰化修饰诱导线粒体自噬促进NETs形成加剧COPD慢性炎症的研究
- 批准号:82370055
- 项目类别:面上项目
- 资助金额:49万元
- 批准年份:2023
- 负责人:陈琼
- 依托单位:
孕激素经c-MYC调节SIRT1/PGC-1α信号轴拮抗线粒体氧化应激改善COPD的机制研究
- 批准号:81770045
- 项目类别:面上项目
- 资助金额:50.0万元
- 批准年份:2017
- 负责人:陈琼
- 依托单位:
国内基金
海外基金
