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

• Published in: Oncotarget Vol. 7; no. 38; pp. 61930 - 61944
• Main Authors: Ho, Chia-Wen, Lin, Chi-Yu, Liaw, Yi-Wei, Chiang, Hsiao-Ling, Chin, Yu-Tang, Huang, Rui-Lan, Lai, Hung-Cheng, Hsu, Yaw-Wen, Kuo, Po-Jan, Chen, Chiao-En, Lin, Hung-Yan, Whang-Peng, Jacqueline, Nieh, Shin, Fu, Earl, Liu, Leroy F, Hwang, Jaulang
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 20.09.2016
• Subjects: Antigens, Tumor-Associated, Carbohydrate - metabolism; Breast Neoplasms - immunology; Breast Neoplasms - metabolism; Bronchi - metabolism; Cell Line; CpG Islands; Culture Media, Conditioned; Disease Progression; DNA Methylation; Female; Fibroblasts - metabolism; Gene Expression Regulation, Neoplastic; Genes, ras; Gingiva - cytology; Humans; Inflammation; Interleukin-6 - metabolism; Male; Molecular Chaperones - metabolism; Prognosis; Promoter Regions, Genetic; Prostatic Neoplasms - immunology; Prostatic Neoplasms - metabolism; Research Paper; Signal Transduction; Tumor Necrosis Factor-alpha - metabolism; Uterine Cervical Neoplasms - immunology; Uterine Cervical Neoplasms - metabolism; cosmc; cytokines; tumor-associated carbohydrate; Tn antigen; hypermethylation
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.11324

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.