LRG-1通过Endoglin活化肿瘤相关成纤维细胞促胰腺癌转移的机制研究

批准号:
81902432
项目类别:
青年科学基金项目
资助金额:
20.0 万元
负责人:
谢志波
依托单位:
学科分类:
H1808.肿瘤微环境
结题年份:
2022
批准年份:
2019
项目状态:
已结题
项目参与者:
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中文摘要
胰腺癌是恶性程度最高的肿瘤之一,常早期发生转移。胰腺癌相关成纤维细胞 (CAF)的活化是胰腺癌侵袭转移的重要因素。TGF-β信号通路是调控CAF活化的关键通路。项目组前期研究发现LRG-1是调控胰腺癌侵袭转移的重要因子,且LRG-1已被证实可通过endoglin激活TGF-β下游Smad-1/5/8信号通路。本项目组预实验亦发现LRG-1表达与胰腺癌肝转移相关,且外源性LRG-1能够调控胰腺癌相关CAF的活化。基于以上证据,本项目组提出如下假说:LRG-1可通过结合endoglin激活TGF-β信号通路,活化CAF,从而促胰腺癌转移。本项目拟先研究LRG-1与胰腺癌转移及CAF活化的关系,进而探讨endoglin/TGF-β信号通路介导了LRG-1调控CAF活化的作用;最后通过在体干预实验,明确LRG-1中和抗体对转移性胰腺癌的治疗作用。通过本研究,为治疗转移性胰腺癌寻找新的靶点。
英文摘要
Pancreatic ductal adenocarcinoma (PDAC) is the one of most malignant tumors and always associate with early metastasis. PDAC associated fibroblast (CAF) is the key factor which promotes the metastasis of PDAC. TGF-β signaling pathway is the key regulator of activating CAF and modulating the phenotype of CAF. Our team has previous found that leucine-rich-alpha-2-glycoprotein 1 (LRG-1) is essential for promoting the PDAC metastasis. And LRG-1 facilitate the malignant behavior of malignant tumors through binding endoglin and activating TGF-β download signaling pathways (Smad-1/5/8). Our previous researches find out that LRG-1 expressions are correlated with PDAC liver metastasis, and LRG-1 could further activate human primary CAF. Based on above evidence, we hypothesis that LRG-1 actives TGF-β signaling pathway via the interaction with endoglin, thus to modulate the activation of CAF and to promote PDAC metastasis. We firstly would like to investigate the relationship between LRG-1 expression and PDAC metastasis, and the relationship between LRG-1 expression and the activation of CAF. Next, to explore the effect of LRG-1 on the CAF in PDAC cells. Moreover, to demonstrate the exact mechanism of how LRG-1 activates CAF in PDAC cells. Fellow animal models are used to prove the mechanism of how LRG-1 promotes PDAC metastasis. This project is aimed to identify the exact role of LRG-1 modulated PDAC metastasis, and further to clarify LRG-1 is the therapeutic target for treating metastatic PDAC. From this, we could search the new target to treat PDAC metastasis.
胰腺癌是恶性程度最高的恶性肿瘤之一,常早期发生转移。胰腺癌相关成纤维细胞 (CAF)的活化是胰腺癌侵袭转移的重要因素。TGF-β信号通路是调控CAF活化的关键通路。项目组前期研究发现LRG-1是调控胰腺癌侵袭转移的重要因子,且LRG-1已被证实可通过endoglin激活TGF-β下游Smad-1/5/8信号通路。本项目组预实验亦发现LRG-1表达水平与胰腺癌肝转移成正相关,且外源性LRG-1能够调控胰腺癌相关CAF的活化。基于以上证据,本项目组提出如下假说:LRG-1可通过结合endoglin激活TGF-β信号通路,活化CAF,从而促胰腺癌转移。本项目拟先研究LRG-1与胰腺癌转移及CAF活化的关系,进而探讨endoglin/TGF-β信号通路介导了LRG-1调控 CAF活化的作用;最后通过在体干预实验,明确LRG-1中和抗体对转移性胰腺癌的治疗作用。研究发现,在人体组织中,LRG-1表达水平与胰腺癌肝转移成正相关,且发生肝转移的胰腺癌患者本身的胰腺组织中CAF显著活化,且其活化程度与LRG-1的表达呈正相关。原位胰腺癌模型中也发现过表达LRG-1可显著的促进胰腺癌肝转移,且其表达与肝转移的胰腺组织中CAF活化密切相关。进一步体外实验证实外源性LRG-1可明显促进CAF活化、增殖、凋亡与迁移能力,且发现外源性LRG-1对原代CAF的调控作用呈剂量-依赖性。进一步的机制实验证实外源性LRG-1可激活胰腺癌相关CAF中TGF-β信号通路。通过本研究探索靶向LRG-1对转移性PDAC进行精准治疗的可能性,探索靶向LRG-1的临床转化价值,为预防及治疗转移性PDAC提供新理论及新思路。
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
Exosome-delivered CD44v6/C1QBP complex drives pancreatic cancer liver metastasis by promoting fibrotic liver microenvironment
外泌体递送的 CD44v6/C1QBP 复合物通过促进肝脏纤维化微环境驱动胰腺癌肝转移
DOI:10.1136/gutjnl-2020-323014
发表时间:2021-04-06
期刊:GUT
影响因子:24.5
作者:Xie, Zhibo;Gao, Ya;Zhang, Yi-Fan
通讯作者:Zhang, Yi-Fan
Controlling Nutritional Status score is superior to Prognostic Nutritional Index score in predicting survival and complications in pancreatic ductal adenocarcinoma: a Chinese propensity score matching study
控制营养状况评分在预测胰腺导管腺癌生存和并发症方面优于预后营养指数评分:一项中国倾向评分匹配研究
DOI:10.1017/s0007114520002299
发表时间:2020-12-14
期刊:BRITISH JOURNAL OF NUTRITION
影响因子:3.6
作者:Mao, Yi-Shen;Hao, Si-Jie;Fu, De-Liang
通讯作者:Fu, De-Liang
呼吸应力通过Piezo2-mTOR抑制巨噬细胞自噬调控外泌体分泌促喉气道纤维化的机制研究
- 批准号:82271151
- 项目类别:面上项目
- 资助金额:52万元
- 批准年份:2022
- 负责人:谢志波
- 依托单位:
国内基金
海外基金
