title: The cytokine-cosmc signaling axis upregulates the tumor-associated carbohydrate antigen Tn.
abstract: Tn antigen (GalNAc-α-O-Ser/Thr), a mucin-type O-linked glycan, is a well-established cell surface marker for tumors and its elevated levels have been correlated with cancer progression and prognosis. There are also reports that Tn is elevated in inflammatory tissues. However, the molecular mechanism for its elevated levels in cancer and inflammation is unclear. In the current studies, we have explored the possibility that cytokines may be one of the common regulatory molecules for elevated Tn levels in both cancer and inflammation. We showed that the Tn level is elevated by the conditioned media of HrasG12V-transformed-BEAS-2B cells. Similarly, the conditioned media obtained from LPS-stimulated monocytes also elevated Tn levels in primary human gingival fibroblasts, suggesting the involvement of cytokines and/or other soluble factors. Indeed, purified inflammatory cytokines such as TNF-α and IL-6 up-regulated Tn levels in gingival fibroblasts. Furthermore, TNF-α was shown to down-regulate the COSMC gene as evidenced by reduced levels of the COSMC mRNA and protein, as well as hypermethylation of the CpG islands of the COSMC gene promoter. Since Cosmc, a chaperone for T-synthase, is known to negatively regulate Tn levels, our results suggest elevated Tn levels in cancer and inflammation may be commonly regulated by the cytokine-Cosmc signaling axis.
authors.affiliation: Center for Cancer Research, Taipei Medical University, Taipei, Taiwan.|Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors.forename: Chia-Wen
authors.initials: CW
authors.lastname: Ho
authors.affiliation: Department of Biochemistry, Medical College, Taipei Medical University, Taipei, Taiwan.
authors.forename: Chi-Yu
authors.initials: CY
authors.lastname: Lin
authors.affiliation: Department of Biochemistry, Medical College, Taipei Medical University, Taipei, Taiwan.|Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Yi-Wei
authors.initials: YW
authors.lastname: Liaw
authors.affiliation: Department of Biochemistry, Medical College, Taipei Medical University, Taipei, Taiwan.
authors.forename: Hsiao-Ling
authors.initials: HL
authors.lastname: Chiang
authors.affiliation: Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yu-Tang
authors.initials: YT
authors.lastname: Chin
authors.affiliation: Department of Obstetrics and Gynecology, Shuang-Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.
authors.forename: Rui-Lan
authors.initials: RL
authors.lastname: Huang
authors.affiliation: Department of Obstetrics and Gynecology, Shuang-Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.|Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.|Department of Obstetrics and Gynecology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Hung-Cheng
authors.initials: HC
authors.lastname: Lai
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Yaw-Wen
authors.initials: YW
authors.lastname: Hsu
authors.affiliation: Department of Periodontology, School of Dentistry, National Defense Medical Center and Tri-Service General Hospital, Taipei, Taiwan.
authors.forename: Po-Jan
authors.initials: PJ
authors.lastname: Kuo
authors.affiliation: Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors.forename: Chiao-En
authors.initials: CE
authors.lastname: Chen
authors.affiliation: Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors.forename: Hung-Yan
authors.initials: HY
authors.lastname: Lin
authors.affiliation: Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Whang-Peng
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.|Department of Pathology, National Defense Medical Center and Tri-Service General Hospital, Taipei, Taiwan.
authors.forename: Shin
authors.initials: S
authors.lastname: Nieh
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.|Department of Periodontology, School of Dentistry, National Defense Medical Center and Tri-Service General Hospital, Taipei, Taiwan.
authors.forename: Earl
authors.initials: E
authors.lastname: Fu
authors.affiliation: Center for Cancer Research, Taipei Medical University, Taipei, Taiwan.|Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors.forename: Leroy F
authors.initials: LF
authors.lastname: Liu
authors.affiliation: Center for Cancer Research, Taipei Medical University, Taipei, Taiwan.|Department of Biochemistry, Medical College, Taipei Medical University, Taipei, Taiwan.|Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan.|Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Jaulang
authors.initials: J
authors.lastname: Hwang
mesh_terms: D015295:Antigens, Tumor-Associated, Carbohydrate / Q000378:metabolism*; D001943:Breast Neoplasms / Q000276:immunology / Q000378:metabolism; D001980:Bronchi / Q000378:metabolism; D002460:Cell Line; D018899:CpG Islands; D017077:Culture Media, Conditioned; D019175:DNA Methylation; D018450:Disease Progression; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D005881:Gingiva / Q000166:cytology; D006801:Humans; D007249:Inflammation; D015850:Interleukin-6 / Q000378:metabolism*; D008297:Male; D018832:Molecular Chaperones / Q000378:metabolism*; D011379:Prognosis; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D002583:Uterine Cervical Neoplasms / Q000276:immunology / Q000378:metabolism
chemical_list: D015295:Antigens, Tumor-Associated, Carbohydrate; C505369:C1GALT1C1 protein, human; D017077:Culture Media, Conditioned; C508600:IL6 protein, human; D015850:Interleukin-6; D018832:Molecular Chaperones; C040286:Tn antigen; D014409:Tumor Necrosis Factor-alpha
keywords: Tn antigen; cosmc; cytokines; hypermethylation; tumor-associated carbohydrate