The nuclear orphan receptor NR4A1 regulates β1-integrin expression in pancreatic and colon cancer cells and can be targeted by NR4A1 antagonists.
The nuclear orphan receptor NR4A1 regulates β1-integrin expression in pancreatic and colon cancer cells and can be targeted by NR4A1 antagonists.
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DOI：
10.1002/mc.22662
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发表时间：
2017-09
影响因子：
4.6
通讯作者：
Safe S
中科院分区：
文献类型：
--
作者：
Hedrick E;Lee SO;Safe S
β1-整合素是结肠癌和胰腺癌患者的高表达并且是负预后因子，并且该基因在细胞迁移和侵袭中起功能性作用。在这项研究中，我们证明了胰腺癌和结肠癌细胞中β1-整合素的表达受原癌孤儿核受体4A 1（NR 4A 1，Nur 77，TR 3）的调节，通过RNA干扰敲低该受体可降低β1-整合素蛋白和mRNA的表达，α5-整合素以及β1-整合素依赖的FAK磷酸化（pFak）的表达。NR 4A 1的敲除还降低了胰腺癌细胞（Panc 1、L3.6pL和MiaPaCa 2）和结肠癌细胞（RKO和SW 480）中的迁移和纤连蛋白诱导的粘附。含有对羟基（DIM-C-pPhOH）和对甲氧羰基（DIM-C-pPhCO 2 Me）的1，1-二（3′-吲哚基）-1-（p-取代苯基）甲烷（C-DIM）化合物是作为该受体拮抗剂的NR 4A 1配体。用DIM-C-pPhOH或DIM-C-pPhCO 2 Me处理胰腺癌和结肠癌细胞模拟NR 4A 1敲低的作用，并降低β1-整联蛋白表达、β1-整联蛋白调节的基因以及包括迁移和粘附的应答。结果证明了一种靶向结肠癌和胰腺癌细胞中β1-整联蛋白的新方法，并表明C-DIM/NR 4A 1拮抗剂用于胰腺癌和结肠癌治疗的可能临床应用。
β1-Integrin is highly expressed and is a negative prognostic factor for colon and pancreatic cancer patients and the gene plays a functional role in cell migration and invasion. In this study, we demonstrate that β1-integrin expression is regulated in pancreatic and colon cancer cells by the pro-oncogenic orphan nuclear receptor 4A1 (NR4A1, Nur77, TR3) and knockdown of this receptor by RNA interference decreases β1-integrin protein and mRNA expression, α5-integrin and also expression of β1-integrin-dependent phosphorylation of FAK (pFak). Knockdown of NR4A1 also decreased migration and fibronectin-induced adhesion in pancreatic (Panc1, L3.6pL and MiaPaCa2) and colon (RKO and SW480) cancer cells. 1,1-Bis(3′-indolyl)-1-(p-substituted phenyl)methane (C-DIM) compounds containing p-hydroxy (DIM-C-pPhOH) and p-carbomethoxy (DIM-C-pPhCO2Me) groups are NR4A1 ligands that act as antagonists for this receptor. Treatment of pancreatic and colon cancer cells with DIM-C-pPhOH or DIM-C-pPhCO2Me mimics the effects of NR4A1 knockdown and decreases β1-integrin expression, β1-integrin regulated genes and responses including migration and adhesion. The results demonstrate a novel method for targeting β1-integrin in colon and pancreatic cancer cells and indicate possible clinical applications for C-DIM/NR4A1 antagonists for pancreatic and colon cancer therapy.
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影响因子：
11.2
作者：
Lee SO;Abdelrahim M;Yoon K;Chintharlapalli S;Papineni S;Kim K;Wang H;Safe S
通讯作者：
Safe S
PRL-3 通过 PRL-3-整合素 beta1-ERK1/2 和-MMP2 信号传导促进 LoVo 结肠癌细胞的运动、侵袭和转移。
影响因子：
37.3
作者：
Peng L;Xing X;Li W;Qu L;Meng L;Lian S;Jiang B;Wu J;Shou C
通讯作者：
Shou C
影响因子：
3.7
作者：
Hedrick E;Lee SO;Kim G;Abdelrahim M;Jin UH;Safe S;Abudayyeh A
通讯作者：
Abudayyeh A
影响因子：
6.4
作者：
Grzesiak, John J.;Cao, Hop S. Tran;Burton, Douglas W.;Kaushal, Sharmeela;Vargas, Fabian;Clopton, Paul;Snyder, Cynthia S.;Deftos, Leonard J.;Hoffman, Robert M.;Bouvet, Michael
通讯作者：
Bouvet, Michael
影响因子：
11.2
作者：
Ke, N;Claassen, G;Li, QX
通讯作者：
Li, QX