Downregulation of programmed cell death 4 by inflammatory conditions contributes to the generation of the tumor promoting microenvironment.
Downregulation of programmed cell death 4 by inflammatory conditions contributes to the generation of the tumor promoting microenvironment.
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DOI：
10.1002/mc.20660
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发表时间：
2010-09
影响因子：
4.6
通讯作者：
Murakami, Akira
中科院分区：
文献类型：
--
作者：
Yasuda, Michiko;Schmid, Tobias;Ruebsamen, Daniela;Colburn, Nancy H.;Irie, Kazuhiro;Murakami, Akira
大量证据表明炎症在肿瘤促进和癌变中的关键作用，并且已知肿瘤相关巨噬细胞促进肿瘤生长和扩散。程序性细胞死亡4（Programmed cell death 4，Pdcd 4）是一种新型的肿瘤抑制因子，虽然已有研究表明Pdcd 4在肿瘤促进中的功能和表达机制，但其在炎症中的作用机制尚不清楚。在本研究中，我们研究是否炎症刺激调节Pdcd 4的表达。12-O-十四烷酰佛波醇13-乙酸酯（TPA）抑制人单核细胞系（U937，THP-1）中pdcd 4 mRNA的表达。同样，细菌内毒素脂多糖（LPS）下调小鼠RAW 264.7和腹腔巨噬细胞中pdcd 4的水平。此外，LPS刺激的RAW264.7巨噬细胞的条件培养基抑制RAW264.7巨噬细胞中的pdcd 4 mRNA，并且用重组肿瘤坏死因子-α（TNF-α）和TNF-α特异性siRNA获得的结果表明TNF-α通过自分泌机制部分介导LPS触发的Pdcd 4下调。磷酸肌醇-3-激酶（PI 3 K）和c-jun N-末端激酶（JNK）的特异性抑制剂恢复LPS破坏的pdcd 4 mRNA。在MCF 7乳腺癌细胞中，TPA分化/活化的U937细胞的条件培养基抑制pdcd 4 mRNA。此外，使用siRNA敲低RAW264.7巨噬细胞中的pdcd 4显著增强LPS诱导的TNF-α蛋白产生以及干扰素-γ、CC趋化因子配体（Ccl）1、Ccl 20和白细胞介素-10 mRNA表达。这些结果表明，Pdcd 4抑制这些炎症介质的诱导。总之，巨噬细胞中Pdcd 4的丢失可能是建立炎症环境的关键步骤，而肿瘤细胞中的Pdcd 4的丢失有助于肿瘤进展。
Ample evidence has shown key roles of inflammation in tumor promotion and carcinogenesis, and tumor-associated macrophages are known to promote tumor growth and dissemination. Programmed cell death 4 (Pdcd4) is a novel tumor suppressor, and although various studies have revealed that the functions and expression mechanisms of Pdcd4 in tumor promotion, those in regard to inflammation remain unclear. In the present study, we examined whether inflammatory stimuli regulate Pdcd4 expression. 12-O-tetradecanoylphorbol 13-acetate (TPA) suppressed expression of pdcd4 mRNA in human monocytic cell lines (U937, THP-1). Similarly, the bacterial endotoxin lipopolysaccharide (LPS) downregulated pdcd4 level in mouse RAW264.7 and peritoneal macrophages. Furthermore, conditioned medium from LPS-stimulated RAW264.7 macrophages suppressed pdcd4 mRNA in RAW264.7 macrophages, and findings obtained with recombinant tumor necrosis factor-α (TNF-α) and TNF-α-specific siRNA suggested that TNF-α partly mediates LPS-triggered Pdcd4 downregulation via an autocrine mechanism. Specific inhibitors of phosphoinositide-3-kinase (PI3K) and c-jun N-terminus kinase (JNK) restored LPS-abolished pdcd4 mRNA. Consistently, in MCF7 mammary carcinoma cells, conditioned medium from TPA-differentiated/activated U937 cells suppressed pdcd4 mRNA. Additionally, knockdown of pdcd4 in RAW264.7 macrophages using siRNA significantly enhanced LPS-induced TNF-α protein production, and interferon-γ, CC chemokine ligand (Ccl) 1, Ccl20, and interleukin-10 mRNA expression. These results suggest that Pdcd4 suppresses the induction of these inflammatory mediators. Taken together, loss of Pdcd4 in macrophages may be a critical step in establishing the inflammatory environment while that in tumor cells contributes to tumor progression.
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影响因子：
56.9
作者：
Dorrello, N. Valerio;Peschiaroli, Angelo;Pagano, Michele
通讯作者：
Pagano, Michele
影响因子：
4.2
作者：
Murakami, A;Shigemori, T;Ohigashi, H
通讯作者：
Ohigashi, H
DOI：
10.1111/j.1749-6632.2009.04738.x
发表时间：
2009-01-01
期刊：
CONTEMPORARY CHALLENGES IN AUTOIMMUNITY
影响因子：
--
作者：
Nishimura, Miyuki;Kuboi, Yoshikazu;Imai, Toshio
通讯作者：
Imai, Toshio
影响因子：
4.4
作者：
Hilliard, Anja;Hilliard, Brendan;Chen, Youhai H.
通讯作者：
Chen, Youhai H.
影响因子：
6.4
作者：
Liu, L;Zhou, XH;Yuan, ZH
通讯作者：
Yuan, ZH