Modulation of CD147-induced matrix metalloproteinase activity: role of CD147 N-glycosylation

Abstract

Degradation of the basement membrane by MMPs (matrix metalloproteinases) is one of the most critical steps in tumour progression. CD147 is a tumour-associated antigen that plays a key regulatory role for MMP activities. In the present study, mass spectrum analysis demonstrated that the purified native CD147 from human lung cancer tissue was N-glycosylated and contained a series of high-mannose and complex-type N-linked glycan structures. Moreover, native glycosylated CD147 existed exclusively as oligomers in solution and directly stimulated MMP production more efficiently than non-glycosylated prokaryotic CD147. The glycosylation site mutation results indicated that, among three N-glycan attachment sites, the N152Q mutants were retained in the endoplasmic reticulum and unfolded protein response signalling was activated. This improper intracellular accumulation impaired its MMP-inducing activity. Increased β1,6-branching of N-glycans as a result of overexpression of GnT-V (N-acetylglucosaminyltransferase V) plays an important role in tumour metastasis. In the present study, we identified CD147 as a target protein of GnT-V and found that overexpression of GnT-V resulted in an elevated level of CD147 at the plasma membrane and in cell-conditioned medium, thereby increasing the induction of MMPs. The present study reveals the important role of N-glycosylation of CD147 in its biological function and implied that targeting aberrant β1,6-branching of N-glycans on CD147 would be valuable for the development of novel therapeutic modalities against carcinoma.

Molecular basis for MMP9 induction and disruption of epithelial cell-cell contacts by galectin-3

“…It is now established that glycosylation is crucial to CD147 biological function, as it is the highly glycosylated species of CD147 that are responsible for the induction of MMPs and are more susceptible to clustering (Iacono et al, 2007;. Interestingly, CD147 glycosylation is attributable to N-acetylglucosaminyltransferase V (MGAT5)-generated, b1,6-branched polylactosamine (Huang et al, 2013;, a glycan structure known to act as a binding partner for galectins (Newlaczyl and Yu, 2011). ), by contrast, displayed drastic impairment of MMP9 immunostaining compared to wildtype.…”

c-Jun-mediated β-1,3-N-acetylglucosaminyltransferase 8 expression: A novel mechanism regulating the invasion and metastasis of colorectal carcinoma cells

“…The glycosylated forms of CD147 are highly expressed on the cell surface of various types of tumor cell, including oral, breast, lung, bladder, kidney, laryngeal, pancreatic, gastric, colorectal cancer, glioma lymphoma and melanoma (20)(21)(22). Additionally, the glycosylated forms of CD147 are able to stimulate tumor cells to produce MMPs, particularly MMP2 and MMP9 (7,8,23). CD147 is able to induce MMP expression via phosphoinositide 3-kinase/protein kinase B (Akt)/inhibitor *** of nuclear factor κB (NF-κB) (IκB) kinase-dependent IκB-α degradation, which is mediated by Ras-related C3 botulinum toxin substrate 1, NF-κB activation and by mitogen-activated protein kinase kinase 7/c-Jun N-terminal kinase-dependent AP-1 activation (20).…”

“…The extracellular region of CD147 contains three Asn glycosylation sites, and the N-glycosylation sites make similar contributions to both high and low glycoforms of CD147 (HG-CD147 and LG-CD147, respectively) (6). A number of studies have confirmed that modulation of CD147 is associated with the expression of matrix metallopeptidases (MMPs) in normal and tumor tissues (7)(8)(9). High glycoforms of CD147 (HG-CD147) stimulate the production of matrix metalloproteinase (6,7).…”

“…A number of studies have confirmed that modulation of CD147 is associated with the expression of matrix metallopeptidases (MMPs) in normal and tumor tissues (7)(8)(9). High glycoforms of CD147 (HG-CD147) stimulate the production of matrix metalloproteinase (6,7). Additionally, increased HG-CD147 glycosylation has been attributed to β1-6-branched N-glycan to form polylactosamine structures (7,8).…”

“…High glycoforms of CD147 (HG-CD147) stimulate the production of matrix metalloproteinase (6,7). Additionally, increased HG-CD147 glycosylation has been attributed to β1-6-branched N-glycan to form polylactosamine structures (7,8). Consistent with these results, our previous study demonstrated that β3GnT8 may have an important role in the CD147 signal transduction pathway as an upstream modulator of MMP2 production in tumor cells (9).…”