C/EBP Mediates TNF--Induced Cancer Cell Migration by Inducing MMP Expression Dependent on p38 MAPK

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.