C/EBP Mediates TNF--Induced Cancer Cell Migration by Inducing MMP Expression Dependent on p38 MAPK
C/EBP Mediates TNF--Induced Cancer Cell Migration by Inducing MMP Expression Dependent on p38 MAPK
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C/EBP 通过诱导依赖于 p38 MAPK 的 MMP 表达来介导 TNF 诱导的癌细胞迁移
DOI：
10.1002/jcb.25219
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发表时间：
2015-12-01
影响因子：
4
通讯作者：
Ge, Gaoxiang
中科院分区：
文献类型：
--
作者：
Xia, Peiyi;Zhang, Rui;Ge, Gaoxiang
肿瘤坏死因子是一种多效性细胞因子，可触发细胞增殖、细胞死亡或炎症。除了对癌细胞的细胞毒作用外，肿瘤坏死因子还具有促肿瘤活性。异常的肿瘤坏死因子信号促进癌细胞的运动、侵袭和促进肿瘤转移。肿瘤细胞的过度迁移、侵袭和转移被认为是由于激活了核因子-B信号。目前尚不清楚是否有其他信号通路和效应分子参与了肿瘤坏死因子诱导的癌细胞迁移和转移。肿瘤坏死因子治疗后，参与新陈代谢、炎症和癌症的转录因子C/EBP的表达增加。肿瘤坏死因子通过增强C/EBP的转录和蛋白稳定性来诱导其表达。在肿瘤坏死因子诱导的C/EBP蛋白的稳定中，p38MAPK的激活起作用，而不是核因子-B或JNK。C/EBP参与了肿瘤坏死因子诱导的癌细胞迁移。C/EBP基因敲除可抑制肿瘤坏死因子诱导的细胞迁移，而C/EBP基因过表达则增加癌细胞迁移。C/EBP利用替代的框内翻译起始点被翻译成转录激活因子LAP1和LAP2以及转录抑制因子LIP。尽管肿瘤坏死因子诱导了所有三种异构体的表达，但LAP1/2而不是LIP促进了癌细胞的迁移。肿瘤坏死因子诱导的MMP1/3表达可被C/EBP基因敲除或p38MAPK抑制。MMP1/3抑制剂或MMP1/3基因敲除可抑制肿瘤坏死因子-1和C/EBP诱导的细胞迁移。因此，C/EBP通过诱导MMP1/3的表达来介导肿瘤坏死因子诱导的癌细胞迁移，并可能参与调控炎症相关的肿瘤转移。J.细胞。生物化学。2015年，116：2766-2777。(C)2015年威利期刊公司。
Tumor necrosis factor (TNF)- is a pleiotropic cytokine that triggers cell proliferation, cell death, or inflammation. Besides its cytotoxic effect on cancer cells, TNF- exerts tumor promoting activity. Aberrant TNF- signaling promotes cancer cell motility, invasiveness, and enhances cancer metastasis. Exaggerated tumor cell migration, invasion, and metastasis by TNF- has been attributed to the activation of NF-B signaling. It is yet to be elucidated if other signaling pathways and effector molecules are involved in TNF--induced cancer cell migration and metastasis. Expression of C/EBP, a transcription factor involved in metabolism, inflammation, and cancer, is increased upon TNF- treatment. TNF- induces C/EBP expression by enhancing its transcription and protein stability. Activation of p38 MAPK, but not NF-B or JNK, is responsible for TNF--induced stabilization of C/EBP protein. C/EBP is involved in TNF--induced cancer cell migration. Knockdown of C/EBP inhibits TNF--induced cell migration, while overexpression of C/EBP increases migration of cancer cells. C/EBP is translated into transcriptional activator LAP1 and LAP2 and transcriptional repressor LIP utilizing alternative in-frame translation start sites. Despite TNF- induces expression of all three isoforms, LAP1/2, but not LIP, promote cancer cell migration. TNF- induced MMP1/3 expression, which was abrogated by C/EBP knockdown or p38 MAPK inhibition. MMP inhibitor or knockdown of MMP1/3 diminished TNF-- and C/EBP-induced cell migration. Thus, C/EBP mediates TNF--induced cancer cell migration by inducing MMP1/3 expression, and may participate in the regulation of inflammation-associated cancer metastasis. J. Cell. Biochem. 116: 2766-2777, 2015. (c) 2015 Wiley Periodicals, Inc.