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Int. J. Mol. Sci. 2016, 17(9), 1467; doi:10.3390/ijms17091467

Aberrant JAK/STAT Signaling Suppresses TFF1 and TFF2 through Epigenetic Silencing of GATA6 in Gastric Cancer

1
Department of Gastroenterology and Hepatology, Chiayi Chang Gung Memorial Hospital, Chiayi 613, Taiwan
2
Department of Surgery, Chiayi Chang Gung Memorial Hospital, Chiayi 613, Taiwan
3
Department of Life Science, National Chung Cheng University, 168 University Road, Min Hsiung, Chiayi 621, Taiwan
4
Department of Fragrance and Cosmetic Science, Kaohsiung Medical University, Kaohsiung 807, Taiwan
5
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, China
6
Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
*
Author to whom correspondence should be addressed.
Academic Editor: Nicoletta Sacchi
Received: 11 May 2016 / Revised: 24 August 2016 / Accepted: 25 August 2016 / Published: 2 September 2016
(This article belongs to the Special Issue Cancer Epigenetics)
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Abstract

Aberrant Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling is crucial to the development of gastric cancer. In this study, we examined the role of STAT3 in the expression and methylation of its targets in gastric cancer patients. Results from RNA sequencing identified an inverse correlation between the expression of STAT3 and GATA6 in 23 pairs of gastric cancer patient samples. We discovered that the expression of GATA6 is epigenetically silenced through promoter methylation in gastric cancer cell lines. Interestingly, the inhibition of STAT3 using a novel STAT3 inhibitor restored the expression of GATA6 and its targets, trefoil factors 1 and 2 (TFF1/2). Moreover, disruption of STAT3 binding to GATA6 promoter by small hairpin RNA restored GATA6 expression in AGS cells. A clinically significant correlation was also observed between the expression of GATA6 and TFF1/2 among tissue samples from 60 gastric cancer patients. Finally, bisulfite pyrosequencing revealed GATA6 methylation in 65% (39/60) of the patients, and those with higher GATA6 methylation tended to have shorter overall survival. In conclusion, we demonstrated that aberrant JAK/STAT signaling suppresses TFF1/2 partially through the epigenetic silencing of GATA6. Therapeutic intervention of STAT3 in reversing the epigenetic status of GATA6 could benefit the treatment of gastric cancer and is worthy of further investigation. View Full-Text
Keywords: epigenetic silencing; gastric cancer; TFF1; TFF2; GATA6; STAT3 epigenetic silencing; gastric cancer; TFF1; TFF2; GATA6; STAT3
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Wu, C.-S.; Wei, K.-L.; Chou, J.-L.; Lu, C.-K.; Hsieh, C.-C.; Lin, J.M.J.; Deng, Y.-F.; Hsu, W.-T.; Wang, H.-M.D.; Leung, C.-H.; Ma, D.-L.; Li, C.; Chan, M.W.Y. Aberrant JAK/STAT Signaling Suppresses TFF1 and TFF2 through Epigenetic Silencing of GATA6 in Gastric Cancer. Int. J. Mol. Sci. 2016, 17, 1467.

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