Abstract
Matrix metalloproteinases (MMPs) comprise a family of 23 zinc-dependent enzymes involved in various pathologic and physiologic processes. In cancer, MMPs contribute to processes from tumour initiation to establishment of distant metastases. Complex signalling and protein transport networks regulate MMP synthesis, cell surface presentation and release. Earlier attempts to disrupt MMP activity in patients have proven to be intolerable and with underwhelming clinical efficacy; thus targeting ancillary proteins that regulate MMP activity may be a useful therapeutic approach. Extracellular matrix metalloproteinase inducer (EMMPRIN) was originally characterized as a factor present on lung cancer cells, which stimulated collagenase (MMP-1) production in fibroblasts. Subsequent studies demonstrated that EMMPRIN was identical with several other protein factors, including basigin (Bsg), all of which are now commonly termed CD147. CD147 modulates the synthesis and activity of soluble and membrane-bound [membrane-type MMPs (MT-MMPs)] in various contexts via homophilic/heterophilic cell interactions, vesicular shedding or cell-autonomous processes. CD147 also participates in inflammation, nutrient and drug transporter activity, microbial pathology and developmental processes. Despite the hundreds of manuscripts demonstrating CD147-mediated MMP regulation, the molecular underpinnings governing this process have not been fully elucidated. The present review summarizes our present knowledge of the complex regulatory systems influencing CD147 biology and provides a framework to understand how CD147 may influence MMP activity.
Highlights
Cluster of differentiation 147 (CD147) was initially identified in various species and tissues as the antigens RET-PE2 [1], CE9 [2] and OX-47 [3] in rats, antigen gp42 [4] and basigin [5] in mice, antigen HT7 [6], neurothelin [7] and antigen 5A11 [8] in chickens, and human leucocyte activation-associated antigen M6 [9], blood group Oka antigen [10], hepatoma-associated antigen HAb18G [11] and extracellular matrix metalloproteinase inducer (EMMPRIN) [12] in humans
We recently found that up-regulation of CD147 expression in non-transformed breast epithelial cells, which resulted in a higher proportion of the 38 kDa compared with 52–58 kDa glycoform, led to similar induction of MMP activity as the previously mentioned effects of HG-CD147 [85]
Of note, elevated MT1-MMP expression was observed after up-regulation of CD147 in our study, though the majority of MT1-MMP remained in the cytoplasm and the proportion that was trafficked to the cell surface probably resided in CD147-enriched lipid rafts
Summary
Cluster of differentiation 147 (CD147) was initially identified in various species and tissues as the antigens RET-PE2 [1], CE9 [2] and OX-47 [3] in rats, antigen gp42 [4] and basigin [5] in mice, antigen HT7 [6], neurothelin [7] and antigen 5A11 [8] in chickens, and human leucocyte activation-associated antigen M6 [9], blood group Oka antigen [10], hepatoma-associated antigen HAb18G [11] and extracellular matrix metalloproteinase inducer (EMMPRIN) [12] in humans. The initial characterization of CD147 in cancer cells demonstrated a proportion of CD147 in tumour-conditioned media [14] and subsequent studies have shown that CD147 is released from the cell surface in a full length soluble form [92] or a 22-kDa proteolytic cleavage product not associated with vesicles [93].
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