Expression level and glycan dynamics determine the net effects of TIMP-1 on cancer progression

Tissue inhibitor of metalloproteinases (TIMPs; TIMP-1, -2, -3 and-4) are endogenous inhibitor for matrix metalloproteinases(MMPs) that are responsible for remodeling the extracellularmatrix (ECM) and involved in migration, invasion and metastasisof tumor cells. Unlike under normal conditions, the imbalancebetween MMPs and TIMPs is associated with various diseasedstates. Among TIMPs, TIMP-1, a 184-residue protein, is the onlyN-linked glycoprotein with glycosylation sites at N30 and N78.The structural analysis of the catalytic domain of humanstromelysin-1 (MMP-3) and human TIMP-1 suggests newpossibilities of the role of TIMP-1 glycan moieties as a tuner forthe proteolytic activities by MMPs. Because the TIMP-1glycosylation participate in the interaction, aberrant glycosylationof TIMP-1 presumably affects the interaction, therebyleading to pathogenic dysfunction in cancer cells. TIMP-1 hasnot only the cell proliferation activities but also anti-oncogenicproperties. Cancer cells appear to utilize these bilateral aspectsof TIMP-1 for cancer progression; an elevated TIMP-1 levelexerts to cancer development via MMP-independent pathwayduring the early phase of tumor formation, whereas it is theaberrant glycosylation of TIMP-1 that overcome the highanti-proteolytic burden. The aberrant glycosylation of TIMP-1can thus be used as staging and/or prognostic biomarker incolon cancer.