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1.
Oncogene ; 35(13): 1619-31, 2016 Mar 31.
Article in English | MEDLINE | ID: mdl-26189796

ABSTRACT

E-cadherin is a central molecule in the process of gastric carcinogenesis and its posttranslational modifications by N-glycosylation have been described to induce a deleterious effect on cell adhesion associated with tumor cell invasion. However, the role that site-specific glycosylation of E-cadherin has in its defective function in gastric cancer cells needs to be determined. Using transgenic mice models and human clinical samples, we demonstrated that N-acetylglucosaminyltransferase V (GnT-V)-mediated glycosylation causes an abnormal pattern of E-cadherin expression in the gastric mucosa. In vitro models further indicated that, among the four potential N-glycosylation sites of E-cadherin, Asn-554 is the key site that is selectively modified with ß1,6 GlcNAc-branched N-glycans catalyzed by GnT-V. This aberrant glycan modification on this specific asparagine site of E-cadherin was demonstrated to affect its critical functions in gastric cancer cells by affecting E-cadherin cellular localization, cis-dimer formation, molecular assembly and stability of the adherens junctions and cell-cell aggregation, which was further observed in human gastric carcinomas. Interestingly, manipulating this site-specific glycosylation, by preventing Asn-554 from receiving the deleterious branched structures, either by a mutation or by silencing GnT-V, resulted in a protective effect on E-cadherin, precluding its functional dysregulation and contributing to tumor suppression.


Subject(s)
Cadherins/metabolism , N-Acetylglucosaminyltransferases/metabolism , Stomach Neoplasms/metabolism , Amino Acid Sequence , Animals , Asparagine/genetics , Cadherins/chemistry , Cadherins/genetics , Cadherins/physiology , Catalytic Domain/genetics , Cell Line, Tumor , Dogs , Gastric Mucosa/metabolism , Gastric Mucosa/pathology , Glycosylation , HT29 Cells , Humans , Madin Darby Canine Kidney Cells , Mice , Mice, Inbred C57BL , Mice, Knockout , Molecular Sequence Data , Mutagenesis, Site-Directed , N-Acetylglucosaminyltransferases/antagonists & inhibitors , N-Acetylglucosaminyltransferases/genetics , Sequence Homology, Amino Acid , Stomach Neoplasms/genetics , Stomach Neoplasms/pathology
2.
Vet Pathol ; 48(1): 98-116, 2011 Jan.
Article in English | MEDLINE | ID: mdl-21149845

ABSTRACT

Studies focusing on the molecular basis of canine mammary tumors (CMT) have long been hampered by limited numbers of molecular tools specific to the canine species. The lack of molecular information for CMT has impeded the identification of clinically relevant tumor markers beyond histopathology and the introduction of new therapeutic concepts. Additionally, the potential use for the dog as a model for human breast cancer is debatable until questions are answered regarding cellular origin, mechanisms, and cellular pathways. During the past years, increasing numbers of canine molecular tools have been developed on the genomic, RNA, and protein levels, and an increasing number of studies have shed light on specific aspects of canine carcinogenesis, particularly of the mammary gland. This review summarizes current knowledge on the molecular carcinogenesis of CMT, including the role of specific oncogenes, tumor suppressors, regulators of apoptosis and DNA repair, proliferation indices, adhesion molecules, circulating tumor cells, and mediators of angiogenesis in CMT progression and clinical behavior. Whereas the data available are far from complete, knowledge of molecular pathways has a significant potential to complement and refine the current diagnostic and therapeutic approach to this tumor type. Furthermore, current data show that significant similarities and differences exist between canine and human mammary tumors at the molecular level. Clearly, this is only the beginning of an understanding of the molecular mechanisms of CMT and their application in clinical patient management.


Subject(s)
Dog Diseases/metabolism , Gene Expression Regulation, Neoplastic/physiology , Mammary Neoplasms, Animal/metabolism , Animals , Dog Diseases/pathology , Dogs , Female , Mammary Neoplasms, Animal/pathology , Neoplasm Proteins/genetics , Neoplasm Proteins/metabolism
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