Inflammatory stimuli promote growth and invasion of pancreatic cancer cells through NF-κB pathway dependent repression of PP2Ac
Inflammatory stimuli promote growth and invasion of pancreatic cancer cells through NF-κB pathway dependent repression of PP2Ac
复制标题
炎症刺激通过 NF-kappa B 通路依赖的 PP2Ac 抑制促进胰腺癌细胞的生长和侵袭
DOI：
10.1080/15384101.2015.1127468
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发表时间：
2016-02-01
期刊：
影响因子：
4.3
通讯作者：
Li, Wei
中科院分区：
文献类型：
--
作者：
Tao, Min;Liu, Lu;Li, Wei
摘要以往的研究表明，炎症刺激可抑制已知的肿瘤抑制因子--蛋白磷酸酶2A(PP2A)。然而，PP2A抑制是否参与胰腺癌的进展还没有得到证实。采用脂多糖(LPS)和巨噬细胞条件培养液(MCM)建立体外炎症模型，研究炎症刺激对胰腺癌细胞生长和侵袭PP2A催化亚单位(PP2Ac)的影响。通过裸鼠原位移植瘤模型和二丁基二氯化锡(DBTC)诱导的慢性胰腺炎模型，我们在体内评价了炎症微环境对PP2Ac表达的影响。我们克隆了PP2Acα和PP2Acβ异构体启动子，以研究PP2Ac转录调控机制。MCM促进胰腺癌细胞生长，MCM和内毒素促进细胞侵袭。DBTC促进移植瘤生长和转移，诱导肿瘤相关巨噬细胞浸润，促进血管生成，激活核因子-κB(NF-κB)途径，抑制PP2Ac表达。在体外，内毒素和MCM下调PP2Ac基因和蛋白的表达。PP2Acα过表达可抑制JNK、ERK、PKC和IKK的磷酸化，降低脂多糖刺激的细胞侵袭和MCM促进的细胞生长。脂多糖和丝裂霉素在体外激活了NF-κB通路。LPS和MCM诱导IKK和IκB的磷酸化，导致p65/relA核转位和转录激活。过表达主要的IKK负性形式的α可减弱内毒素和巨噬细胞对PP2Ac的下调，提示炎症刺激抑制PP2Ac的表达是依赖于NF-κB途径的。荧光素酶报告基因分析证实，内毒素和微囊藻毒素通过依赖于NF-κB的途径下调PP2Ac的转录。我们的研究提出了一种新的机制，通过依赖于NF-κB通路的PP2Ac抑制炎症驱动的癌症进展。
ABSTRACT Previous studies have indicated that inflammatory stimulation represses protein phosphatase 2A (PP2A), a well-known tumor suppressor. However, whether PP2A repression participates in pancreatic cancer progression has not been verified. We used lipopolysaccharide (LPS) and macrophage-conditioned medium (MCM) to establish in vitro inflammation models, and investigated whether inflammatory stimuli affect pancreatic cancer cell growth and invasion PP2A catalytic subunit (PP2Ac)-dependently. Via nude mouse models of orthotopic tumor xenografts and dibutyltin dichloride (DBTC)-induced chronic pancreatitis, we evaluated the effect of an inflammatory microenvironment on PP2Ac expression in vivo. We cloned the PP2Acα and PP2Acβ isoform promoters to investigate the PP2Ac transcriptional regulation mechanisms. MCM accelerated pancreatic cancer cell growth; MCM and LPS promoted cell invasion. DBTC promoted xenograft growth and metastasis, induced tumor-associated macrophage infiltration, promoted angiogenesis, activated the nuclear factor-κB (NF-κB) pathway, and repressed PP2Ac expression. In vitro, LPS and MCM downregulated PP2Ac mRNA and protein. PP2Acα overexpression attenuated JNK, ERK, PKC, and IKK phosphorylation, and impaired LPS/MCM-stimulated cell invasion and MCM-promoted cell growth. LPS and MCM activated the NF-κB pathway in vitro. LPS and MCM induced IKK and IκB phosphorylation, leading to p65/RelA nuclear translocation and transcriptional activation. Overexpression of the dominant negative forms of IKKα attenuated LPS and MCM downregulation of PP2Ac, suggesting inflammatory stimuli repress PP2Ac expression NF-κB pathway–dependently. Luciferase reporter gene assay verified that LPS and MCM downregulated PP2Ac transcription through an NF-κB–dependent pathway. Our study presents a new mechanism in inflammation-driven cancer progression through NF-κB pathway–dependent PP2Ac repression.