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胰腺癌内质网应激微环境活化NF-κB通路对内质网分子伴侣GRP78的调控作用
NF-κB signaling is activated by endoplasmic reticulum stress microenvironment in pancreatic cancer and regulates endoplasmic reticulum chaperon GRP78
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DOI:
作者:
施思,刘辰,徐永锋,程合,鹿语,虞先濬
SHI Si,LIU Chen,XU Yongfeng,CHENG He,LU Yu,YU Xianjun
作者单位:
复旦大学附属肿瘤医院胰腺肝胆外科,复旦大学上海医学院肿瘤学系,复旦大学胰腺肿瘤研究所
Department of Pancreatic and Hepatobiliary Surgery,Fudan University Shanghai Cancer Center;Department of Oncology,Shanghai Medical College,Fudan University;Pancreatic Cancer Institute,Fudan University,Shanghai 200032,China.
关键词:
胰腺癌;内质网应激;核转录因子κB;葡萄糖调节蛋白78
Pancreatic cancer;Endoplasmic reticulum stress;NF-κB;GRP78
摘要:
目的 胰腺癌是一种恶性程度高,预后差的肿瘤,这可能与其乏氧乏血供所导致的特殊的肿瘤微环境密切相关。为适应这种微环境,一系列胰腺癌相关信号通路被激活,又促进了胰腺癌的进展。NF-κB信号通路已被证实在胰腺癌中高度活化,并与胰腺癌的发生、发展密切相关,但其与胰腺癌肿瘤微环境的相关性尚未可知。本研究旨在探讨内质网应激肿瘤微环境对胰腺癌中NF-κB信号通路的激活效应及NF-κB对内质网应激分子伴侣GRP78的调控作用。方法 蛋白印迹法(Western Blot)检测内质网应激诱导剂毒胡萝卜素(thapsigargin,Tg)处理后人胰腺癌PANC-1细胞内质网分子伴侣GRP78和NF-κB信号通路相关分子的表达变化;RNA干扰NF-κB/p65表达后,GRP78的表达变化。通过反复Tg诱导PANC-1细胞,建立内质网应激诱导细胞系PANC-ERS,并通过CCK-8比色法检测其增殖能力及Transwell迁移试验检测其迁移能力。同时,用Western Blot检测PANC-ERS细胞GRP78和NF-κB信号通路相关分子的表达变化。结果 Tg诱导PANC-1细胞内质网应激后GRP78和NF-κB/p65蛋白表达上调。RNA干扰NF-κB/p65表达后,GRP78的蛋白表达下调。CCK-8增殖试验和Transwell迁移试验显示PANC-ERS的增殖和迁移能力均较PANC-1增强,并且NF-κB/p65和GRP78表达也较PANC-1高。结论 体外模拟胰腺癌内质网应激微环境, NF-κB信号通路可以被激活,同时GRP78表达上调。内质网应激微环境下GRP78表达上调可能和NF-κB信号通路激活相关。慢性的内质网应激刺激可以增加胰腺癌细胞的恶性表型,胰腺癌的高度恶性可能和其内质网应激微环境相关。
Objective Pancreatic cancer is a malignant tumor with a poor prognosis and this may be associated with its hypoxia and hypovascular tumor microenvironment. A lot of cancer-associated signaling pathways are activated to ensure that pancreatic cancer cells can survive in this microenvironment and also lead to more malignant phenotype. NF-κB signaling pathway has been identified to be widely activated in pancreatic cancer and promote tumor progression. However, its role in pancreatic cancer microenvironment is not clear. Methods The pancreatic cancer cell line, PANC-1, was treated with endoplasmic reticulum stress inducer thapsigargin (Tg) and the changes of GRP78 and the molecules in NF-κB signaling pathway were measured by Western blot. GRP78 protein was also detected with NF-κB/p65 down-regulation by RNA interference. We established a cell line named PANC-ERS through treating PANC-1 with Tg periodically and repeatedly. We performed CCK-8 proliferation assay and transwell migration assay to find out its proliferation and migration activity. Meanwhile, western blot was also conducted to detect the protein levels of GRP78 and the molecules in NF-κB signaling pathway. Results GRP78 and NF-κB/p65 were up-regulated after Tg treated. GRP78 was correspondingly down-regulated after NF-κB/p65 down-regulation by RNA interference. CCK-8 proliferation assay and transwell migration assay revealed that PANC-ERS becomes more proliferative and motile than PANC-1. The protein levels of GRP78 and NF-κB/p65 were also higher in PANC-ERS than PANC-1. Conclusion NF-κB signaling pathway can be activated in a stimulated endoplasmic reticulum stress microenvironment in vitro with GRP78 increased. Up-regulation of GRP78 in endoplasmic reticulum stress may correlate with NF-κB signaling pathway activation. Chronic stimulation of endoplasmic reticulum stress can result in more malignant phenotype of pancreatic cancer. The malignancy of pancreatic cancer may be related to endoplasmic reticulum stress microenvironment.
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