Glycosylation and Integrin Regulation in Cancer.

Integrins are transmembrane receptors that coordinate extracellular matrix (ECM)-cell and cell-cell interactions, signal transmission, gene expression, and cell function. The aberration of integrin function is one of the well-recognized mechanisms of cancer. The activity of integrins is strongly influenced by glycans through glycosylation events and the establishment of glycan-mediated interactions. Glycans represent a class of ubiquitous biomolecules that display an extraordinary complexity and diversity in both structure and function. Widely expressed both in the ECM and on the cell surface, they play a crucial role in mediating cell proliferation, survival, and metastasis during cancer. The purpose of this review is to provide an overview of how both glycosylation of integrins and integrin interaction with the cancer glyco-microenvironment can regulate cancer progression.

[1]  J. Wakefield,et al.  Hypersialylation of beta1 integrins, observed in colon adenocarcinoma, may contribute to cancer progression by up-regulating cell motility. , 2005, Cancer research.

[2]  Jeffrey C Gildersleeve,et al.  Modifications of glycans: biological significance and therapeutic opportunities. , 2012, ACS chemical biology.

[3]  A. Theocharis,et al.  Syndecans – key regulators of cell signaling and biological functions , 2017, The FEBS journal.

[4]  C. Reis,et al.  Early GalNAc O-Glycosylation: Pushing the Tumor Boundaries. , 2017, Cancer cell.

[5]  C. Ohyama,et al.  Core3 O-Glycan Synthase Suppresses Tumor Formation and Metastasis of Prostate Carcinoma PC3 and LNCaP Cells through Down-regulation of α2β1 Integrin Complex* , 2009, The Journal of Biological Chemistry.

[6]  J. Gu,et al.  Integrin α5 Suppresses the Phosphorylation of Epidermal Growth Factor Receptor and Its Cellular Signaling of Cell Proliferation via N-Glycosylation* , 2015, The Journal of Biological Chemistry.

[7]  Anthony P Corfield,et al.  Glycan variation and evolution in the eukaryotes. , 2015, Trends in biochemical sciences.

[8]  A. Theocharis,et al.  Proteoglycans remodeling in cancer: Underlying molecular mechanisms. , 2017, Matrix biology : journal of the International Society for Matrix Biology.

[9]  I. Lai,et al.  β-1,4-Galactosyltransferase III suppresses β1 integrin-mediated invasive phenotypes and negatively correlates with metastasis in colorectal cancer. , 2014, Carcinogenesis.

[10]  I. Lai,et al.  C1GALT1 Promotes Invasive Phenotypes of Hepatocellular Carcinoma Cells by Modulating Integrin β1 Glycosylation and Activity , 2014, PloS one.

[11]  Y. Wada,et al.  N-Glycosylation of Laminin-332 Regulates Its Biological Functions , 2008, Journal of Biological Chemistry.

[12]  C. DiPersio,et al.  Beyond adhesion: emerging roles for integrins in control of the tumor microenvironment , 2017, F1000Research.

[13]  J. Gu,et al.  Significance of β-Galactoside α2,6 Sialyltranferase 1 in Cancers , 2015, Molecules.

[14]  M. Fukuda,et al.  Study of the biological functions of mucin type core 3 O-glycans. , 2013, Methods in molecular biology.

[15]  Shengjin Yu,et al.  Caveolin‐1 up‐regulates integrin α2,6‐sialylation to promote integrin α5β1‐dependent hepatocarcinoma cell adhesion , 2013, FEBS letters.

[16]  John M Tarbell,et al.  Cancer cell glycocalyx mediates mechanotransduction and flow-regulated invasion. , 2013, Integrative biology : quantitative biosciences from nano to macro.

[17]  R. Fässler,et al.  Consequences of lack of beta 1 integrin gene expression in mice. , 1995, Genes & development.

[18]  Sanjay Kumar,et al.  CD44-Mediated Adhesion to Hyaluronic Acid Contributes to Mechanosensing and Invasive Motility , 2014, Molecular Cancer Research.

[19]  G. Rabinovich,et al.  Linking tumor hypoxia with VEGFR2 signaling and compensatory angiogenesis , 2014, Oncoimmunology.

[20]  R. Brentani,et al.  α6β1-Integrin, a Major Cell Surface Carrier of β1-6-branched Oligosaccharides, Mediates Migration of EJ-ras-transformed Fibroblasts on Laminin-1 Independently of Its Glycosylation State , 1996 .

[21]  Adam Byron,et al.  Integrin ligands at a glance , 2006, Journal of Cell Science.

[22]  Haining Jin,et al.  Cytoplasmic Domain Interactions of Syndecan-1 and Syndecan-4 with α6β4 Integrin Mediate Human Epidermal Growth Factor Receptor (HER1 and HER2)-dependent Motility and Survival*♦ , 2014, The Journal of Biological Chemistry.

[23]  P. Janmey,et al.  Augmentation of integrin-mediated mechanotransduction by hyaluronic acid. , 2014, Biomaterials.

[24]  C. Cabañas,et al.  Conformational equilibria and intrinsic affinities define integrin activation , 2017, The EMBO journal.

[25]  O. Suzuki,et al.  Sialylation and glycosylation modulate cell adhesion and invasion to extracellular matrix in human malignant lymphoma: Dependency on integrin and the Rho GTPase family , 2015, International journal of oncology.

[26]  S. Bellis,et al.  Ras oncogene directs expression of a differentially sialylated, functionally altered β1 integrin , 2003, Oncogene.

[27]  G. Fields,et al.  Glycosylation Modulates Melanoma Cell α2β1 and α3β1 Integrin Interactions with Type IV Collagen* , 2014, The Journal of Biological Chemistry.

[28]  L. Borsig.  Heparin as an inhibitor of cancer progression. , 2010, Progress in molecular biology and translational science.

[29]  N. Taniguchi,et al.  Suppression of lung metastasis of B16 mouse melanoma by N-acetylglucosaminyltransferase III gene transfection. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[30]  R. Brentani,et al.  Functionally distinct roles for glycosylation of alpha and beta integrin chains in cell-matrix interactions. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[31]  Brian J. Ell,et al.  Vascular endothelial‐cadherin stimulates syndecan‐1‐coupled insulin‐like growth factor‐1 receptor and cross‐talk between αVβ3 integrin and vascular endothelial growth factor receptor 2 at the onset of endothelial cell dissemination during angiogenesis , 2013, The FEBS journal.

[32]  L. Borsig,et al.  Altered Tumor-Cell Glycosylation Promotes Metastasis , 2014, Front. Oncol..

[33]  S. Akiyama,et al.  Aberrant N-glycosylation of beta1 integrin causes reduced alpha5beta1 integrin clustering and stimulates cell migration. , 2002, Cancer research.

[34]  Y. Zhuo,et al.  Tumor cell migration and invasion are regulated by expression of variant integrin glycoforms. , 2008, Experimental cell research.

[35]  A. Rapraeger,et al.  Syndecan-1 couples the insulin-like growth factor-1 receptor to inside-out integrin activation , 2010, Journal of Cell Science.

[36]  M. Davidson,et al.  The cancer glycocalyx mechanically primes integrin-mediated growth and survival , 2014, Nature.

[37]  E. Pocheć,et al.  Aberrant glycosylation of αvβ3 integrin is associated with melanoma progression. , 2015, Anticancer research.

[38]  K. Handa,et al.  Involvement of O-glycosylation defining oncofetal fibronectin in epithelial-mesenchymal transition process , 2011, Proceedings of the National Academy of Sciences.

[39]  Yuhua Song,et al.  Role of altered sialylation of the I-like domain of beta1 integrin in the binding of fibronectin to beta1 integrin: thermodynamics and conformational analyses. , 2010, Biophysical journal.

[40]  Dragana Nikitovic,et al.  Glycosaminoglycans: key players in cancer cell biology and treatment , 2012, The FEBS journal.

[41]  J. Gu,et al.  A Key Regulator of Cell Adhesion: Identification and Characterization of Important N-Glycosylation Sites on Integrin α5 for Cell Migration , 2017, Molecular and Cellular Biology.

[42]  A. Rapraeger.  Synstatin: a selective inhibitor of the syndecan‐1‐coupled IGF1R–αvβ3 integrin complex in tumorigenesis and angiogenesis , 2013, The FEBS journal.

[43]  N. Packer,et al.  Structural analysis of N- and O-glycans released from glycoproteins , 2012, Nature Protocols.

[44]  A. Amoresano,et al.  Characterisation of alpha3beta1 and alpha(v)beta3 integrin N-oligosaccharides in metastatic melanoma WM9 and WM239 cell lines. , 2008, Biochimica et biophysica acta.

[45]  S. Pinho,et al.  Glycosylation in cancer: mechanisms and clinical implications , 2015, Nature Reviews Cancer.

[46]  K. Katagiri,et al.  Occurrence of Oligosialic Acids on Integrin α5Subunit and Their Involvement in Cell Adhesion to Fibronectin* , 2001, The Journal of Biological Chemistry.

[47]  J. Gu,et al.  Importance of N-Glycosylation on a51 Integrin for Its Biological Functions , 2009 .

[48]  S. Nakahara,et al.  Galectin-3 in apoptosis, a novel therapeutic target , 2007, Journal of bioenergetics and biomembranes.

[49]  A. Lityńska,et al.  Cell migration-the role of integrin glycosylation. , 2010, Biochimica et biophysica acta.

[50]  M. Pavão,et al.  Heparan Sulfate Proteoglycans May Promote or Inhibit Cancer Progression by Interacting with Integrins and Affecting Cell Migration , 2015, BioMed research international.

[51]  S. Tsuboi,et al.  Two opposing roles of O-glycans in tumor metastasis. , 2012, Trends in molecular medicine.

[52]  A. Ranjan,et al.  Glycosylation of the laminin receptor (α3β1) regulates its association with tetraspanin CD151: Impact on cell spreading, motility, degradation and invasion of basement membrane by tumor cells. , 2014, Experimental cell research.

[53]  J. Gu,et al.  Bisecting GlcNAc Residues on Laminin-332 Down-regulate Galectin-3-dependent Keratinocyte Motility* , 2009, The Journal of Biological Chemistry.

[54]  Qiuyan Wang,et al.  Nm23-H1 suppresses hepatocarcinoma cell adhesion and migration on fibronectin by modulating glycosylation of integrin beta1 , 2010, Journal of experimental & clinical cancer research : CR.

[55]  S. Goodman,et al.  Integrins as Therapeutic Targets: Successes and Cancers , 2017, Cancers.

[56]  A. Rapraeger,et al.  The syndecan-1 ectodomain regulates αvβ3 integrin activity in human mammary carcinoma cells , 2004, The Journal of cell biology.

[57]  S. Hakomori.  Carbohydrate-to-carbohydrate interaction, through glycosynapse, as a basis of cell recognition and membrane organization , 2004, Glycoconjugate Journal.

[58]  J. Olsen,et al.  Immature truncated O-glycophenotype of cancer directly induces oncogenic features , 2014, Proceedings of the National Academy of Sciences.

[59]  A. Friedl,et al.  Syndecan-1-Induced ECM Fiber Alignment Requires Integrin αvβ3 and Syndecan-1 Ectodomain and Heparan Sulfate Chains , 2016, PloS one.

[60]  Richard O Hynes,et al.  Integrins Bidirectional, Allosteric Signaling Machines , 2002, Cell.

[61]  J. Gu,et al.  Regulation of integrin functions by N-glycans , 2004, Glycoconjugate Journal.

[62]  E. Pocheć,et al.  Expression of integrins α3β1 and α5β1 and GlcNAc β1,6 glycan branching influences metastatic melanoma cell migration on fibronectin. , 2013, European journal of cell biology.

[63]  The importance of N-glycosylation on β3 integrin ligand binding and conformational regulation , 2017, Scientific Reports.

[64]  Andrei V Bakin,et al.  Role of β5-integrin in epithelial-mesenchymal transition in response to TGF-β , 2010, Cell cycle.

[65]  R. Brentani,et al.  alpha6beta1-Integrin, a major cell surface carrier of beta1-6-branched oligosaccharides, mediates migration of EJ-ras-transformed fibroblasts on laminin-1 independently of its glycosylation state. , 1996, Cancer Research.

[66]  S. Hakomori,et al.  Functional role of N-glycosylation in alpha 5 beta 1 integrin receptor. De-N-glycosylation induces dissociation or altered association of alpha 5 and beta 1 subunits and concomitant loss of fibronectin binding activity. , 1994, The Journal of biological chemistry.

[67]  Y. Zhuo,et al.  Emerging Role of α2,6-Sialic Acid as a Negative Regulator of Galectin Binding and Function* , 2010, The Journal of Biological Chemistry.

[68]  J. Dennis,et al.  Suppression of tumor growth and metastasis in Mgat5-deficient mice , 2000, Nature Medicine.

[69]  K. Segawa,et al.  Increased expression of highly branched N-glycans at cell surface is correlated with the malignant phenotypes of mouse tumor cells. , 1997, Cancer research.

[70]  C. Antonescu,et al.  Integrins and Cell Metabolism: An Intimate Relationship Impacting Cancer , 2017, International journal of molecular sciences.

[71]  Jun Du,et al.  Dynamic Sialylation in Transforming Growth Factor-β (TGF-β)-induced Epithelial to Mesenchymal Transition* , 2015, The Journal of Biological Chemistry.

[72]  L. Borsig,et al.  The role of VLA-4 binding for experimental melanoma metastasis and its inhibition by heparin. , 2014, Thrombosis research.

[73]  Shiyong Wu,et al.  Effect of alpha 2,6 sialylation on integrin-mediated adhesion of breast cancer cells to fibronectin and collagen IV. , 2016, Life Science.

[74]  D. Cheresh,et al.  Integrins and cancer: regulators of cancer stemness, metastasis, and drug resistance. , 2015, Trends in cell biology.

[75]  A. Paller,et al.  Carbohydrate-Carbohydrate Binding of Ganglioside to Integrin α5 Modulates α5β1Function* , 2001, The Journal of Biological Chemistry.

[76]  Kelley W. Moremen,et al.  Vertebrate protein glycosylation: diversity, synthesis and function , 2012, Nature Reviews Molecular Cell Biology.

[77]  Hellyeh Hamidi,et al.  The complexity of integrins in cancer and new scopes for therapeutic targeting , 2016, British Journal of Cancer.

[78]  Eiji Miyoshi,et al.  The α1-6-fucosyltransferase gene and its biological significance , 1999 .

[79]  Xiaopeng Zhang,et al.  Knockdown of ST6Gal-I increases cisplatin sensitivity in cervical cancer cells , 2016, BMC Cancer.

[80]  Luís Lima,et al.  Hypoxia enhances the malignant nature of bladder cancer cells and concomitantly antagonizes protein O-glycosylation extension , 2016, Oncotarget.

[81]  Albrecht Schwab,et al.  The glycocalyx maintains a cell surface pH nanoenvironment crucial for integrin-mediated migration of human melanoma cells , 2009, Pflügers Archiv - European Journal of Physiology.

[82]  M. Hollingsworth,et al.  Expression of core 3 synthase in human pancreatic cancer cells suppresses tumor growth and metastasis , 2013, International journal of cancer.

[83]  R. Blaheta,et al.  Cyr61 is a target for heparin in reducing MV3 melanoma cell adhesion and migration via the integrin VLA-4 , 2013, Thrombosis and Haemostasis.

[84]  S. Van slambrouck,et al.  Carbohydrate-to-carbohydrate interactions between α2,3-linked sialic acids on α2 integrin subunits and asialo-GM1 underlie the bone metastatic behaviour of LNCAP-derivative C4-2B prostate cancer cells , 2014, Bioscience reports.

[85]  David A. Cheresh,et al.  Integrins in cancer: biological implications and therapeutic opportunities , 2010, Nature Reviews Cancer.

[86]  J. Gu,et al.  Inhibition of fucosylation by 2-fluorofucose suppresses human liver cancer HepG2 cell proliferation and migration as well as tumor formation , 2017, Scientific Reports.

[87]  J. Couchman,et al.  Syndecan-2 regulation of morphology in breast carcinoma cells is dependent on RhoGTPases. , 2014, Biochimica et biophysica acta.

[88]  J. Gu,et al.  N-Acetylglucosaminyltransferase III Antagonizes the Effect of N-Acetylglucosaminyltransferase V on α3β1 Integrin-mediated Cell Migration* , 2006, Journal of Biological Chemistry.

[89]  S. Akiyama,et al.  Aberrant N-Glycosylation of β1 Integrin Causes Reduced α5β1 Integrin Clustering and Stimulates Cell Migration , 2002 .

[90]  Donald Gullberg,et al.  Integrins , 2009, Cell and Tissue Research.

[91]  A. Varki,et al.  Biological roles of oligosaccharides: all of the theories are correct , 1993, Glycobiology.