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A7094 - Fucosyltransferase 4 Enables Cancer Metastasis Via Enhancing TGFBR-Mediated Epithelial-to-Mesenchymal Transition and Is Associated with Poor Prognosis in Non-Small Cell Lung Cancer
Author Block: H. Lu1, Y. Juan1, Y. Chen2, S. Lin3, H. Hou1, R. R. Weng1, Z. Hung4, Y. Huang2, T. Yang2, W. Yi-Chieh2, G. A. Oswita2, J. Shih1, H. Tsai2, C. Yu1; 1Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan, 2Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan, 3Department of Internal Medicine, National Taiwan University Hospital Jin-Shan Branch, New Tapei City, Taiwan, 4Department of Primary Care Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
Rationale: Aberrant glycosylation has been known to regulate cancer cell trafficking via promoting intravascular adhesion during the process of metastasis. Clinicopathological studies have also shown a strong correlation between aberrant glycosylation and invasive/metastatic potentials of human cancers. However, the major glycosylation enzymes that drive lung cancer metastases and the signaling networks involved in the process remain incompletely understood. Methods: We identified fucosyltransferase 4 (FUT4) as a strong predictor of patient prognosis from two independent cohorts of patients with non-small cell lung cancer. (TCGA and NTUH) We investigated functional roles of FUT4 through over-expression and knock-down studies using human lung cancer cell lines in vitro, in terms of proliferation, invasion, migration abilities. Metastatic and homing potentials of FUT4-overexpressed and/or knockdown cells were evaluated in vivo in NOD-SCID mice via orthotopic implantation and/or tail vein injections. Molecular pathways and signaling networks were studied using genome-wide RNA-seq experiments. Results: High expressions of FUT4 were associated with poor survivals in lung adenocarcinomas in the Taiwan cohort (p = 0.0169) and in the TCGA database (p = 0.000681). FUT4-overexpressed lung cancer cells showed significantly increased migration, invasion, and adhesion abilities in vitro, as well as enhanced homing ability to the lungs in vivo. Two FUT4 over-expressed subclones of a human lung cancer cell line, A549 (FUT4hi and FUT4lo) displayed typical characteristics of epithelial-to-mesenchymal transition (EMT) in a protein level-dependent manner. These FUT4 subclones also revealed decreased proliferative ability, in consistent with the EMT phenomenon. Flow cytometric analysis revealed significant up-regulation of Lewis X and AAL antigens in A549-FUT4 cells, which facilitated binding to E-, L- and P-selections. Molecularly, FUT4 enhanced TGFBR signaling through glycosylation of TGFBR, which lead to increased binding affinity between TGF-β and its receptors. Conclusion: FUT4 promoted lung cancer cell metastasis through enhancing mesenchymal phenotype mediated by glycosylated TGFBR signaling, and through increasing binding affinity of cancer cells to selectins. High levels of FUT4 in tumor tissues significantly correlate with poor prognosis in NSCLC patients. Our study not only provided new insights into the role of FUT4 on molecular signaling as a potential therapeutic target, but also identified FUT4 as a prognostic marker in NSCLC.