Oncotarget

Research Papers:

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

Chia-Wen Ho, Chi-Yu Lin, Yi-Wei Liaw, Hsiao-Ling Chiang, Yu-Tang Chin, Rui-Lan Huang, Hung-Cheng Lai, Yaw-Wen Hsu, Po-Jan Kuo, Chiao-En Chen, Hung-Yun Lin, Jacqueline Whang-Peng, Shin Nieh, Earl Fu, Leroy F. Liu and Jaulang Hwang _

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Oncotarget. 2016; 7:61930-61944. https://doi.org/10.18632/oncotarget.11324

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Abstract

Chia-Wen Ho1,4,*, Chi-Yu Lin2,*, Yi-Wei Liaw2,3,*, Hsiao-Ling Chiang2, Yu-Tang Chin4, Rui-Lan Huang5, Hung-Cheng Lai5,6,7, Yaw-Wen Hsu6, Po-Jan Kuo8, Chiao-En Chen4, Hung-Yun Lin4, Jacqueline Whang-Peng4, Shin Nieh6,9, Earl Fu6,8, Leroy F. Liu1,4,#, Jaulang Hwang1,2,3,6

1Center for Cancer Research, Taipei Medical University, Taipei, Taiwan

2Department of Biochemistry, Medical College, Taipei Medical University, Taipei, Taiwan

3Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan

4Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan

5Department of Obstetrics and Gynecology, Shuang-Ho Hospital, Taipei Medical University, New Taipei City, Taiwan

6Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan

7Department of Obstetrics and Gynecology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

8Department of Periodontology, School of Dentistry, National Defense Medical Center and Tri-Service General Hospital, Taipei, Taiwan

9Department 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: [email protected]

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 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.


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