Blimp-1 transcriptionally induced by growth factors, TNF-α and TLR ligands inhibits keratinocyte migration and inflammation but enhances cell migration in squamous cell carcinoma

Abstract

Abstract B lymphocyte-induced maturation protein-1 (Blimp-1) is a transcriptional repressor, and plays a crucial role in the regulation of development and functions of various immune cells. Currently, there is limited understanding about the regulation of Blimp-1 expression and cellular functions in keratinocytes and cancer cells. The aim of the study was to investigate the regulation and functional link between EGFR and Blimp-1 in human epidermal keratinocytes and squamous cell carcinoma (SCC). We found that EGF, PMA, TNF-α, LPS (TLR4 activator) and polyIC (TLR3 activator) can upregulate the protein and mRNA levels of Blimp-1 in NHEK and/or HaCaT cells. This effect of EGF was dependent on PKC, p38, and ERK activation, and Syk is also involved in the action of PMA. Additionally, the stability of Blimp-1 protein was under the control of the proteasome and lysosome degradation systems. PMA, LPS and polyIC also can activate EGFR and Syk in HaCaT cells. In addition, Blimp-1 knockdown enhanced the EGFR-mediated IL8, CXCL5 and IL6 gene expression and keratinocyte migration, but reduced the EGFR-mediated suppression of differentiation marker K10. On the other hand, EGF, TNF-α, TGF-β and PMA could also upregulate Blimp-1 expression in SCC, and EGFR activation by TNF-α and PMA was observed. Unlike the action of Blimp-1 in keratinocytes, Blimp-1 silencing reduces SCC cell migration either in the absence or presence of TNF-α and PMA. Taken together, Blimp-1 can be upregulated by several growth factors, innate immune receptors and PKC signaling pathway. Blimp-1 is a negative regulator of EGF-induced inflammation and migration in keratinocytes, but mediates cell migration in SCC.