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ID: 548 (Conflict of Interest: K)

Hypoxie-induzierte Tn Antigen Expression reguliert onkogene Signalwege und Zellmetabolismus im Pankreaskarzinom

B.Mercanoglu, G.Wolters-Eisfeld, B. T.Hofmann, C.Güngör, J. R.Izbicki, M.Bockhorn
Universitätsklinikum Hamburg-Eppendorf, Hamburg

Einleitung

In hypoxic environments, cancer cell metabolism changes from oxidative phosphorylation to anaerobic glycolysis, also known as the Warburg effect. Hypoxia may also lead to a different glycosylation of cancer cells. In particular, alterations in gene expression of COSMC result in the expression of Tn antigen and thereby in the formation of truncated O-glycosylation. Hypoxia-induced reprogramming of cell energy metabolism and differential O-glycosylation are hallmarks of cancer. Hypoxia promotes metastasis and treatment resistance in cancer cells, resulting in a poor prognosis.

Material und Methoden

The aim of the present study was to investigate the impact of hypoxia on O-glycosylation with consecutive changes in cancer cell metabolism and signal transduction pathways in vitro in human pancreatic cancer cell lines. Therefore, we hypothesized that hypoxia-induced Tn antigen expression promotes oncogenic signaling pathways and adaption of cell metabolism to hypoxic conditions. For this purpose, we examined the glyco-phenotype of hypoxia-treated pancreatic cancer cells and generated CRISPR/Cas9 COSMC knockout cells. Subsequently, we profiled the expression of 88 glycosylation related genes by qRT-PCR. We also performed glycolysis and mitochondrial stress tests. Furthermore, we analyzed phosphotyrosine and serine/threonine kinase activity in multiple signaling pathways.

Ergebnisse

Mechanistically, we demonstrated that hypoxia-induced and hypoxia-inducible factor 1-alpha (HIF1A)-mediated decreased expression levels of COSMC consecutively lead to Tn antigen expression. Moreover, downregulation of COSMC leads to a decrease in glycolytic function and mitochondrial respiration to promote cell survival under hypoxia. In addition, COSMC knockout induces a broad kinase activity reduction in multiple oncogenic signaling pathways.

Schlussfolgerung

In summary, in our presented study here, causality between hypoxia and Tn antigen expression is shown, which highlights the pathophysiological relevance of truncated O-glycan formation. Altogether, HIF1A-mediated downregulation of COSMC and subsequent Tn antigen expression support the cellular adaptation to hypoxic conditions.