Abstract
In our previous studies we have described that ST3Gal III transfected pancreatic adenocarcinoma Capan-1 and MDAPanc-28 cells show increased membrane expression levels of sialyl-Lewis x (SLex) along with a concomitant decrease in α2,6-sialic acid compared to control cells. Here we have addressed the role of this glycosylation pattern in the functional properties of two glycoproteins involved in the processes of cancer cell invasion and migration, α2β1 integrin, the main receptor for type 1 collagen, and E-cadherin, responsible for cell-cell contacts and whose deregulation determines cell invasive capabilities. Our results demonstrate that ST3Gal III transfectants showed reduced cell-cell aggregation and increased invasive capacities. ST3Gal III transfected Capan-1 cells exhibited higher SLex and lower α2,6-sialic acid content on the glycans of their α2β1 integrin molecules. As a consequence, higher phosphorylation of focal adhesion kinase tyrosine 397, which is recognized as one of the first steps of integrin-derived signaling pathways, was observed in these cells upon adhesion to type 1 collagen. This molecular mechanism underlies the increased migration through collagen of these cells. In addition, the pancreatic adenocarcinoma cell lines as well as human pancreatic tumor tissues showed colocalization of SLex and E-cadherin, which was higher in the ST3Gal III transfectants. In conclusion, changes in the sialylation pattern of α2β1 integrin and E-cadherin appear to influence the functional role of these two glycoproteins supporting the role of these glycans as an underlying mechanism regulating pancreatic cancer cell adhesion and invasion.
Highlights
Cell adhesion is a dynamic process that allows cells of multicellular organisms to be cohesive, communicate and interact among them and with the extracellular matrix (ECM), playing an essential role in many cellular functions, such as cell normal embryonic development, morphogenesis and tissue repair, as well as in many pathological processes such as tumor invasion and metastasis, thrombosis and inflammation [1]
In previous studies we have described that a2,3-sialyltransferase ST3Gal III transfection of pancreatic adenocarcinoma cell lines Capan-1 and MDAPanc-28 leads to the overexpression of sialyl-Lewis x (SLex) antigen and the decrease of a2,6-sialic acid in their cell surface
These results showed a competitive expression between a2,3- and a2,6-sialic acid, which are in accordance with the competition among a2,3-sialyltransferases ST3Gal III-IV and a2,6-sialyltransferase ST6Gal I enzymes to sialylate type II glycan chains previously described [23]
Summary
Cell adhesion is a dynamic process that allows cells of multicellular organisms to be cohesive, communicate and interact among them and with the extracellular matrix (ECM), playing an essential role in many cellular functions, such as cell normal embryonic development, morphogenesis and tissue repair, as well as in many pathological processes such as tumor invasion and metastasis, thrombosis and inflammation [1]. A key stone of cancer invasion is the disruption of the cellular junctions through the downregulation of the function and/or important signaling pathways carried out by critical cell adhesion molecules (CAMs) such as cadherins and integrins. This loss of adhesiveness allows tumor cells to disobey the social order, resulting in the alteration of the normal histological structure and dissociation from cancer nests [3]. E-cadherin is one of the key molecular markers along the process of Epithelial to Mesenchymal Transition (EMT), which is a fundamental biological process associated with the progression from adenoma to carcinoma and the subsequent steps of cancer cell invasion and metastasis [6,7]
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