Epigenetic Silencing of STAT3-Targeted miR-193a, by Constitutive Activation of JAK/STAT Signaling, Leads to Tumor Progression Through Overexpression of YWHAZ in Gastric Cancer
PurposeThe purpose of this study was to identify genes that were epigenetically silenced by STAT3 in gastric cancer.MethodsMBDcap-Seq and expression microarray were performed to identify genes that were epigenetically silenced in AGS gastric cancer cell lines depleted of STAT3. Cell lines and animal...
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Frontiers Media S.A.
2021-02-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2021.575667/full |
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| author | Kuo-Liang Wei Jian-Liang Chou Jian-Liang Chou Jian-Liang Chou Yin-Chen Chen Jie-Ting Low Jie-Ting Low Guan-Ling Lin Jing-Lan Liu Te-Sheng Chang Wei-Ming Chen Yung-Yu Hsieh Pearlly S. Yan Yu-Ming Chuang Jora M. J. Lin Shu-Fen Wu Shu-Fen Wu Ming-Ko Chiang Chin Li Chin Li Cheng-Shyong Wu Michael W. Y. Chan Michael W. Y. Chan Michael W. Y. Chan |
| author_facet | Kuo-Liang Wei Jian-Liang Chou Jian-Liang Chou Jian-Liang Chou Yin-Chen Chen Jie-Ting Low Jie-Ting Low Guan-Ling Lin Jing-Lan Liu Te-Sheng Chang Wei-Ming Chen Yung-Yu Hsieh Pearlly S. Yan Yu-Ming Chuang Jora M. J. Lin Shu-Fen Wu Shu-Fen Wu Ming-Ko Chiang Chin Li Chin Li Cheng-Shyong Wu Michael W. Y. Chan Michael W. Y. Chan Michael W. Y. Chan |
| author_sort | Kuo-Liang Wei |
| collection | DOAJ |
| description | PurposeThe purpose of this study was to identify genes that were epigenetically silenced by STAT3 in gastric cancer.MethodsMBDcap-Seq and expression microarray were performed to identify genes that were epigenetically silenced in AGS gastric cancer cell lines depleted of STAT3. Cell lines and animal experiments were performed to investigate proliferation and metastasis of miR-193a and YWHAZ in gastric cancer cell lines. Bisulfite pyrosequencing and tissue microarray were performed to investigate the promoter methylation of miR-193a and expression of STAT3, YWHAZ in patients with gastritis (n = 8) and gastric cancer (n = 71). Quantitative methylation-specific PCR was performed to examine miR-193a promoter methylation in cell-free DNA of serum samples in gastric cancer patients (n = 19).ResultsAs compared with parental cells, depletion of STAT3 resulted in demethylation of a putative STAT3 target, miR-193a, in AGS gastric cancer cells. Although bisulfite pyrosequencing and epigenetic treatment confirmed that miR-193a was epigenetically silenced in gastric cancer cell lines, ChIP-PCR found that it may be indirectly affected by STAT3. Ectopic expression of miR-193a in AGS cells inhibited proliferation and migration of gastric cancer cells. Further expression microarray and bioinformatics analysis identified YWHAZ as one of the target of miR-193a in AGS gastric cancer cells, such that depletion of YWHAZ reduced migration in AGS cells, while its overexpression increased invasion in MKN45 cells in vitro and in vivo. Clinically, bisulfite pyrosequencing revealed that promoter methylation of miR-193a was significantly higher in human gastric cancer tissues (n = 11) as compared to gastritis (n = 8, p < 0.05). Patients infected with H. pylori showed a significantly higher miR-193a methylation than those without H. pylori infection (p < 0.05). Tissue microarray also showed a positive trend between STAT3 and YWHAZ expression in gastric cancer patients (n = 60). Patients with serum miR-193a methylation was associated with shorter overall survival than those without methylation (p < 0.05).ConclusionsConstitutive activation of JAK/STAT signaling may confer epigenetic silencing of the STAT3 indirect target and tumor suppressor microRNA, miR-193a in gastric cancer. Transcriptional suppression of miR-193a may led to overexpression of YWHAZ resulting in tumor progression. Targeted inhibition of STAT3 may be a novel therapeutic strategy against gastric cancer. |
| first_indexed | 2024-12-22T19:44:53Z |
| format | Article |
| id | doaj.art-5c1eb056c1a4416dbfb061e85c05283d |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-22T19:44:53Z |
| publishDate | 2021-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-5c1eb056c1a4416dbfb061e85c05283d2022-12-21T18:14:42ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2021-02-011110.3389/fonc.2021.575667575667Epigenetic Silencing of STAT3-Targeted miR-193a, by Constitutive Activation of JAK/STAT Signaling, Leads to Tumor Progression Through Overexpression of YWHAZ in Gastric CancerKuo-Liang Wei0Jian-Liang Chou1Jian-Liang Chou2Jian-Liang Chou3Yin-Chen Chen4Jie-Ting Low5Jie-Ting Low6Guan-Ling Lin7Jing-Lan Liu8Te-Sheng Chang9Wei-Ming Chen10Yung-Yu Hsieh11Pearlly S. Yan12Yu-Ming Chuang13Jora M. J. Lin14Shu-Fen Wu15Shu-Fen Wu16Ming-Ko Chiang17Chin Li18Chin Li19Cheng-Shyong Wu20Michael W. Y. Chan21Michael W. Y. Chan22Michael W. Y. Chan23Division of Gastroenterology, Chang Gung Memorial Hospital, Chiayi, TaiwanDivision of Gastroenterology, Chang Gung Memorial Hospital, Chiayi, TaiwanDepartment of Biomedical Sciences, National Chung Cheng University, Chiayi, TaiwanInstrument Center, Department of Research and Development, National Defense Medical Center, Taipei, TaiwanDivision of Gastroenterology, Chang Gung Memorial Hospital, Chiayi, TaiwanDivision of Gastroenterology, Chang Gung Memorial Hospital, Chiayi, TaiwanDepartment of Biomedical Sciences, National Chung Cheng University, Chiayi, TaiwanDepartment of Biomedical Sciences, National Chung Cheng University, Chiayi, TaiwanDepartment of Anatomical Pathology, Chang Gung Memorial Hospital, Chiayi, TaiwanDivision of Gastroenterology, Chang Gung Memorial Hospital, Chiayi, TaiwanDivision of Gastroenterology, Chang Gung Memorial Hospital, Chiayi, TaiwanDivision of Gastroenterology, Chang Gung Memorial Hospital, Chiayi, TaiwanDivision of Hematology, Department of Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United StatesDepartment of Biomedical Sciences, National Chung Cheng University, Chiayi, TaiwanDepartment of Biomedical Sciences, National Chung Cheng University, Chiayi, TaiwanDepartment of Biomedical Sciences, National Chung Cheng University, Chiayi, TaiwanEpigenomics and Human Disease Research Center, National Chung Cheng University, Chiayi, TaiwanDepartment of Biomedical Sciences, National Chung Cheng University, Chiayi, TaiwanDepartment of Biomedical Sciences, National Chung Cheng University, Chiayi, TaiwanEpigenomics and Human Disease Research Center, National Chung Cheng University, Chiayi, TaiwanDivision of Gastroenterology, Chang Gung Memorial Hospital, Chiayi, TaiwanDepartment of Biomedical Sciences, National Chung Cheng University, Chiayi, TaiwanEpigenomics and Human Disease Research Center, National Chung Cheng University, Chiayi, TaiwanCenter for Innovative Research on Aging Society (CIRAS), National Chung Cheng University, Chiayi, TaiwanPurposeThe purpose of this study was to identify genes that were epigenetically silenced by STAT3 in gastric cancer.MethodsMBDcap-Seq and expression microarray were performed to identify genes that were epigenetically silenced in AGS gastric cancer cell lines depleted of STAT3. Cell lines and animal experiments were performed to investigate proliferation and metastasis of miR-193a and YWHAZ in gastric cancer cell lines. Bisulfite pyrosequencing and tissue microarray were performed to investigate the promoter methylation of miR-193a and expression of STAT3, YWHAZ in patients with gastritis (n = 8) and gastric cancer (n = 71). Quantitative methylation-specific PCR was performed to examine miR-193a promoter methylation in cell-free DNA of serum samples in gastric cancer patients (n = 19).ResultsAs compared with parental cells, depletion of STAT3 resulted in demethylation of a putative STAT3 target, miR-193a, in AGS gastric cancer cells. Although bisulfite pyrosequencing and epigenetic treatment confirmed that miR-193a was epigenetically silenced in gastric cancer cell lines, ChIP-PCR found that it may be indirectly affected by STAT3. Ectopic expression of miR-193a in AGS cells inhibited proliferation and migration of gastric cancer cells. Further expression microarray and bioinformatics analysis identified YWHAZ as one of the target of miR-193a in AGS gastric cancer cells, such that depletion of YWHAZ reduced migration in AGS cells, while its overexpression increased invasion in MKN45 cells in vitro and in vivo. Clinically, bisulfite pyrosequencing revealed that promoter methylation of miR-193a was significantly higher in human gastric cancer tissues (n = 11) as compared to gastritis (n = 8, p < 0.05). Patients infected with H. pylori showed a significantly higher miR-193a methylation than those without H. pylori infection (p < 0.05). Tissue microarray also showed a positive trend between STAT3 and YWHAZ expression in gastric cancer patients (n = 60). Patients with serum miR-193a methylation was associated with shorter overall survival than those without methylation (p < 0.05).ConclusionsConstitutive activation of JAK/STAT signaling may confer epigenetic silencing of the STAT3 indirect target and tumor suppressor microRNA, miR-193a in gastric cancer. Transcriptional suppression of miR-193a may led to overexpression of YWHAZ resulting in tumor progression. Targeted inhibition of STAT3 may be a novel therapeutic strategy against gastric cancer.https://www.frontiersin.org/articles/10.3389/fonc.2021.575667/fullSTAT3epigeneticsmiR-193aYWHAZgastric cancer |
| spellingShingle | Kuo-Liang Wei Jian-Liang Chou Jian-Liang Chou Jian-Liang Chou Yin-Chen Chen Jie-Ting Low Jie-Ting Low Guan-Ling Lin Jing-Lan Liu Te-Sheng Chang Wei-Ming Chen Yung-Yu Hsieh Pearlly S. Yan Yu-Ming Chuang Jora M. J. Lin Shu-Fen Wu Shu-Fen Wu Ming-Ko Chiang Chin Li Chin Li Cheng-Shyong Wu Michael W. Y. Chan Michael W. Y. Chan Michael W. Y. Chan Epigenetic Silencing of STAT3-Targeted miR-193a, by Constitutive Activation of JAK/STAT Signaling, Leads to Tumor Progression Through Overexpression of YWHAZ in Gastric Cancer Frontiers in Oncology STAT3 epigenetics miR-193a YWHAZ gastric cancer |
| title | Epigenetic Silencing of STAT3-Targeted miR-193a, by Constitutive Activation of JAK/STAT Signaling, Leads to Tumor Progression Through Overexpression of YWHAZ in Gastric Cancer |
| title_full | Epigenetic Silencing of STAT3-Targeted miR-193a, by Constitutive Activation of JAK/STAT Signaling, Leads to Tumor Progression Through Overexpression of YWHAZ in Gastric Cancer |
| title_fullStr | Epigenetic Silencing of STAT3-Targeted miR-193a, by Constitutive Activation of JAK/STAT Signaling, Leads to Tumor Progression Through Overexpression of YWHAZ in Gastric Cancer |
| title_full_unstemmed | Epigenetic Silencing of STAT3-Targeted miR-193a, by Constitutive Activation of JAK/STAT Signaling, Leads to Tumor Progression Through Overexpression of YWHAZ in Gastric Cancer |
| title_short | Epigenetic Silencing of STAT3-Targeted miR-193a, by Constitutive Activation of JAK/STAT Signaling, Leads to Tumor Progression Through Overexpression of YWHAZ in Gastric Cancer |
| title_sort | epigenetic silencing of stat3 targeted mir 193a by constitutive activation of jak stat signaling leads to tumor progression through overexpression of ywhaz in gastric cancer |
| topic | STAT3 epigenetics miR-193a YWHAZ gastric cancer |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2021.575667/full |
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