Modulation of glycosyltransferase ST6Gal-I in gastric cancer-derived organoids disrupts homeostatic epithelial cell turnover

Abstract

Programmed cell death promotes homeostatic cell turnover in the epithelium but is dysregulated in cancer. The glycosyltransferase ST6Gal-I is known to block homeostatic apoptosis through α2,6-linked sialylation of the death receptor TNFR1 in many cell types. However, its role has not been investigated in gastric epithelial cells or gastric tumorigenesis. We determined that human gastric antral epithelium rarely expressed ST6Gal-I, but the number of ST6Gal-I–expressing epithelial cells increased significantly with advancing premalignancy leading to cancer. The mRNA expression levels of ST6GAL-I and SOX9 in human gastric epithelial cells correlated positively with one another through the premalignancy cascade, indicating that increased epithelial cell expression of ST6Gal-I is associated with premalignant progression. To determine the functional impact of increased ST6Gal-I, we generated human gastric antral organoids from epithelial stem cells and differentiated epithelial monolayers from gastric organoids. Gastric epithelial stem cells strongly expressed ST6Gal-I, suggesting a novel biomarker of stemness. In contrast, organoid-derived epithelial monolayers expressed markedly reduced ST6Gal-I and underwent TNF-induced, caspase-mediated apoptosis, consistent with homeostasis. Conversely, epithelial monolayers generated from gastric cancer stem cells retained high levels of ST6Gal-I and resisted TNF-induced apoptosis, supporting prolonged survival. Protection from TNF-induced apoptosis depended on ST6Gal-I overexpression, because forced ST6Gal-I overexpression in normal gastric stem cell–differentiated monolayers inhibited TNF-induced apoptosis, and cleavage of α2,6-linked sialic acids from gastric cancer organoid-derived monolayers restored susceptibility to TNF-induced apoptosis. These findings implicate up-regulated ST6Gal-I expression in blocking homeostatic epithelial cell apoptosis in gastric cancer pathogenesis, suggesting a mechanism for prolonged epithelioid tumor cell survival. Programmed cell death promotes homeostatic cell turnover in the epithelium but is dysregulated in cancer. The glycosyltransferase ST6Gal-I is known to block homeostatic apoptosis through α2,6-linked sialylation of the death receptor TNFR1 in many cell types. However, its role has not been investigated in gastric epithelial cells or gastric tumorigenesis. We determined that human gastric antral epithelium rarely expressed ST6Gal-I, but the number of ST6Gal-I–expressing epithelial cells increased significantly with advancing premalignancy leading to cancer. The mRNA expression levels of ST6GAL-I and SOX9 in human gastric epithelial cells correlated positively with one another through the premalignancy cascade, indicating that increased epithelial cell expression of ST6Gal-I is associated with premalignant progression. To determine the functional impact of increased ST6Gal-I, we generated human gastric antral organoids from epithelial stem cells and differentiated epithelial monolayers from gastric organoids. Gastric epithelial stem cells strongly expressed ST6Gal-I, suggesting a novel biomarker of stemness. In contrast, organoid-derived epithelial monolayers expressed markedly reduced ST6Gal-I and underwent TNF-induced, caspase-mediated apoptosis, consistent with homeostasis. Conversely, epithelial monolayers generated from gastric cancer stem cells retained high levels of ST6Gal-I and resisted TNF-induced apoptosis, supporting prolonged survival. Protection from TNF-induced apoptosis depended on ST6Gal-I overexpression, because forced ST6Gal-I overexpression in normal gastric stem cell–differentiated monolayers inhibited TNF-induced apoptosis, and cleavage of α2,6-linked sialic acids from gastric cancer organoid-derived monolayers restored susceptibility to TNF-induced apoptosis. These findings implicate up-regulated ST6Gal-I expression in blocking homeostatic epithelial cell apoptosis in gastric cancer pathogenesis, suggesting a mechanism for prolonged epithelioid tumor cell survival. Epithelial cell homeostasis in the gastrointestinal mucosa is maintained by the finely tuned balance between cell proliferation and apoptosis. This balance is disrupted transiently in mucosal injury and permanently in mucosal cancer cells, which acquire ineffective apoptosis. The latter leads to increased survival and proliferation with the dysregulated apoptosis unable to eliminate cancer cells and restrict progressive tumor cell development (1Hanahan D. Weinberg R.A. The hallmarks of cancer.Cell. 2000; 100 (10647931): 57-7010.1016/S0092-8674(00)81683-9Abstract Full Text Full Text PDF PubMed Scopus (20695) Google Scholar, 2Plati J. Bucur O. Khosravi-Far R. Dysregulation of apoptotic signaling in cancer: Molecular mechanisms and therapeutic opportunities.J. Cell. Biochem. 2008; 104 (18459149): 1124-114910.1002/jcb.21707Crossref PubMed Scopus (116) Google Scholar, 3Evan G.I. Vousden K.H. Proliferation, cell cycle and apoptosis in cancer.Nature. 2001; 411 (11357141): 342-34810.1038/35077213Crossref PubMed Scopus (2486) Google Scholar, 4Fernald K. Kurokawa M. Evading apoptosis in cancer.Trends Cell Biol. 2013; 23 (23958396): 620-63310.1016/j.tcb.2013.07.006Abstract Full Text Full Text PDF PubMed Scopus (261) Google Scholar). In the stomach, impaired epithelial apoptosis has been detected in tissue sections of premalignant gastric lesions (5Rosania R. Varbanova M. Wex T. Langner C. Bornschein J. Giorgio F. Ierardi E. Malfertheiner P. Regulation of apoptosis is impaired in atrophic gastritis associated with gastric cancer.BMC Gastroenterol. 2017; 17 (28662697): 8410.1186/s12876-017-0640-7Crossref PubMed Scopus (9) Google Scholar), suggesting that dysregulated apoptosis may contribute to the histological changes leading to gastric cancer. Gastric cancer cells and epithelial stem cells have many features in common, including prolonged survival. Thus, elucidation of the cellular pathways involved in prolonging epithelial stem cell survival could inform our understanding of gastric cancer pathogenesis. However, the mechanism of dysregulated apoptosis during the malignant transformation of gastric epithelial cells, especially at the stem cell level, has received insufficient investigative attention. The glycosyltransferase ST6Gal-I has been shown to contribute to multiple cell processes, including apoptosis, differentiation, and survival (6Schultz M.J. Swindall A.F. Bellis S.L. Regulation of the metastatic cell phenotype by sialylated glycans.Cancer Metastasis Rev. 2012; 31 (22699311): 501-51810.1007/s10555-012-9359-7Crossref PubMed Scopus (186) Google Scholar, 7Schultz M.J. Holdbrooks A.T. Chakraborty A. Grizzle W.E. Landen C.N. Buchsbaum D.J. Conner M.G. Arend R.C. Yoon K.J. Klug C.A. Bullard D.C. Kesterson R.A. Oliver P.G. O'Connor A.K. Yoder B.K. et al.The tumor-associated glycosyltransferase ST6Gal-I regulates stem cell transcription factors and confers a cancer stem cell phenotype.Cancer Res. 2016; 76 (27216178): 3978-398810.1158/0008-5472.CAN-15-2834Crossref PubMed Scopus (71) Google Scholar). ST6Gal-I is located in the Golgi, where it catalyzes the addition of α2,6-linked sialic acids to N-glycans on glycoproteins destined via the trans-Golgi network for the plasma membrane. Homeostatic epithelial cell death receptors tumor necrosis receptor 1 (TNFR1) and Fas are key glycoproteins targeted by ST6Gal-I for addition of α2,6 sialic acids (α2,6 sialylation). The α2,6 sialylation of TNFR1 does not block ligand binding but prevents TNFR1 internalization, thereby blocking TNF-induced apoptosis and subsequent cell turnover (8Liu Z. Swindall A.F. Kesterson R.A. Schoeb T.R. Bullard D.C. Bellis S.L. ST6Gal-I regulates macrophage apoptosis via α2-6 sialylation of the TNFR1 death receptor.J. Biol. Chem. 2011; 286 (21930713): 39654-3966210.1074/jbc.M111.276063Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar, 9Holdbrooks A.T. Britain C.M. Bellis S.L. ST6Gal-I sialyltransferase promotes tumor necrosis factor (TNF)-mediated cancer cell survival via sialylation of the TNF receptor 1 (TNFR1) death receptor.J. Biol. Chem. 2018; 293 (29233887): 1610-162210.1074/jbc.M117.801480Abstract Full Text Full Text PDF PubMed Google Scholar). ST6Gal-I is typically expressed at low levels in differentiated epithelium, but its overexpression occurs in several epithelioid cancers, including colonic, pancreatic, and ovarian adenocarcinomas (7Schultz M.J. Holdbrooks A.T. Chakraborty A. Grizzle W.E. Landen C.N. Buchsbaum D.J. Conner M.G. Arend R.C. Yoon K.J. Klug C.A. Bullard D.C. Kesterson R.A. Oliver P.G. O'Connor A.K. Yoder B.K. et al.The tumor-associated glycosyltransferase ST6Gal-I regulates stem cell transcription factors and confers a cancer stem cell phenotype.Cancer Res. 2016; 76 (27216178): 3978-398810.1158/0008-5472.CAN-15-2834Crossref PubMed Scopus (71) Google Scholar, 8Liu Z. Swindall A.F. Kesterson R.A. Schoeb T.R. Bullard D.C. Bellis S.L. ST6Gal-I regulates macrophage apoptosis via α2-6 sialylation of the TNFR1 death receptor.J. Biol. Chem. 2011; 286 (21930713): 39654-3966210.1074/jbc.M111.276063Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar, 10Martin L.T. Marth J.D. Varki A. Varki N.M. Genetically altered mice with different sialyltransferase deficiencies show tissue-specific alterations in sialylation and sialic acid 9-O-acetylation.J. Biol. Chem. 2002; 277 (12068010): 32930-3293810.1074/jbc.M203362200Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar, 11Hasehira K. Tateno H. Onuma Y. Ito Y. Asashima M. Hirabayashi J. Structural and quantitative evidence for dynamic glycome shift on production of induced pluripotent stem cells.Mol. Cell. Proteomics. 2012; 11 (23023295): 1913-192310.1074/mcp.M112.020586Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar, 12Costa-Nogueira C. Villar-Portela S. Cuevas E. Gil-Martín E. Fernández-Briera A. Synthesis and expression of CDw75 antigen in human colorectal cancer.BMC Cancer. 2009; 9 (20003255): 43110.1186/1471-2407-9-431Crossref PubMed Scopus (17) Google Scholar, 13Vazquez-Martin C. Gil-Martin E. Fernandez-Briera A. Elevation of ST6Gal I activity in malignant and transitional tissue in human colorectal cancer.Oncology. 2005; 69 (16319516): PubMed Scopus Google Scholar). The role of ST6Gal-I in gastric epithelial cell homeostasis and the of gastric is not gastric cancer the cancer and the leading of F. J. A. cancer of and for in J. 2018; PubMed Scopus Google Scholar). we determined the expression of ST6Gal-I in normal human gastric and in the gastric of the premalignant histological leading and gastric We stem cells M. P. M. T. H. M. E. S. J. A. et stem cells in the and gastric in Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, M. M. H. R. gastric epithelial stem cells and 2017; PubMed Scopus Google from human normal gastric and gastric to epithelial stem cell organoids and dynamic in of normal antral epithelium and gastric tumor epithelium In J. O. M. Biol. 2017; PubMed Scopus (17) Google Scholar). We with ST6Gal-I overexpression and to the role of ST6Gal-I in normal epithelial homeostasis and gastric is the factor for gastric cancer M. F. M. Malfertheiner P. K. Gastric cancer Gastroenterol. 2017; Full Text Full Text PDF PubMed Scopus Google Scholar, D. Malfertheiner P. of and 2017; Full Text Full Text PDF PubMed Scopus Google Scholar, A. M. C. P. F. E. C. in gastric cancer with to and by J. Cancer. Full Text Full Text PDF PubMed Scopus Google Scholar, The of in the J. Cancer. PubMed Scopus Google Scholar). during and for M.J. D. of in to the S. A. PubMed Scopus Google Scholar, M.J. and PubMed Scopus Google Scholar), H. the in of the D. Malfertheiner P. of and 2017; Full Text Full Text PDF PubMed Scopus Google Scholar). H. through and to in of P. J. of Full Text Full Text PDF PubMed Scopus Google Scholar, A. in the human of the Rev. 2013; 11 PubMed Scopus Google Scholar). the premalignancy may of H. in of the because of of the of the H. S. K. M. H. A. K. K. H. Y. T. O. M. of atrophic gastritis associated with of gastric J. Cancer. PubMed Scopus Google Scholar). gastric tissue from in where H. is we show that epithelial cell expression of ST6Gal-I increased with advancing histological have been to to of the cascade, leading to and including gastric cancer gastric tissue from and with H. rarely gastric cancer in gastric Full Text Full Text PDF PubMed Scopus Google Scholar, C. F. J. A. A. P. E. gastritis in is associated with a 2008; Full Text Full Text PDF PubMed Scopus Google Scholar, Gastric in and Cancer. 2011; PubMed Scopus Google Scholar), ST6Gal-I–expressing gastric epithelial cells, in to the increased expression in the epithelium from gastric tissue We ST6Gal-I expression in gastric tissue The number of ST6Gal-I–expressing cells increased in gastric epithelium with of gastric tissue from the ST6Gal-I overexpression in gastric cancer and we correlated ST6GAL-I expression with the expression of a transcription factor expression is associated with the development and of cancer M. M. E. M. R. E. C. SOX9 and functional in PubMed Scopus Google and induced by H. shown in a of the T. Y. Y. K. Y. S. H. H. K. K. Gastric induced by is associated with SOX9 expression via 2016; PubMed Scopus Google Scholar). of the gastric epithelial cells that expressed ST6Gal-I expressed the mRNA expression of and SOX9 in gastric epithelial cells correlated positively with one another through the premalignancy indicating that increased epithelial cell expression of ST6Gal-I is associated with premalignant in the human These findings the epithelioid that ST6Gal-I to gastric To determine the role of ST6Gal-I in gastric epithelial cell and gastric pathogenesis, we gastric epithelial stem cell organoids and organoid-derived monolayers to antral stem cells and epithelium, of normal human gastric and for stem cells through in the of H. In and of gastrointestinal stem cells in 2013; PubMed Scopus Google Scholar). epithelial stem cells to organoids by a of cells with the epithelial the The stem cell organoids expressed high levels of mRNA for the stem cell biomarker and levels of the in differentiated cells, with the tissue from which the organoids The gastric epithelial stem cell organoids expressed 1 and epithelial cell Epithelial stem cells generated from normal gastric strongly for ST6Gal-I and which to the sialic acid to a in α2,6 functional ST6Gal-I To determine ST6Gal-I is associated with we the expression of ST6Gal-I in of stem cell Gastric epithelial expression of and mRNA in the of levels of stem cell factor and indicating that stem cell expression of and at in on factor To differentiated gastric epithelium, gastric organoids and the stem cells on with in the of reduced The epithelial stem cells monolayers that up-regulated mRNA with the organoids indicating differentiated gastric Epithelial stem cell monolayers expressed and but low levels of ST6Gal-I the of gastric organoids epithelial monolayers in in mRNA expression of and and monolayers in stem cell factor not of or These ST6Gal-I is a biomarker of human antral gastric epithelial stem cells but not differentiated epithelium and that factor signaling to ST6Gal-I We investigated the of epithelial ST6Gal-I on homeostatic apoptosis. Epithelial stem cell organoids from antral mucosa with (7Schultz M.J. Holdbrooks A.T. Chakraborty A. Grizzle W.E. Landen C.N. Buchsbaum D.J. Conner M.G. Arend R.C. Yoon K.J. Klug C.A. Bullard D.C. Kesterson R.A. Oliver P.G. O'Connor A.K. Yoder B.K. et al.The tumor-associated glycosyltransferase ST6Gal-I regulates stem cell transcription factors and confers a cancer stem cell phenotype.Cancer Res. 2016; 76 (27216178): 3978-398810.1158/0008-5472.CAN-15-2834Crossref PubMed Scopus (71) Google to ST6Gal-I or with (7Schultz M.J. Holdbrooks A.T. Chakraborty A. Grizzle W.E. Landen C.N. Buchsbaum D.J. Conner M.G. Arend R.C. Yoon K.J. Klug C.A. Bullard D.C. Kesterson R.A. Oliver P.G. O'Connor A.K. Yoder B.K. et al.The tumor-associated glycosyltransferase ST6Gal-I regulates stem cell transcription factors and confers a cancer stem cell phenotype.Cancer Res. 2016; 76 (27216178): 3978-398810.1158/0008-5472.CAN-15-2834Crossref PubMed Scopus (71) Google to mRNA and overexpression in the organoids at the mRNA and and Epithelial stem cells organoids in the of ST6Gal-I indicating ST6Gal-I not for forced overexpression of ST6Gal-I in gastric organoids in ST6Gal-I expression in the organoid-derived epithelial monolayers at the mRNA and and TNFR1 in a of signaling including homeostatic apoptosis, and is expressed in H. K. P. necrosis factor PubMed Scopus Google Scholar). TNFR1 is in the and via the trans-Golgi network to the cell where it with its ligand TNF S. of and tumor necrosis factor receptors in human J. Google Scholar, J. TNF to the plasma but not the trans-Golgi the of Google Scholar). TNF of TNFR1 cell receptor that TNFR1 internalization, to apoptosis A.T. Britain C.M. Bellis S.L. ST6Gal-I sialyltransferase promotes tumor necrosis factor (TNF)-mediated cancer cell survival via sialylation of the TNF receptor 1 (TNFR1) death receptor.J. Biol. Chem. 2018; 293 (29233887): 1610-162210.1074/jbc.M117.801480Abstract Full Text Full Text PDF PubMed Google Scholar, S. Regulation of TNFR1 and by receptor Rev. Cell Biol. 2008; 9 PubMed Scopus Google Scholar, J. M. S. J. M. O. M. D. R. D. S. of TNF receptor 1 TNF death signaling Full Text Full Text PDF PubMed Scopus Google Scholar, S. T. D. R. K. M. M. M. of receptor by tumor necrosis factor receptor death Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, O. J. of TNF receptor apoptosis via signaling Full Text Full Text PDF PubMed Scopus Google Scholar). α2,6-linked sialylation of TNFR1 N-glycans of the thereby apoptosis (8Liu Z. Swindall A.F. Kesterson R.A. Schoeb T.R. Bullard D.C. Bellis S.L. ST6Gal-I regulates macrophage apoptosis via α2-6 sialylation of the TNFR1 death receptor.J. Biol. Chem. 2011; 286 (21930713): 39654-3966210.1074/jbc.M111.276063Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar, 9Holdbrooks A.T. Britain C.M. Bellis S.L. ST6Gal-I sialyltransferase promotes tumor necrosis factor (TNF)-mediated cancer cell survival via sialylation of the TNF receptor 1 (TNFR1) death receptor.J. Biol. Chem. 2018; 293 (29233887): 1610-162210.1074/jbc.M117.801480Abstract Full Text Full Text PDF PubMed Google Scholar). key of ST6Gal-I, we determined the impact of ST6Gal-I overexpression on the of epithelial monolayers from gastric to apoptosis. of the organoids with a the increased levels of TNFR1 in the epithelial cell monolayers consistent with impaired receptor and TNFR1 to the epithelial cell M. of death on J. 2013; PubMed Scopus Google Scholar, J. A. M. of receptor Rev. 2016; PubMed Scopus Google Scholar). the levels of expression in ST6Gal-I and monolayers from normal gastric indicating the increased expression of TNFR1 in the ST6Gal-I monolayers because of reduced receptor and not increased mRNA To determine the impact of increased ST6Gal-I expression on TNF-induced epithelial cell apoptosis, we epithelial monolayers generated from normal and ST6Gal-I or gastric stem cell organoids with TNF for and activity increased in the normal monolayers and the monolayers from ST6Gal-I organoids indicating susceptibility to TNF-induced apoptosis. In contrast, activity not significantly by TNF of ST6Gal-I monolayers Thus, increased epithelial ST6Gal-I expression leads to the of apoptosis, to epithelial cell in To determine the impact of ST6Gal-I expression on epithelial cell in gastric we generated epithelial organoids from gastric differentiated epithelial cell and ST6Gal-I expression and The gastric cancer monolayers to monolayers from normal antral organoids However, in to normal epithelial tumor monolayers retained high levels of expression the gastric and normal organoids expressed but monolayers generated from tumor organoids maintained expression consistent with the of in M. M. E. M. R. E. C. SOX9 and functional in PubMed Scopus Google Scholar, A. M. C. M. A. R.A. A. J. M. et of the transcription factor Res. 2012; PubMed Scopus Google Scholar, E. S. S. D. M. S. Molecular in gastric PubMed Scopus Google and H. S. H. SOX9 expression in and 2017; PubMed Scopus Google Scholar). The expression in tumor monolayers at the monolayers generated from tumor organoids not significantly increased activity in the of TNF indicating to apoptosis. We monolayers for with to α2,6-linked sialic in with O. M. cell and cell death in human cell of cell J. PubMed Scopus Google Scholar, Y. Y. T. of from Biochem. PubMed Scopus Google Scholar, A. Oliver P.G. Buchsbaum D.J. Bellis S.L. ST6Gal-I sialyltransferase promotes in by Biol. Chem. 2018; 293 Full Text Full Text PDF PubMed Scopus Google Scholar). A. α2,6 and sialic α2,6 sialic acids are sialic acids with A. Y. Y. T. of from Biochem. PubMed Scopus Google Scholar, A. Oliver P.G. Buchsbaum D.J. Bellis S.L. ST6Gal-I sialyltransferase promotes in by Biol. Chem. 2018; 293 Full Text Full Text PDF PubMed Scopus Google Scholar). of α2,6 sialic acids by of the sialic acids from tumor monolayers induced in activity indicating susceptibility to TNF-induced apoptosis. our that ST6Gal-I is strongly up-regulated in gastric epithelial cells, where the homeostatic apoptosis to epithelial cell survival. To epithelial cell in the gastric mucosa has not been at the stem cell and in malignant we show that epithelial stem cells from normal expressed high levels of the glycosyltransferase ST6Gal-I in a but of the reduced during and stem cell epithelial cell suggesting ST6Gal-I expression epithelial stemness. This with a of the low ST6Gal-I expression in differentiated epithelium in the and (7Schultz M.J. Holdbrooks A.T. Chakraborty A. Grizzle W.E. Landen C.N. Buchsbaum D.J. Conner M.G. Arend R.C. Yoon K.J. Klug C.A. Bullard D.C. Kesterson R.A. Oliver P.G. O'Connor A.K. Yoder B.K. et al.The tumor-associated glycosyltransferase ST6Gal-I regulates stem cell transcription factors and confers a cancer stem cell phenotype.Cancer Res. 2016; 76 (27216178): 3978-398810.1158/0008-5472.CAN-15-2834Crossref PubMed Scopus (71) Google Scholar). has not been O. J. K. S. H. of a in the 2016; PubMed Scopus Google Scholar), our that ST6Gal-I is a biomarker of epithelial stem cells in the antral mucosa of the In to the of ST6Gal-I in normal antral epithelium, we show that the number of epithelial cells that ST6Gal-I in advancing of H. gastric premalignancy leading and gastric This the of mucosal epithelioid in which the is to gastric cancer and ST6Gal-I a role in the of malignant transformation of gastric epithelium (7Schultz M.J. Holdbrooks A.T. Chakraborty A. Grizzle W.E. Landen C.N. Buchsbaum D.J. Conner M.G. Arend R.C. Yoon K.J. Klug C.A. Bullard D.C. Kesterson R.A. Oliver P.G. O'Connor A.K. Yoder B.K. et al.The tumor-associated glycosyltransferase ST6Gal-I regulates stem cell transcription factors and confers a cancer stem cell phenotype.Cancer Res. 2016; 76 (27216178): 3978-398810.1158/0008-5472.CAN-15-2834Crossref PubMed Scopus (71) Google Scholar, A.F. Bellis S.L. of the Fas death receptor by ST6Gal-I apoptosis in Biol. Chem. 2011; 286 Full Text Full Text PDF PubMed Scopus Google Scholar, A.F. M.J. Buchsbaum D.J. Bellis S.L. ST6Gal-I expression is in human epithelial and with stem cell in normal and cancer cell Res. 2013; PubMed Scopus Google Scholar). with H. the premalignant changes in the and is the factor for the development of gastric cancer. the of H. has in and in and have the D. Malfertheiner P. of and 2017; Full Text Full Text PDF PubMed Scopus Google Scholar). gastric from rarely gastric low levels of ST6Gal-I–expressing epithelial The expression of ST6Gal-I in gastric tumor epithelium from and the of tumor epithelium to TNF-induced apoptosis is in normal epithelial monolayers with forced ST6Gal-I with of apoptosis, gastric tumor epithelium to TNF-induced apoptosis, and cleavage of sialic acids implicate increased expression of ST6Gal-I homeostatic apoptosis, thereby to gastric cancer cell In the between ST6Gal-I expression in ovarian cancer and reduced survival (7Schultz M.J. Holdbrooks A.T. Chakraborty A. Grizzle W.E. Landen C.N. Buchsbaum D.J. Conner M.G. Arend R.C. Yoon K.J. Klug C.A. Bullard D.C. Kesterson R.A. Oliver P.G. O'Connor A.K. Yoder B.K. et al.The tumor-associated glycosyltransferase ST6Gal-I regulates stem cell transcription factors and confers a cancer stem cell phenotype.Cancer Res. 2016; 76 (27216178): 3978-398810.1158/0008-5472.CAN-15-2834Crossref PubMed Scopus (71) Google and increased to in ST6Gal-I–expressing cancer cell A. Oliver P.G. Buchsbaum D.J. Bellis S.L. ST6Gal-I sialyltransferase promotes in by Biol. Chem. 2018; 293 Full Text Full Text PDF PubMed Scopus Google Scholar), the that ST6Gal-I expression in gastric cancer could contribute to the survival and in with The and of gastric stem cell organoids to the premalignant of gastric cancer at the stem cell of the human gastric epithelium and its with H. have been because of the of The gastric epithelium is epithelial Full Text PDF PubMed Scopus Google Scholar), by stem cells in to the of homeostasis and The progressive expression of of including ST6Gal-I, in epithelial monolayers from organoids could contribute to for the of gastric cancer. In addition to gastric organoids in J. T. A. M. T. colorectal cancer in mice with and 2018; PubMed Scopus Google Scholar, H. R. signaling to tissue 2012; PubMed Scopus Google and human C.M. F. M. J. M. S. S. A. K.J. et of cells by of and tumor 2018; Full Text Full Text PDF PubMed Scopus Google Scholar, H. M. R.A. W.E. cells of in with Full Text Full Text PDF PubMed Scopus Google Scholar, J. M. cell of differentiated pluripotent stem cells for PubMed Scopus Google to or to our human cancer organoids have been with cells to cells of the cells C.M. F. M. J. M. S. S. A. K.J. et of cells by of and tumor 2018; Full Text Full Text PDF PubMed Scopus Google Scholar). cleavage of sialic acids from TNFR1 the of tissue-specific to TNF-induced apoptosis in ST6Gal-I gastric cancer cells, thereby the for gastric Thus, key cellular in gastric stem cells our understanding of gastric cancer and inform novel stem cell In our findings that ST6Gal-I is a novel biomarker of gastric antral epithelial stem cells, is strongly in gastric cancer epithelial cells, and dysregulated homeostatic apoptosis, a role for ST6Gal-I in epithelial cell in gastric with for from the gastric of mucosal and from gastric cancer lesions from with gastric in and Epithelial stem cell organoids generated from gastric tissue in the of at Cell N.M. for gastrointestinal epithelial stem cell activity levels multiple Cell Res. PubMed Scopus (17) Google Scholar, H. C. of human gastrointestinal epithelial to PubMed Scopus Google Scholar). To epithelial stem cell finely and for to at in to the The with H. In and of gastrointestinal stem cells in 2013; PubMed Scopus Google Scholar), and the cell through a and for at cells and or in in The to with the to the epithelial cells from to the to which H. In and of gastrointestinal stem cells in 2013; PubMed Scopus Google a of H. In and of gastrointestinal stem cells in 2013; PubMed Scopus Google and with 100 and with and addition to the maintained at and and In the of in reduced from to or by with ST6Gal-I generated by with a the ST6GAL-I or with ST6GAL-I (7Schultz M.J. Holdbrooks A.T. Chakraborty A. Grizzle W.E. Landen C.N. Buchsbaum D.J. Conner M.G. Arend R.C. Yoon K.J. Klug C.A. Bullard D.C. Kesterson R.A. Oliver P.G. O'Connor A.K. Yoder B.K. et al.The tumor-associated glycosyltransferase ST6Gal-I regulates stem cell transcription factors and confers a cancer stem cell phenotype.Cancer Res. 2016; 76 (27216178): 3978-398810.1158/0008-5472.CAN-15-2834Crossref PubMed Scopus (71) Google Scholar). ST6Gal-I expression in the organoids organoids and and with a for α2,6 sialic epithelial stem cell in H. In and of gastrointestinal stem cells in 2013; PubMed Scopus Google Scholar), through a to cell in and or cell which with in for at and to the addition of epithelial stem The stem cells to to a gastric epithelial cell typically at for which the monolayers in the of the of the of the with a organoids or monolayers in and the of to with the expression and to and the to the and organoid-derived epithelial cell monolayers in and with and to ST6Gal-I and or with a and with of organoids and epithelial cell monolayers and with a and with Epithelial cell monolayers to in to the cells, in and with for at in the in and on for sections from and through the cascade, including gastric by a sections of the with ST6Gal-I or or for 1 at and the number of cells high in tissue to our (7Schultz M.J. Holdbrooks A.T. Chakraborty A. Grizzle W.E. Landen C.N. Buchsbaum D.J. Conner M.G. Arend R.C. Yoon K.J. Klug C.A. Bullard D.C. Kesterson R.A. Oliver P.G. O'Connor A.K. Yoder B.K. et al.The tumor-associated glycosyltransferase ST6Gal-I regulates stem cell transcription factors and confers a cancer stem cell phenotype.Cancer Res. 2016; 76 (27216178): 3978-398810.1158/0008-5472.CAN-15-2834Crossref PubMed Scopus (71) Google Scholar). Epithelial cell monolayers in and with TNF for to and 100 of Cell to 100 of the cells and at for The for at and for In epithelial cell monolayers with from A. for to α2,6-linked sialic acids O. M. cell and cell death in human cell of cell J. PubMed Scopus Google Scholar, Y. Y. T. of from Biochem. PubMed Scopus Google Scholar, A. Oliver P.G. Buchsbaum D.J. Bellis S.L. ST6Gal-I sialyltransferase promotes in by Biol. Chem. 2018; 293 Full Text Full Text PDF PubMed Scopus Google Scholar). of sialic acids by with a for α2,6 sialic acids A. Oliver P.G. Buchsbaum D.J. Bellis S.L. ST6Gal-I sialyltransferase promotes in by Biol. Chem. 2018; 293 Full Text Full Text PDF PubMed Scopus Google Scholar). or of by in the with to is and are in the or to the tumor necrosis factor quantitative

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