{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T04:14:14Z","timestamp":1760242454702,"version":"build-2065373602"},"reference-count":101,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2017,9,7]],"date-time":"2017-09-07T00:00:00Z","timestamp":1504742400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The insulin\/insulin-like growth factor (IGF) system in mammals comprises a dynamic network of proteins that modulate several biological processes such as development, cell growth, metabolism, and aging. Dysregulation of the insulin\/IGF system has major implications for several pathological conditions such as diabetes and cancer. Metabolic changes also culminate in aberrant glycosylation, which has been highlighted as a hallmark of cancer. Changes in glycosylation regulate every pathophysiological step of cancer progression including tumour cell-cell dissociation, cell migration, cell signaling and metastasis. This review discusses how the insulin\/IGF system integrates with glycosylation alterations and impacts on cell behaviour, metabolism and drug resistance in cancer.<\/jats:p>","DOI":"10.3390\/ijms18091921","type":"journal-article","created":{"date-parts":[[2017,9,7]],"date-time":"2017-09-07T13:59:10Z","timestamp":1504792750000},"page":"1921","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Glycans as Regulatory Elements of the Insulin\/IGF System: Impact in Cancer Progression"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2070-1432","authenticated-orcid":false,"given":"Julio","family":"De-Freitas-Junior","sequence":"first","affiliation":[{"name":"Cellular and Molecular Oncobiology Program, Brazilian National Cancer Institute (INCA), Rio de Janeiro 20231-050, Brazil"}]},{"given":"J\u00e9ssica","family":"Andrade-da-Costa","sequence":"additional","affiliation":[{"name":"Cellular and Molecular Oncobiology Program, Brazilian National Cancer Institute (INCA), Rio de Janeiro 20231-050, Brazil"}]},{"given":"Mariana","family":"Silva","sequence":"additional","affiliation":[{"name":"Institute of Molecular Pathology and Immunology of University of Porto (IPATIMUP) & Institute for Research and Innovation in Health (i3S), University of Porto, 4200-135 Porto, Portugal"},{"name":"Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3484-5162","authenticated-orcid":false,"given":"Salom\u00e9","family":"Pinho","sequence":"additional","affiliation":[{"name":"Institute of Molecular Pathology and Immunology of University of Porto (IPATIMUP) & Institute for Research and Innovation in Health (i3S), University of Porto, 4200-135 Porto, Portugal"},{"name":"Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2017,9,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e193","DOI":"10.1038\/oncsis.2016.2","article-title":"Dietary and pharmacological modification of the insulin\/IGF-1 system: Exploiting the full repertoire against cancer","volume":"5","author":"Klement","year":"2016","journal-title":"Oncogenesis"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/s12943-016-0576-5","article-title":"IGF-IR signaling in epithelial to mesenchymal transition and targeting IGF-IR therapy: Overview and new insights","volume":"16","author":"Li","year":"2017","journal-title":"Mol. Cancer"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.canlet.2017.02.014","article-title":"IGF1\/IGF1R\/Stat3 signaling-inducible IFITM2 promotes gastric cancer growth and metastasis","volume":"393","author":"Xu","year":"2017","journal-title":"Cancer Lett."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"40138","DOI":"10.1038\/srep40138","article-title":"IGF-IR cooperates with er\u03b1 to inhibit breast cancer cell aggressiveness by regulating the expression and localisation of ecm molecules","volume":"7","author":"Afratis","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Bailey, K.L., Agarwal, E., Chowdhury, S., Luo, J., Brattain, M.G., Black, J.D., and Wang, J. (2017). TGF\u0392\/SMAD3 regulates proliferation and apoptosis through IRS-1 inhibition in colon cancer cells. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0176096"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3273","DOI":"10.2741\/2925","article-title":"The type I insulin-like growth factor receptor pathway: A key player in cancer therapeutic resistance","volume":"13","author":"Casa","year":"2008","journal-title":"Front. Biosci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"10","DOI":"10.3389\/fendo.2014.00010","article-title":"The emerging role of insulin and insulin-like growth factor signaling in cancer stem cells","volume":"5","author":"Malaguarnera","year":"2014","journal-title":"Front. Endocrinol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1038\/nrc3982","article-title":"Glycosylation in cancer: Mechanisms and clinical implications","volume":"15","author":"Pinho","year":"2015","journal-title":"Nat. Rev. Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1002\/(SICI)1098-2825(1999)13:4<166::AID-JCLA5>3.0.CO;2-X","article-title":"Insulin-like growth factors (IGF-I, free IGF-I and IGF-II) and insulin-like growth factor binding proteins (IGFBP-2, IGFBP-3, IGFBP-6, and ALS) in blood circulation","volume":"13","author":"Yu","year":"1999","journal-title":"J. Clin. Lab. Anal."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1038\/nrc3215","article-title":"The insulin and insulin-like growth factor receptor family in neoplasia: An update","volume":"12","author":"Pollak","year":"2012","journal-title":"Nat. Rev. Cancer"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"38","DOI":"10.3389\/fendo.2012.00038","article-title":"Insulin-like growth factor binding proteins: A structural perspective","volume":"3","author":"Forbes","year":"2012","journal-title":"Front. Endocrinol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/(SICI)1097-4652(200004)183:1<1::AID-JCP1>3.0.CO;2-J","article-title":"Role of insulin-like growth factors and their binding proteins in growth control and carcinogenesis","volume":"183","author":"Grimberg","year":"2000","journal-title":"J. Cell. Physiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.cca.2017.01.017","article-title":"IGFBP, a novel target of lung cancer?","volume":"466","author":"Hu","year":"2017","journal-title":"Clin. Chim. Acta"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"824","DOI":"10.1210\/er.2001-0033","article-title":"Cellular actions of the insulin-like growth factor binding proteins","volume":"23","author":"Firth","year":"2002","journal-title":"Endocr. Rev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"R1","DOI":"10.1530\/JME-11-0022","article-title":"Signalling by insulin and IGF receptors: Supporting acts and new players","volume":"47","author":"Siddle","year":"2011","journal-title":"J. Mol. Endocrinol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1006\/bbrc.2000.4046","article-title":"Autophosphorylation of the insulin-like growth factor I receptor cytoplasmic domain","volume":"279","author":"Lopaczynski","year":"2000","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2969","DOI":"10.1016\/S0021-9258(18)69163-X","article-title":"A cascade of tyrosine autophosphorylation in the \u03b2-subunit activates the phosphotransferase of the insulin receptor","volume":"263","author":"White","year":"1988","journal-title":"J. Biol. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1002\/prot.21768","article-title":"N-linked glycans of the human insulin receptor and their distribution over the crystal structure","volume":"71","author":"Sparrow","year":"2008","journal-title":"Proteins"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1002\/prot.21261","article-title":"The location and characterisation of the O-linked glycans of the human insulin receptor","volume":"66","author":"Sparrow","year":"2007","journal-title":"Proteins"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1042\/bj3470771","article-title":"Mutational analysis of the N-linked glycosylation sites of the human insulin receptor","volume":"347","author":"Elleman","year":"2000","journal-title":"Biochem. J."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/S0167-4889(00)00109-9","article-title":"Alternative glycosylation of the insulin receptor prevents oligomerization and acquisition of insulin-dependent tyrosine kinase activity","volume":"1499","author":"Hwang","year":"2000","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"966","DOI":"10.2337\/diab.42.7.966","article-title":"Glycosylation of ASN397 or ASN418 is required for normal insulin receptor biosynthesis and processing","volume":"42","author":"Bastian","year":"1993","journal-title":"Diabetes"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2503","DOI":"10.1002\/j.1460-2075.1986.tb04528.x","article-title":"Insulin-like growth factor I receptor primary structure: Comparison with insulin receptor suggests structural determinants that define functional specificity","volume":"5","author":"Ullrich","year":"1986","journal-title":"EMBO J."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1210\/mend-5-2-281","article-title":"Biosynthesis of the insulin-like growth factor-II (IGF-II)\/mannose-6-phosphate receptor in rat c6 glial cells: The role of N-linked glycosylation in binding of IGF-II to the receptor","volume":"5","author":"Kiess","year":"1991","journal-title":"Mol. Endocrinol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.placenta.2016.01.005","article-title":"Gestation-associated changes in the glycosylation of placental insulin and insulin-like growth factor receptors","volume":"39","author":"Robajac","year":"2016","journal-title":"Placenta"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"13567","DOI":"10.1038\/ncomms13567","article-title":"IRS4 induces mammary tumorigenesis and confers resistance to HER2-targeted therapy through constitutive PI3K\/AKT-pathway hyperactivation","volume":"7","author":"Ikink","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1023\/A:1006812218502","article-title":"Regulation of the insulin signalling pathway by cellular protein-tyrosine phosphatases","volume":"182","author":"Goldstein","year":"1998","journal-title":"Mol. Cell. Biochem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1172\/JCI10934","article-title":"Insulin\/IGF-1 and TNF-\u03b1 stimulate phosphorylation of IRS-1 at inhibitory Ser307 via distinct pathways","volume":"107","author":"Rui","year":"2001","journal-title":"J. Clin. Investig."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1828","DOI":"10.1038\/onc.2013.122","article-title":"ERK and AKT signaling cooperate to translationally regulate survivin expression for metastatic progression of colorectal cancer","volume":"33","author":"Ye","year":"2014","journal-title":"Oncogene"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1038\/372182a0","article-title":"Insulin resistance and growth retardation in mice lacking insulin receptor substrate-1","volume":"372","author":"Tamemoto","year":"1994","journal-title":"Nature"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1038\/372186a0","article-title":"Alternative pathway of insulin signalling in mice with targeted disruption of the IRS-1 gene","volume":"372","author":"Araki","year":"1994","journal-title":"Nature"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1697","DOI":"10.1007\/s00125-002-0945-z","article-title":"Absence of functional insulin receptor substrate-3 (IRS-3) gene in humans","volume":"45","author":"He","year":"2002","journal-title":"Diabetologia"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.gendis.2014.10.004","article-title":"Insulin-like growth factor (IGF) signaling in tumorigenesis and the development of cancer drug resistance","volume":"2","author":"Denduluri","year":"2015","journal-title":"Genes Dis."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1038\/nrc3447","article-title":"Regulatory networks defining emt during cancer initiation and progression","volume":"13","author":"Berx","year":"2013","journal-title":"Nat. Rev. Cancer"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2479","DOI":"10.1158\/0008-5472.CAN-07-2559","article-title":"Insulin-like growth factor-I-dependent up-regulation of ZEB1 drives epithelial-to-mesenchymal transition in human prostate cancer cells","volume":"68","author":"Graham","year":"2008","journal-title":"Cancer Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"44332","DOI":"10.18632\/oncotarget.6293","article-title":"Implication of epithelial-mesenchymal transition in IGF1R-induced resistance to EGFR-TKIs in advanced non-small cell lung cancer","volume":"6","author":"Zhou","year":"2015","journal-title":"Oncotarget"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1016\/j.cell.2008.03.027","article-title":"The epithelial-mesenchymal transition generates cells with properties of stem cells","volume":"133","author":"Mani","year":"2008","journal-title":"Cell"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1038\/nrc2620","article-title":"Transitions between epithelial and mesenchymal states: Acquisition of malignant and stem cell traits","volume":"9","author":"Polyak","year":"2009","journal-title":"Nat. Rev. Cancer"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Shibue, T., and Weinberg, R.A. (2017). EMT, CSCs, and drug resistance: The mechanistic link and clinical implications. Nat. Rev. Clin. Oncol.","DOI":"10.1038\/nrclinonc.2017.44"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"R39","DOI":"10.1186\/bcr3423","article-title":"The expression and significance of insulin-like growth factor-1 receptor and its pathway on breast cancer stem\/progenitors","volume":"15","author":"Chang","year":"2013","journal-title":"Breast Cancer Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1210\/jc.2010-1255","article-title":"Insulin receptor isoforms and insulin-like growth factor receptor in human follicular cell precursors from papillary thyroid cancer and normal thyroid","volume":"96","author":"Malaguarnera","year":"2011","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1276","DOI":"10.1038\/onc.2016.293","article-title":"Addiction to the IGF2-ID1-IGF2 circuit for maintenance of the breast cancer stem-like cells","volume":"36","author":"Tominaga","year":"2017","journal-title":"Oncogene"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1004","DOI":"10.1002\/hep.25745","article-title":"Nanog regulates self-renewal of cancer stem cells through the insulin-like growth factor pathway in human hepatocellular carcinoma","volume":"56","author":"Shan","year":"2012","journal-title":"Hepatology"},{"key":"ref_44","first-page":"5645","article-title":"Insulin-like growth factor binding protein-1 inhibits cancer cell invasion and is associated with poor prognosis in hepatocellular carcinoma","volume":"7","author":"Dai","year":"2014","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1186\/1476-4598-13-136","article-title":"Ubiquitin ligase Cbl-b represses IGF-I-induced epithelial mesenchymal transition via ZEB2 and microRNA-200c regulation in gastric cancer cells","volume":"13","author":"Li","year":"2014","journal-title":"Mol. Cancer"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"4757","DOI":"10.18632\/oncotarget.3023","article-title":"Fak activation is required for IGF1R-mediated regulation of EMT, migration, and invasion in mesenchymal triple negative breast cancer cells","volume":"6","author":"Oberlick","year":"2015","journal-title":"Oncotarget"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1593\/neo.101590","article-title":"Insulin-like growth factor-dependent proliferation and survival of triple-negative breast cancer cells: Implications for therapy","volume":"13","author":"Davison","year":"2011","journal-title":"Neoplasia"},{"key":"ref_48","first-page":"67","article-title":"Inhibition of N-linked glycosylation down-regulates insulin-like growth factor-1 receptor at the cell surface and kills ewing\u2019s sarcoma cells: Therapeutic implications","volume":"15","author":"Girnita","year":"2000","journal-title":"Anti-Cancer Drug Des."},{"key":"ref_49","first-page":"32568","article-title":"miR-29a regulated ER-positive breast cancer cell growth and invasion and is involved in the insulin signaling pathway","volume":"8","author":"Li","year":"2017","journal-title":"Oncotarget"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"225","DOI":"10.3727\/096504016X14648701447931","article-title":"IGF-I induces epithelial-to-mesenchymal transition via the IGF-IR-Src-microRNA-30a-E-cadherin pathway in nasopharyngeal carcinoma cells","volume":"24","author":"Wang","year":"2016","journal-title":"Oncol. Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1038\/s41598-017-00826-0","article-title":"Identification of IGF-1-enhanced cytokine expressions targeted by miR-181d in glioblastomas via an integrative miRNA\/mRNA regulatory network analysis","volume":"7","author":"Ho","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1951","DOI":"10.1158\/0008-5472.CAN-08-2023","article-title":"Chemoresistant colorectal cancer cells, the cancer stem cell phenotype, and increased sensitivity to insulin-like growth factor-i receptor inhibition","volume":"69","author":"Dallas","year":"2009","journal-title":"Cancer Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1016\/j.canlet.2014.08.023","article-title":"IGF-1R inhibition potentiates cytotoxic effects of chemotherapeutic agents in early stages of chemoresistant ovarian cancer cells","volume":"354","author":"Singh","year":"2014","journal-title":"Cancer Lett."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1200\/JCO.2015.62.6598","article-title":"Lapatinib in combination with capecitabine plus oxaliplatin in human epidermal growth factor receptor 2-positive advanced or metastatic gastric, esophageal, or gastroesophageal adenocarcinoma: TRIO-013\/LOGIC\u2014A randomized phase III trial","volume":"34","author":"Hecht","year":"2016","journal-title":"J. Clin. Oncol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"4559","DOI":"10.1158\/1078-0432.CCR-13-3396","article-title":"Functional genetic approach identifies MET, HER3, IGF1R, INSR pathways as determinants of lapatinib unresponsiveness in HER2-positive gastric cancer","volume":"20","author":"Zhang","year":"2014","journal-title":"Clin. Cancer Res."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Kim, J.G., Kang, M.J., Yoon, Y.K., Kim, H.P., Park, J., Song, S.H., Han, S.W., Park, J.W., Kang, G.H., and Kang, K.W. (2012). Heterodimerization of glycosylated insulin-like growth factor-1 receptors and insulin receptors in cancer cells sensitive to anti-IGF1R antibody. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0033322"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1016\/j.imbio.2015.06.007","article-title":"Activation of insulin-like growth factor 1 receptor regulates the radiation-induced lung cancer cell apoptosis","volume":"220","author":"Zhang","year":"2015","journal-title":"Immunobiology"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1002\/stem.1328","article-title":"IGF1 receptor signaling regulates adaptive radioprotection in glioma stem cells","volume":"31","author":"Osuka","year":"2013","journal-title":"Stem Cells"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1528","DOI":"10.1016\/j.ijrobp.2009.11.022","article-title":"Sialylation of integrin \u03b21 is involved in radiation-induced adhesion and migration in human colon cancer cells","volume":"76","author":"Lee","year":"2010","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"2957","DOI":"10.1002\/jcb.24173","article-title":"N-glycan biosynthesis inhibitors induce in vitro anticancer activity in colorectal cancer cells","volume":"113","author":"Bastos","year":"2012","journal-title":"J. Cell. Biochem."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"3205","DOI":"10.1158\/1078-0432.CCR-09-3331","article-title":"Molecular imaging of N-linked glycosylation suggests glycan biosynthesis is a novel target for cancer therapy","volume":"16","author":"Contessa","year":"2010","journal-title":"Clin. Cancer Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.cmet.2007.10.002","article-title":"The biology of cancer: Metabolic reprogramming fuels cell growth and proliferation","volume":"7","author":"DeBerardinis","year":"2008","journal-title":"Cell Metab."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1016\/j.ccr.2008.05.005","article-title":"Tumor cell metabolism: Cancer\u2019s achilles\u2019 heel","volume":"13","author":"Kroemer","year":"2008","journal-title":"Cancer Cell"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1007\/s10585-005-2343-7","article-title":"Lactate dehydrogenase 5 (LDH5) relates to up-regulated hypoxia inducible factor pathway and metastasis in colorectal cancer","volume":"22","author":"Koukourakis","year":"2005","journal-title":"Clin. Exp. Metastasis"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.semcancer.2008.11.010","article-title":"Is Akt the \u201cWarburg kinase\u201d?\u2014Akt-energy metabolism interactions and oncogenesis","volume":"19","author":"Robey","year":"2009","journal-title":"Semin. Cancer Biol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1304","DOI":"10.1210\/me.2004-0239","article-title":"Regulation of hypoxia-inducible factor (HIF)-1 activity and expression of hif hydroxylases in response to insulin-like growth factor I","volume":"19","author":"Treins","year":"2005","journal-title":"Mol. Endocrinol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.brainres.2011.10.046","article-title":"IGF-1 induces hypoxia-inducible factor 1\u03b1-mediated GLUT3 expression through PI3K\/Akt\/mTOR dependent pathways in PC12 cells","volume":"1430","author":"Yu","year":"2012","journal-title":"Brain Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1016\/j.bbrc.2014.11.014","article-title":"Treatment with insulin-like growth factor 1 receptor inhibitor reverses hypoxia-induced epithelial-mesenchymal transition in non-small cell lung cancer","volume":"455","author":"Nurwidya","year":"2014","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"193","DOI":"10.4093\/dmj.2011.35.3.193","article-title":"Diabetes and cancer: Is diabetes causally related to cancer?","volume":"35","author":"Suh","year":"2011","journal-title":"Diabetes Metab. J."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1607","DOI":"10.1007\/s00125-012-2525-1","article-title":"Diabetes and cancer (1): Evaluating the temporal relationship between type 2 diabetes and cancer incidence","volume":"55","author":"Johnson","year":"2012","journal-title":"Diabetologia"},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Alisson-Silva, F., Freire-de-Lima, L., Donadio, J.L., Lucena, M.C., Penha, L., S\u00e1-Diniz, J.N., Dias, W.B., and Todeschini, A.R. (2013). Increase of O-glycosylated oncofetal fibronectin in high glucose-induced epithelial-mesenchymal transition of cultured human epithelial cells. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0060471"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1038\/sj.bjc.6606050","article-title":"Diabetogenic glucose and insulin concentrations modulate transcriptome and protein levels involved in tumour cell migration, adhesion and proliferation","volume":"104","author":"Masur","year":"2011","journal-title":"Br. J. Cancer"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"e306","DOI":"10.1038\/oncsis.2017.2","article-title":"Hyperglycemia exacerbates colon cancer malignancy through hexosamine biosynthetic pathway","volume":"6","author":"Loponte","year":"2017","journal-title":"Oncogenesis"},{"key":"ref_74","first-page":"BR357","article-title":"Growth factors enhance endothelial progenitor cell proliferation under high-glucose conditions","volume":"15","author":"Li","year":"2009","journal-title":"Med. Sci. Monit."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1038\/nature07782","article-title":"Tumours with PI3K activation are resistant to dietary restriction","volume":"458","author":"Kalaany","year":"2009","journal-title":"Nature"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"4706","DOI":"10.1016\/S0021-9258(19)67706-9","article-title":"Discovery of a metabolic pathway mediating glucose-induced desensitization of the glucose transport system. Role of hexosamine biosynthesis in the induction of insulin resistance","volume":"266","author":"Marshall","year":"1991","journal-title":"J. Biol. Chem."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"65231","DOI":"10.18632\/oncotarget.11245","article-title":"O-mannosylation and N-glycosylation: Two coordinated mechanisms regulating the tumour suppressor functions of E-cadherin in cancer","volume":"7","author":"Carvalho","year":"2016","journal-title":"Oncotarget"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1619","DOI":"10.1038\/onc.2015.225","article-title":"Preventing E-cadherin aberrant N-glycosylation at Asn-554 improves its critical function in gastric cancer","volume":"35","author":"Carvalho","year":"2016","journal-title":"Oncogene"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"2690","DOI":"10.1016\/j.bbagen.2012.10.021","article-title":"E-cadherin and adherens-junctions stability in gastric carcinoma: Functional implications of glycosyltransferases involving N-glycan branching biosynthesis, N-acetylglucosaminyltransferases III and V","volume":"1830","author":"Pinho","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"19395","DOI":"10.18632\/oncotarget.6283","article-title":"The role of N-glycans in colorectal cancer progression: Potential biomarkers and therapeutic applications","volume":"7","year":"2016","journal-title":"Oncotarget"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1007\/s00280-010-1477-8","article-title":"Inhibition of N-linked glycosylation by tunicamycin induces E-cadherin-mediated cell-cell adhesion and inhibits cell proliferation in undifferentiated human colon cancer cells","volume":"68","author":"Silva","year":"2011","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"De-Freitas-Junior, J.C., Carvalho, S., Dias, A.M., Oliveira, P., Cabral, J., Seruca, R., Oliveira, C., Morgado-D\u00edaz, J.A., Reis, C.A., and Pinho, S.S. (2013). Insulin\/IGF-I signaling pathways enhances tumor cell invasion through bisecting glcnac N-glycans modulation. An interplay with E-cadherin. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0081579"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1007\/BF00925741","article-title":"Induction of N-acetylglucosaminyltransferase V by elevated expression of activated or proto-Ha-ras oncogenes","volume":"122","author":"Lu","year":"1993","journal-title":"Mol. Cell. Biochem."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"2599","DOI":"10.1093\/hmg\/ddp194","article-title":"The role of N-acetylglucosaminyltransferase III and V in the post-transcriptional modifications of E-cadherin","volume":"18","author":"Pinho","year":"2009","journal-title":"Hum. Mol. Genet."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1016\/j.molmed.2013.07.003","article-title":"Gastric cancer: Adding glycosylation to the equation","volume":"19","author":"Pinho","year":"2013","journal-title":"Trends Mol. Med."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"772","DOI":"10.5483\/BMBRep.2011.44.12.772","article-title":"Branched N-glycans and their implications for cell adhesion, signaling and clinical applications for cancer biomarkers and in therapeutics","volume":"44","author":"Taniguchi","year":"2011","journal-title":"BMB Rep."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1038\/73163","article-title":"Suppression of tumor growth and metastasis in Mgat5-deficient mice","volume":"6","author":"Granovsky","year":"2000","journal-title":"Nat. Med."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"2344","DOI":"10.1128\/MCB.18.4.2344","article-title":"Requirement for both Shc and phosphatidylinositol 3\u2032 kinase signaling pathways in polyomavirus middle T-mediated mammary tumorigenesis","volume":"18","author":"Webster","year":"1998","journal-title":"Mol. Cell. Biol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1126\/science.1102109","article-title":"Regulation of cytokine receptors by golgi N-glycan processing and endocytosis","volume":"306","author":"Partridge","year":"2004","journal-title":"Science"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1016\/j.sbi.2007.09.002","article-title":"Functions of cell surface galectin-glycoprotein lattices","volume":"17","author":"Rabinovich","year":"2007","journal-title":"Curr. Opin. Struct. Biol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1016\/S0304-4165(02)00311-2","article-title":"Oligosaccharide specificity of galectins: A search by frontal affinity chromatography","volume":"1572","author":"Hirabayashi","year":"2002","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.cell.2007.01.049","article-title":"Complex N-glycan number and degree of branching cooperate to regulate cell proliferation and differentiation","volume":"129","author":"Lau","year":"2007","journal-title":"Cell"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1126\/science.1222278","article-title":"Phosphofructokinase 1 glycosylation regulates cell growth and metabolism","volume":"337","author":"Yi","year":"2012","journal-title":"Science"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1016\/j.tibs.2010.04.005","article-title":"O-glcnac signaling: A metabolic link between diabetes and cancer?","volume":"35","author":"Slawson","year":"2010","journal-title":"Trends Biochem. Sci."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1146\/annurev-biochem-060608-102511","article-title":"Cross talk between O-glcnacylation and phosphorylation: Roles in signaling, transcription, and chronic disease","volume":"80","author":"Hart","year":"2011","journal-title":"Annu. Rev. Biochem."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"34457","DOI":"10.1074\/jbc.R114.577718","article-title":"Cancer metabolism and elevated O-glcnac in oncogenic signaling","volume":"289","author":"Ma","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"2733","DOI":"10.1074\/mcp.M900207-MCP200","article-title":"O-linked N-acetylglucosamine modification of insulin receptor substrate-1 occurs in close proximity to multiple SH2 domain binding motifs","volume":"8","author":"Klein","year":"2009","journal-title":"Mol. Cell. Proteomics"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"3051","DOI":"10.1016\/j.febslet.2006.04.051","article-title":"Akt1 is dynamically modified with O-glcnac following treatments with pugnac and insulin-like growth factor-1","volume":"580","author":"Gandy","year":"2006","journal-title":"FEBS Lett."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1016\/j.trecan.2016.08.003","article-title":"Cadherins glycans in cancer: Sweet players in a bitter process","volume":"2","author":"Carvalho","year":"2016","journal-title":"Trends Cancer"},{"key":"ref_100","first-page":"2881","article-title":"Progression of hepatic neoplasms is severely retarded in mice lacking the bisecting n-acetylglucosamine on N-glycans: Evidence for a glycoprotein factor that facilitates hepatic tumor progression","volume":"58","author":"Bhaumik","year":"1998","journal-title":"Cancer Res."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"2506","DOI":"10.1158\/1078-0432.CCR-05-1938","article-title":"N-acetylglucosaminyltransferase V and \u03b21-6 branching N-linked oligosaccharides are associated with good prognosis of patients with bladder cancer","volume":"12","author":"Ishimura","year":"2006","journal-title":"Clin. Cancer Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/18\/9\/1921\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T18:44:23Z","timestamp":1760208263000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/18\/9\/1921"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,9,7]]},"references-count":101,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2017,9]]}},"alternative-id":["ijms18091921"],"URL":"https:\/\/doi.org\/10.3390\/ijms18091921","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2017,9,7]]}}}