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.