The cytokine-cosmc signaling axis upregulates the tumor-associated carbohydrate antigen Tn

// Chia-Wen Ho 1, 4, * , Chi-Yu Lin 2, * , Yi-Wei Liaw 2, 3, * , Hsiao-Ling Chiang 2 , Yu-Tang Chin 4 , Rui-Lan Huang 5 , Hung-Cheng Lai 5, 6, 7 , Yaw-Wen Hsu 6 , Po-Jan Kuo 8 , Chiao-En Chen 4 , Hung-Yun Lin 4 , Jacqueline Whang-Peng 4 , Shin Nieh 6, 9 , Earl Fu 6, 8 , Leroy F. Liu 1, 4, # , Jaulang Hwang 1, 2, 3, 6 1 Center for Cancer Research, Taipei Medical University, Taipei, Taiwan 2 Department of Biochemistry, Medical College, Taipei Medical University, Taipei, Taiwan 3 Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan 4 Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan 5 Department of Obstetrics and Gynecology, Shuang-Ho Hospital, Taipei Medical University, New Taipei City, Taiwan 6 Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan 7 Department of Obstetrics and Gynecology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan 8 Department of Periodontology, School of Dentistry, National Defense Medical Center and Tri-Service General Hospital, Taipei, Taiwan 9 Department of Pathology, National Defense Medical Center and Tri-Service General Hospital, Taipei, Taiwan # Co-corresponding author * These authors have contributed equally to this work Correspondence to: Jaulang Hwang, email: jaulang@tmu.edu.tw Keywords: Tn antigen, tumor-associated carbohydrate, cytokines, cosmc, hypermethylation Received: October 22, 2015     Accepted: July 16, 2016     Published: August 17, 2016 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 Hras G12V -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.