title: C/EBPβ Mediates TNF-α-Induced Cancer Cell Migration by Inducing MMP Expression Dependent on p38 MAPK.
abstract: 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.
authors.affiliation: Key Laboratory of Systems Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, People's Republic of China.
authors.forename: Peiyi
authors.initials: P
authors.lastname: Xia
authors.affiliation: Key Laboratory of Systems Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, People's Republic of China.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Systems Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, People's Republic of China.
authors.forename: Gaoxiang
authors.initials: G
authors.lastname: Ge
mesh_terms: D022782:CCAAT-Enhancer-Binding Protein-beta / Q000096:biosynthesis* / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis / Q000235:genetics*; D016328:NF-kappa B / Q000235:genetics; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D011401:Promoter Regions, Genetic; D015398:Signal Transduction / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis*
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; D016328:NF-kappa B; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1
keywords: C/EBPβ; CELL MIGRATION; INFLAMMATION; MMP; TNF-α; p38 MAPK