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Cross-talk between Colon Cells and Macrophages Increases ST6GALNAC1 and MUC1-sTn Expression in Ulcerative Colitis and Colitis-Associated Colon Cancer.
Kvorjak, Michael; Ahmed, Yasmine; Miller, Michelle L; Sriram, Raahul; Coronnello, Claudia; Hashash, Jana G; Hartman, Douglas J; Telmer, Cheryl A; Miskov-Zivanov, Natasa; Finn, Olivera J; Cascio, Sandra.
Afiliação
  • Kvorjak M; Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania.
  • Ahmed Y; Department of Electrical and Computer Engineering, University of Pittsburgh, Pittsburgh, Pennsylvania.
  • Miller ML; Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania.
  • Sriram R; Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania.
  • Coronnello C; Fondazione Ri.Med, Palermo, Italy.
  • Hashash JG; Department of Gastroenterology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
  • Hartman DJ; Department of Pathology University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
  • Telmer CA; Molecular Biosensor and Imaging Center, Carnegie Mellon University, Pittsburgh, Pennsylvania.
  • Miskov-Zivanov N; Department of Electrical and Computer Engineering, University of Pittsburgh, Pittsburgh, Pennsylvania.
  • Finn OJ; Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania.
  • Cascio S; Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania. sac131@pitt.edu.
Cancer Immunol Res ; 8(2): 167-178, 2020 02.
Article em En | MEDLINE | ID: mdl-31831633
Patients with ulcerative colitis have an increased risk of developing colitis-associated colon cancer (CACC). Changes in glycosylation of the oncoprotein MUC1 commonly occur in chronic inflammation, including ulcerative colitis, and this abnormally glycosylated MUC1 promotes cancer development and progression. It is not known what causes changes in glycosylation of MUC1. Gene expression profiling of myeloid cells in inflamed and malignant colon tissues showed increased expression levels of inflammatory macrophage-associated cytokines compared with normal tissues. We analyzed the involvement of macrophage-associated cytokines in the induction of aberrant MUC1 glycoforms. A coculture system was used to examine the effects of M1 and M2 macrophages on glycosylation-related enzymes in colon cancer cells. M2-like macrophages induced the expression of the glycosyltransferase ST6GALNAC1, an enzyme that adds sialic acid to O-linked GalNAc residues, promoting the formation of tumor-associated sialyl-Tn (sTn) O-glycans. Immunostaining of ulcerative colitis and CACC tissue samples confirmed the elevated number of M2-like macrophages as well as high expression of ST6GALNAC1 and the altered MUC1-sTn glycoform on colon cells. Cytokine arrays and blocking antibody experiments indicated that the macrophage-dependent ST6GALNAC1 activation was mediated by IL13 and CCL17. We demonstrated that IL13 promoted phosphorylation of STAT6 to activate transcription of ST6GALNAC1. A computational model of signaling pathways was assembled and used to test IL13 inhibition as a possible therapy. Our findings revealed a novel cellular cross-talk between colon cells and macrophages within the inflamed and malignant colon that contributes to the pathogenesis of ulcerative colitis and CACC.See related Spotlight on p. 160.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Sialiltransferases / Glicopeptídeos / Colite Ulcerativa / Colite / Colo / Neoplasias do Colo / Células Mieloides Idioma: En Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Sialiltransferases / Glicopeptídeos / Colite Ulcerativa / Colite / Colo / Neoplasias do Colo / Células Mieloides Idioma: En Ano de publicação: 2020 Tipo de documento: Article