Tumor-Selective Altered Glycosylation and Functional Attenuation of CD73 in Human Hepatocellular Carcinoma.

Autor: Alcedo KP; Department of Cell Biology and Physiology University of North Carolina at Chapel Hill Chapel Hill NC., Guerrero A; Department of Chemistry University of California Davis Davis CA., Basrur V; Department of Pathology University of Michigan Ann Arbor MI., Fu D; Department of Cell Biology and Physiology University of North Carolina at Chapel Hill Chapel Hill NC., Richardson ML; Department of Cell Biology and Physiology University of North Carolina at Chapel Hill Chapel Hill NC., McLane JS; Department of Cell Biology and Physiology University of North Carolina at Chapel Hill Chapel Hill NC., Tsou CC; Department of Computational Medicine and Bioinformatics University of Michigan Ann Arbor MI., Nesvizhskii AI; Department of Pathology University of Michigan Ann Arbor MI.; Department of Computational Medicine and Bioinformatics University of Michigan Ann Arbor MI., Welling TH; Perlmutter Cancer Center and Department of Surgery New York University Langone Health New York NY., Lebrilla CB; Department of Chemistry University of California Davis Davis CA., Otey CA; Department of Cell Biology and Physiology University of North Carolina at Chapel Hill Chapel Hill NC., Kim HJ; Department of Surgery University of North Carolina at Chapel Hill Chapel Hill NC., Omary MB; Department of Molecular and Integrative Physiology University of Michigan Ann Arbor MI.; Department of Medicine University of Michigan Ann Arbor MI.; Center for Advanced Biotechnology & Medicine Rutgers University Piscataway NJ.; Rutgers Biomedical Health Sciences Newark NJ., Snider NT; Department of Cell Biology and Physiology University of North Carolina at Chapel Hill Chapel Hill NC.
Jazyk: angličtina
Zdroj: Hepatology communications [Hepatol Commun] 2019 Aug 09; Vol. 3 (10), pp. 1400-1414. Date of Electronic Publication: 2019 Aug 09 (Print Publication: 2019).
DOI: 10.1002/hep4.1410
Abstrakt: CD73, a cell-surface N -linked glycoprotein that produces extracellular adenosine, is a novel target for cancer immunotherapy. Although anti-CD73 antibodies have entered clinical development, CD73 has both protumor and antitumor functions, depending on the target cell and tumor type. The aim of this study was to characterize CD73 regulation in human hepatocellular carcinoma (HCC). We examined CD73 expression, localization, and activity using molecular, biochemical, and cellular analyses on primary HCC surgical specimens, coupled with mechanistic studies in HCC cells. We analyzed CD73 glycan signatures and global alterations in transcripts encoding other N -linked glycoproteins by using mass spectrometry glycomics and RNA sequencing (RNAseq), respectively. CD73 was expressed on tumor hepatocytes where it exhibited abnormal N -linked glycosylation, independent of HCC etiology, tumor stage, or fibrosis presence. Aberrant glycosylation of tumor-associated CD73 resulted in a 3-fold decrease in 5'-nucleotidase activity ( P <  0.0001). Biochemically, tumor-associated CD73 was deficient in hybrid and complex glycans specifically on residues N311 and N333 located in the C-terminal catalytic domain. Blocking N311/N333 glycosylation by site-directed mutagenesis produced CD73 with significantly decreased 5'-nucleotidase activity in vitro , similar to the primary tumors. Glycosylation-deficient CD73 partially colocalized with the Golgi structural protein GM130, which was strongly induced in HCC tumors. RNAseq analysis further revealed that N -linked glycoprotein-encoding genes represented the largest category of differentially expressed genes between HCC tumor and adjacent tissue. Conclusion: We provide the first detailed characterization of CD73 glycosylation in normal and tumor tissue, revealing a novel mechanism that leads to the functional suppression of CD73 in human HCC tumor cells. The present findings have translational implications for therapeutic candidate antibodies targeting cell-surface CD73 in solid tumors and small-molecule adenosine receptor agonists that are in clinical development for HCC.
(© 2019 The Authors. Hepatology Communications published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases.)
Databáze: MEDLINE
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