CD147-Cyclophilin a Interactions Promote Proliferation and Survival of Cutaneous T-Cell Lymphoma

Abstract

CD147, a transmembrane glycoprotein that belongs to the immunoglobulin superfamily, and cyclophilin A (CypA), one of the binding partners of CD147, are overexpressed in tumor cells and associated with the progression of several malignancies, including both solid and hematological malignancies. However, CD147 and CypA involvement in cutaneous T-cell lymphoma (CTCL) has not been reported. In this study, we examined CD147 and CypA expression and function using clinical samples of mycosis fungoides (MF) and Sézary syndrome (SS) and CTCL cell lines. CD147 and CypA were overexpressed by tumor cells of MF/SS, and CypA was also expressed by epidermal keratinocytes in MF/SS lesional skin. Serum CypA levels were increased and correlated with disease severity markers in MF/SS patients. Anti-CD147 antibody and/or anti-CypA antibody suppressed the proliferation of CTCL cell lines, both in vitro and in vivo, via downregulation of phosphorylated extracellular-regulated kinase 1/2 and Akt. These results suggest that CD147-CypA interactions can contribute to the proliferation of MF/SS tumor cells in both a autocrine and paracrine manner, and that the disruption of CD147-CypA interactions could be a new therapeutic strategy for the treatment of MF/SS.

Mini-Review: Can the Metastatic Cascade Be Inhibited by Targeting CD147/EMMPRIN to Prevent Tumor Recurrence?

“…CD147 also regulates Hyaluronan synthesis and can bind to the Hyaluronan receptor CD44, contributing to tumor cell invasiveness and chemoresistance ( 119 , 135 ). Extracellular Cyclophilin, especially Cyclophilin A (CyPA) secreted by tumor cells, binds to its receptor CD147 to enhance tumor cell proliferation and survival and leukocyte chemotaxis and adhesion ( 105 , 136 ). It was also suggested that by binding to CD147, CypA enhanced the localization of CD147 and CD44 complexes to lipid rafts and initiated a STAT3 signaling, thus activating Cyclin D1 and Survivin and promoting cell proliferation and survival ( 118 ).…”

“…Invasiveness of malignant cells was associated with the increased expression of another binding partner - S100A9 ( 122 , 139 ). Most importantly, CD147 activates the Wnt, the TGFβ1-Smad4, and/or the ERK1/2 pathways to enhance cell proliferation ( 101 , 105 , 140 , 141 ), potentially implicating CD147 in the regulation of metastasis and escape from dormancy. Collectively, these studies suggest that CD147 acts as a scaffold protein that promotes the assembly of many proteins into one or more signaling complexes that enhances cell proliferation, metabolism, angiogenesis, invasiveness, EMT and survival.…”

Current update on theranostic roles of cyclophilin A in kidney diseases

“…Besides the PPIase isomerization function, CyPA can be secreted to the extracellular compartment to mediate chemotactic effects 14 - 16 . This action occurs via specific binding of CyPA to a type I integral membrane glycoprotein, CD147 14 - 16 .…”

“…Besides the PPIase isomerization function, CyPA can be secreted to the extracellular compartment to mediate chemotactic effects 14 - 16 . This action occurs via specific binding of CyPA to a type I integral membrane glycoprotein, CD147 14 - 16 . Proline and glycine residues at positions 180 and 181 (P180 and G181) of the CD147 extracellular domain are the key amino acids that mediate CyPA-CD147 interaction 17 .…”

“…For almost two decades, we have known that CD147 is a membrane-bound glycoprotein that serves as a principal signaling receptor for circulating eCyPA 15 , 19 . It has been documented that eCyPA-CD147 binding can activate ERK/NF-κB pathway, leading to proinflammatory cytokines/chemokines release, leukocyte recruitment, and matrix overproduction 14 , 49 . Additional evidence has demonstrated that the complex of CyPA-CD147 is associated with inflammatory lesions 50 .…”