Functional Proteomics Study Reveals That N-Acetylglucosaminyltransferase V Reinforces the Invasive/Metastatic Potential of Colon Cancer through Aberrant Glycosylation on Tissue Inhibitor of Metalloproteinase-

Abstract

Cancer is a very complicated process, characterized by the uncontrolled, unbalanced overgrowth of malignant cells. The complexity of oncogenic processes and cancer progressions has demanded the discovery of biomarkers with a high sensitivity and specificity for diagnosis, prognosis, diseases monitoring, and therapeutic response prediction. Unfortunately, a discrete biomarker for colon cancer has yet to be discovered, although nearly 800,000 new colorectal cancer cases are thought to globally occur each year, which account for ϳ10% of all incident cancers, and the mortality from colorectal cancer is estimated at nearly 450,000 per year (1). MLI1 and MSH genes are associated with hereditary non-polyposis colon cancer (2), and the APC gene is associated with familial adenomatous polyposis (3), but those factors fail to account for an occurrence of wide range of colon cancer. Moreover, colon cancer is one of the epithelium-derived cancers in which the circumstantial factors govern over hereditary genetic factors. These require a clear marker that serves as tracer molecule for the efficacious treatment of colon cancer.Recent proteomics have focused on a dynamic alteration of post-translational modification of proteins, and many lines of evidence indicate that changes in post-translational modification of proteins are closely associated with the pathogenic processes of cells. An aberrant glycosylation induced by Nacetylglucosaminyltransferase V (GnT-V), 1 is a representative example of such protein modification as is implicated in tumor progression. An increase in ␤1,6-branching on N-linked glycans is associated with metastatic potential of cancer cells (4). Several target molecules for GnT-V were proposed to be involved in cancer progressions, including matriptase (5), ␤ 1 integrin (6), and N-cadherin (7). However, those proteins are membrane-bound proteins and were not demonstrated to be aberrantly glycosylated in sera or tissues of cancer patients. Recent work stresses the discrete roles of the microenviron-

Branched N-glycans and their implications for cell adhesion, signaling and clinical applications for cancer biomarkers and in therapeutics

“…Ko's group reported that TIMP-1 is also a target molecule against GnT-V and plays a key role in cancer metastasis. They also found that TIMP-1 was aberrantly glycosylated by GnT-V showed a weaker inhibition with respect to both matrix metalloproteinase (MMP)-2 and MMP-9, and this aberrancy was closely associated with cancer cell invasion and metastasis in vivo as well as in vitro (72). As described above, GnT-V and GnT-III have adverse effects in cancer invasion and metastasis (5,6,(23)(24)(25)(26).…”

Semi-quantitative Measurement of a Specific Glycoform Using a DNA-tagged Antibody and Lectin Affinity Chromatography for Glyco-biomarker Development *

“…Aberrant protein glycosylation has been observed during cancer development and progression and the pathological implications of aberrant glycosylation have been elucidated in several functional studies (2,(21)(22)(23). One of the best characterized features is the role of aberrant glycans of tissue inhibitor of metalloproteinase-1 during invasion of colon cancer cells (2).…”

“…One of the best characterized features is the role of aberrant glycans of tissue inhibitor of metalloproteinase-1 during invasion of colon cancer cells (2). The tetra-antennary adducts created by GnT-V play an interfering role in the tissue inhibitor of metalloproteinase-1/gelatinases interactions, thereby resulting in elevated gelatinase activity and enhanced invasive potential in colon cancer.…”

“…However, cumulative lines of evidence indicate that aberrant glycosylation is associated with various diseases including cancer (1), either by influencing the functionality of proteins and cells or as nonfunctional participants (2)(3)(4). Causal roles of aberrant glycosylation have been widely investigated in the development and progression of diseases, and significant progress has been made in the realm of cancer research (5).…”

Pros and cons of using aberrant glycosylation as companion biomarkers for therapeutics in cancer

“…Aberrant glycosylation is a functional marker that can be used to gauge the clinic-pathogenic process in cancer. This notion is well illustrated by the functional role of the aberrant tissue inhibitor of metalloproteinase-1 (TIMP-1) in cancer invasion and metastasis (38). TIMP-1 is an endogenous glycoprotein which inhibits several matrix metalloproteinases (MMPs) in a 1：1 stoichiometric manner, and is known to regulate cancer metastasis.…”