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C/EBPβ Mediates TNF‐α‐Induced Cancer Cell Migration by Inducing MMP Expression Dependent on p38 MAPK
Author(s) -
Xia Peiyi,
Zhang Rui,
Ge Gaoxiang
Publication year - 2015
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.25219
Subject(s) - cancer cell , cancer research , tumor necrosis factor alpha , cell migration , gene knockdown , biology , microbiology and biotechnology , mapk/erk pathway , cell , signal transduction , chemistry , cancer , apoptosis , immunology , biochemistry , genetics
Tumor necrosis factor (TNF)‐α is a pleiotropic cytokine that triggers cell proliferation, cell death, or inflammation. Besides its cytotoxic effect on cancer cells, TNF‐α exerts tumor promoting activity. Aberrant TNF‐α signaling promotes cancer cell motility, invasiveness, and enhances cancer metastasis. Exaggerated tumor cell migration, invasion, and metastasis by TNF‐α has been attributed to the activation of NF‐κB signaling. It is yet to be elucidated if other signaling pathways and effector molecules are involved in TNF‐α‐induced cancer cell migration and metastasis. Expression of C/EBPβ, a transcription factor involved in metabolism, inflammation, and cancer, is increased upon TNF‐α treatment. TNF‐α induces C/EBPβ expression by enhancing its transcription and protein stability. Activation of p38 MAPK, but not NF‐κB or JNK, is responsible for TNF‐α‐induced stabilization of C/EBPβ protein. C/EBPβ is involved in TNF‐α‐induced cancer cell migration. Knockdown of C/EBPβ inhibits TNF‐α‐induced cell migration, while overexpression of C/EBPβ increases migration of cancer cells. C/EBPβ is translated into transcriptional activator LAP1 and LAP2 and transcriptional repressor LIP utilizing alternative in‐frame translation start sites. Despite TNF‐α induces expression of all three isoforms, LAP1/2, but not LIP, promote cancer cell migration. TNF‐α induced MMP1/3 expression, which was abrogated by C/EBPβ knockdown or p38 MAPK inhibition. MMP inhibitor or knockdown of MMP1/3 diminished TNF‐α‐ and C/EBPβ‐induced cell migration. Thus, C/EBPβ mediates TNF‐α‐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. © 2015 Wiley Periodicals, Inc.