70 results on '"Ming-Chuan Hsu"'
Search Results
2. Protein arginine methyltransferase 3-induced metabolic reprogramming is a vulnerable target of pancreatic cancer
- Author
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Ming-Chuan Hsu, Ya-Li Tsai, Chia-Hsien Lin, Mei-Ren Pan, Yan-Shen Shan, Tsung-Yen Cheng, Skye Hung-Chun Cheng, Li-Tzong Chen, and Wen-Chun Hung
- Subjects
Protein arginine methyltransferase 3 ,Methylation ,Glyceraldehyde-3-phosphate dehydrogenase ,Metabolic reprogramming ,Diseases of the blood and blood-forming organs ,RC633-647.5 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background The biological function of protein arginine methyltransferase 3 (PRMT3) is not well known because very few physiological substrates of this methyltransferase have been identified to date. Methods The clinical significance of PRMT3 in pancreatic cancer was studied by database analysis. The PRMT3 protein level of human pancreatic tumors was detected by immunoblotting and immunohistochemical staining. PRMT3-associated proteins and the methylation sites on the proteins were investigated using mass spectrometry. Seahorse Bioscience analyzed the metabolic reprogramming. Combination index analysis and xenograft animal model were conducted to explore the effects of combination of inhibitors of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and oxidative phosphorylation on tumor growth. Results We found that the expression of PRMT3 is upregulated in pancreatic cancer, and its expression is associated with poor survival. We identified GAPDH as a PRMT3-binding protein and demonstrated that GAPDH is methylated at R248 by PRMT3 in vivo. The methylation of GAPDH by PRMT3 enhanced its catalytic activity while the mutation of R248 abolished the effect. In cells, PRMT3 overexpression triggered metabolic reprogramming and enhanced glycolysis and mitochondrial respiration simultaneously in a GAPDH-dependent manner. PRMT3-overexpressing cancer cells were addicted to GAPDH-mediated metabolism and sensitive to the inhibition of GAPDH and mitochondrial respiration. The combination of inhibitors of GAPDH and oxidative phosphorylation induced a synergistic inhibition on cellular growth in vitro and in vivo. Conclusion Our results suggest that PRMT3 mediates metabolic reprogramming and cellular proliferation through methylating R248 of GAPDH, and double blockade of GAPDH and mitochondrial respiration could be a novel strategy for the treatment of PRMT3-overexpressing pancreatic cancer.
- Published
- 2019
- Full Text
- View/download PDF
3. Pyruvate kinase M2 fuels multiple aspects of cancer cells: from cellular metabolism, transcriptional regulation to extracellular signaling
- Author
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Ming-Chuan Hsu and Wen-Chun Hung
- Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Originally identified as a metabolic enzyme that catalyzes the transfer of a phosphate group from phosphoenolpyruvate (PEP) to ADP in the glycolytic pathway, pyruvate kinase M2-type (PKM2) has been shown to exhibit novel biological activities in the nucleus and outside the cells. Although cell-based studies reveal new non-canonical functions of PKM2 in gene transcription, epigenetic modulation and cell cycle progression, the importance of these non-canonical functions in PKM2-mediated tumorigenesis is still under debate because studies in genetically modified mice do not consistently echo the findings observed in cultured cancer cells. In addition to regulation of gene expression, the existence of PKM2 in exosomes opens a new venue to study the potential role of this glycolytic enzyme in cell-cell communication and extracellular signal initiation. In this review, we briefly summarize current understanding of PKM2 in metabolic switch and gene regulation. We will then emphasize recent progress of PKM2 in extracellular signaling and tumor microenvironment reprogramming. Finally, the discrepancy of some PKM2’s functions in vitro and in vivo, and the application of PKM2 in cancer detection and treatment will be discussed.
- Published
- 2018
- Full Text
- View/download PDF
4. Alteration of Epigenetic Modifiers in Pancreatic Cancer and Its Clinical Implication
- Author
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Yu-Hsuan Hung, Ming-Chuan Hsu, Li-Tzong Chen, Wen-Chun Hung, and Mei-Ren Pan
- Subjects
pancreatic cancer ,epigenetic regulation ,SWItch/Sucrose Non-Fermentable (SWI/SNF) complex ,histone methylation ,synthetic lethality ,Medicine - Abstract
The incidence of pancreatic cancer has considerably increased in the past decade. Pancreatic cancer has the worst prognosis among the cancers of the digestive tract because the pancreas is located in the posterior abdominal cavity, and most patients do not show clinical symptoms for early detection. Approximately 55% of all patients are diagnosed with pancreatic cancer only after the tumors metastasize. Therefore, identifying useful biomarkers for early diagnosis and screening high-risk groups are important to improve pancreatic cancer therapy. Recent emerging evidence has suggested that genetic and epigenetic alterations play a crucial role in the molecular aspects of pancreatic tumorigenesis. Here, we summarize recent progress in our understanding of the epigenetic alterations in pancreatic cancer and propose potential synthetic lethal strategies to target these genetic defects to treat this deadly disease.
- Published
- 2019
- Full Text
- View/download PDF
5. Two Birds, One Stone: Double Hits on Tumor Growth and Lymphangiogenesis by Targeting Vascular Endothelial Growth Factor Receptor 3
- Author
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Ming-Chuan Hsu, Mei-Ren Pan, and Wen-Chun Hung
- Subjects
VEGF-C ,VEGFR3 ,lymphangiogenesis ,lymphatic metastasis ,Cytology ,QH573-671 - Abstract
Vascular endothelial growth factor receptor 3 (VEGFR3) has been known for its involvement in tumor-associated lymphangiogenesis and lymphatic metastasis. The VEGFR3 signaling is stimulated by its main cognate ligand, vascular endothelial growth factor C (VEGF-C), which in turn promotes tumor progression. Activation of VEGF-C/VEGFR3 signaling in lymphatic endothelial cells (LECs) was shown to enhance the proliferation of LECs and the formation of lymphatic vessels, leading to increased lymphatic metastasis of tumor cells. In the past decade, the expression and pathological roles of VEGFR3 in tumor cells have been described. Moreover, the VEGF-C/VEGFR3 axis has been implicated in regulating immune tolerance and suppression. Therefore, the inhibition of the VEGF-C/VEGFR3 axis has emerged as an important therapeutic strategy for the treatment of cancer. In this review, we discuss the current findings related to VEGF-C/VEGFR3 signaling in cancer progression and recent advances in the development of therapeutic drugs targeting VEGF-C/VEGFR3.
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- 2019
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6. Protein Arginine Methyltransferase 3 Enhances Chemoresistance in Pancreatic Cancer by Methylating hnRNPA1 to Increase ABCG2 Expression
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Ming-Chuan Hsu, Mei-Ren Pan, Pei-Yi Chu, Ya-Li Tsai, Chia-Hua Tsai, Yan-Shen Shan, Li-Tzong Chen, and Wen-Chun Hung
- Subjects
PRMT3 ,hnRNP A1 ,ABCG2 ,RRM ,drug resistance ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Pancreatic cancer is poorly responsive to chemotherapy due to intrinsic or acquired resistance. Our previous study showed that epigenetic modifying enzymes including protein arginine methyltransferase 3 (PRMT3) are dysregulated in gemcitabine (GEM)-resistant pancreatic cancer cells. Here, we attempt to elucidate the role of PRMT3 in chemoresistance. Overexpression of PRMT3 led to increased resistance to GEM in pancreatic cancer cells, whereas reduction of PRMT3 restored GEM sensitivity in resistant cells. We identified a novel PRMT3 target, ATP-binding cassette subfamily G member 2 (ABCG2), which is known to play a critical role in drug resistance. PRMT3 overexpression upregulated ABCG2 expression by increasing its mRNA stability. Mass spectrometric analysis identified hnRNPA1 as a PRMT3 interacting protein, and methylation of hnRNPA1 at R31 by PRMT3 in vivo and in vitro. The expression of methylation-deficient hnRNPA1-R31K mutant reduced the RNA binding activity of hnRNPA1 and the expression of ABCG2 mRNA. Taken together, this provides the first evidence that PRMT3 methylates the RNA recognition motif (RRM) of hnRNPA1 and promotes the binding between hnRNPA1 and ABCG2 to enhance drug resistance. Inhibition of PRMT3 could be a novel strategy for the treatment of GEM-resistant pancreatic cancer.
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- 2018
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7. Supplementary Figure 4 from Caspase-Independent Cell Death Is Involved in the Negative Effect of EGF Receptor Inhibitors on Cisplatin in Non–Small Cell Lung Cancer Cells
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Mien-Chie Hung, Roy Herbst, How-Wen Ko, Yi Du, Shih-Shin Chang, Ming-Chuan Hsu, Ying-Nai Wang, Chun-Te Chen, Jennifer L. Hsu, and Hirohito Yamaguchi
- Abstract
PDF file - 35K, The effects of cisplatin and/or gefitinib on A549-Bcl-XL tumor growth in vivo
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- 2023
8. Supplementary Figure 7 from Caspase-Independent Cell Death Is Involved in the Negative Effect of EGF Receptor Inhibitors on Cisplatin in Non–Small Cell Lung Cancer Cells
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Mien-Chie Hung, Roy Herbst, How-Wen Ko, Yi Du, Shih-Shin Chang, Ming-Chuan Hsu, Ying-Nai Wang, Chun-Te Chen, Jennifer L. Hsu, and Hirohito Yamaguchi
- Abstract
PDF file - 45K, The effects of NAC on cisplain-induced caspase activation
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- 2023
9. Supplementary Figure 9 from Caspase-Independent Cell Death Is Involved in the Negative Effect of EGF Receptor Inhibitors on Cisplatin in Non–Small Cell Lung Cancer Cells
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Mien-Chie Hung, Roy Herbst, How-Wen Ko, Yi Du, Shih-Shin Chang, Ming-Chuan Hsu, Ying-Nai Wang, Chun-Te Chen, Jennifer L. Hsu, and Hirohito Yamaguchi
- Abstract
PDF file - 87K, The effects of cisplatin and/or gefitinb on FOXO3a phosphorylation and Mn-SOD expression in H1299-Blc-XL xenograft tumors
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- 2023
10. Supplementary Figure 2 from Caspase-Independent Cell Death Is Involved in the Negative Effect of EGF Receptor Inhibitors on Cisplatin in Non–Small Cell Lung Cancer Cells
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Mien-Chie Hung, Roy Herbst, How-Wen Ko, Yi Du, Shih-Shin Chang, Ming-Chuan Hsu, Ying-Nai Wang, Chun-Te Chen, Jennifer L. Hsu, and Hirohito Yamaguchi
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PDF file - 298K, Caspase-independent cell death in H1299 cells
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- 2023
11. Supplementary Figure 1 from Caspase-Independent Cell Death Is Involved in the Negative Effect of EGF Receptor Inhibitors on Cisplatin in Non–Small Cell Lung Cancer Cells
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Mien-Chie Hung, Roy Herbst, How-Wen Ko, Yi Du, Shih-Shin Chang, Ming-Chuan Hsu, Ying-Nai Wang, Chun-Te Chen, Jennifer L. Hsu, and Hirohito Yamaguchi
- Abstract
PDF file - 53K, The effects of gefitinib or cisplatin on cell growth and cell death
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- 2023
12. Data from Caspase-Independent Cell Death Is Involved in the Negative Effect of EGF Receptor Inhibitors on Cisplatin in Non–Small Cell Lung Cancer Cells
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Mien-Chie Hung, Roy Herbst, How-Wen Ko, Yi Du, Shih-Shin Chang, Ming-Chuan Hsu, Ying-Nai Wang, Chun-Te Chen, Jennifer L. Hsu, and Hirohito Yamaguchi
- Abstract
Purpose: Results of multiple clinical trials suggest that EGF receptor (EGFR) tyrosine kinase inhibitors (TKI) exhibit negative effects on platinum-based chemotherapy in patients with lung cancer with wild-type (WT) EGFR, but the underlying molecular mechanisms are still uncertain. Studies that identify the mechanism of how TKIs negatively affect patients with WT EGFR are important for future development of effective strategies to target lung cancer. Thus, we returned to in vitro study to investigate and determine a possible explanation for this phenomenon.Experimental Design: We investigated the effects of TKIs and cisplatin on caspase-independent cell death (CID) and the role of CID in the efficacy of each drug and the combination. Furthermore, we studied the mechanism by which EGFR signaling pathway is involved in CID. Finally, on the basis of the identified mechanism, we tested the combinational effects of cisplatin plus suberoylanilide hydroxamic acid (SAHA) or erastin on CID.Results: We found that gefitinib inhibited cisplatin-induced CID but not caspase-dependent apoptotic cell death. In WT EGFR cells, gefitinib not only inhibited CID but also failed to induce apoptosis, therefore compromising the efficacy of cisplatin. Inhibition of EGFR-ERK/AKT by gefitinib activates FOXO3a, which in turn reduces reactive oxygen species (ROS) and ROS-mediated CID. To overcome this, we showed that SAHA and erastin, the inducers of ROS-mediated CID, strongly enhanced the effect of cisplatin in WT EGFR cells.Conclusion: TKI-mediated inhibition of CID plays an important role in the efficacy of chemotherapy. Moreover, FOXO3a is a key factor in the negative effects of TKI by eliminating cisplatin-induced ROS. Clin Cancer Res; 19(4); 845–54. ©2012 AACR.
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- 2023
13. Supplementary Figure 5 from Caspase-Independent Cell Death Is Involved in the Negative Effect of EGF Receptor Inhibitors on Cisplatin in Non–Small Cell Lung Cancer Cells
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Mien-Chie Hung, Roy Herbst, How-Wen Ko, Yi Du, Shih-Shin Chang, Ming-Chuan Hsu, Ying-Nai Wang, Chun-Te Chen, Jennifer L. Hsu, and Hirohito Yamaguchi
- Abstract
PDF file - 63K, Evaluation of AKT activity by using AKT substrates antibody
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- 2023
14. Supplementary Figure 6 from Caspase-Independent Cell Death Is Involved in the Negative Effect of EGF Receptor Inhibitors on Cisplatin in Non–Small Cell Lung Cancer Cells
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Mien-Chie Hung, Roy Herbst, How-Wen Ko, Yi Du, Shih-Shin Chang, Ming-Chuan Hsu, Ying-Nai Wang, Chun-Te Chen, Jennifer L. Hsu, and Hirohito Yamaguchi
- Abstract
PDF file - 38K, The effects of MEK or AKT inhibitor on cisplatin-induced CID
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- 2023
15. Supplementary Figure Legend from Caspase-Independent Cell Death Is Involved in the Negative Effect of EGF Receptor Inhibitors on Cisplatin in Non–Small Cell Lung Cancer Cells
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Mien-Chie Hung, Roy Herbst, How-Wen Ko, Yi Du, Shih-Shin Chang, Ming-Chuan Hsu, Ying-Nai Wang, Chun-Te Chen, Jennifer L. Hsu, and Hirohito Yamaguchi
- Abstract
PDF file - 113K
- Published
- 2023
16. Supplementary Figure 8 from Caspase-Independent Cell Death Is Involved in the Negative Effect of EGF Receptor Inhibitors on Cisplatin in Non–Small Cell Lung Cancer Cells
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Mien-Chie Hung, Roy Herbst, How-Wen Ko, Yi Du, Shih-Shin Chang, Ming-Chuan Hsu, Ying-Nai Wang, Chun-Te Chen, Jennifer L. Hsu, and Hirohito Yamaguchi
- Abstract
PDF file - 154K, The role of Mn-SOD or catalase on cisplatin-induced CID
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- 2023
17. Management and Education on the Case-Based Complex e-Business Systems Based On Agent Centric Ontology and Simulation Games.
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Shen-Tzay Huang, Ming-Chuan Hsu, and Wen-Hao Lin
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- 2007
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18. Protein arginine methyltransferase 3-induced metabolic reprogramming is a vulnerable target of pancreatic cancer
- Author
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Skye Hung Chun Cheng, Ming Chuan Hsu, Mei-Ren Pan, Chia-Hsien Lin, Tsung Yen Cheng, Ya Li Tsai, Li-Tzong Chen, Wen Chun Hung, and Yan Shen Shan
- Subjects
0301 basic medicine ,Cancer Research ,Protein-Arginine N-Methyltransferases ,Methyltransferase ,Oxidative phosphorylation ,Methylation ,lcsh:RC254-282 ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Downregulation and upregulation ,stomatognathic system ,Pancreatic cancer ,Cell Line, Tumor ,medicine ,Protein arginine methyltransferase 3 ,Animals ,Humans ,Glycolysis ,Cellular Reprogramming Techniques ,Molecular Biology ,Glyceraldehyde 3-phosphate dehydrogenase ,biology ,Chemistry ,lcsh:RC633-647.5 ,Research ,Metabolic reprogramming ,Hematology ,lcsh:Diseases of the blood and blood-forming organs ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Cell biology ,Pancreatic Neoplasms ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cancer cell ,biology.protein ,Glyceraldehyde-3-phosphate dehydrogenase - Abstract
Background The biological function of protein arginine methyltransferase 3 (PRMT3) is not well known because very few physiological substrates of this methyltransferase have been identified to date. Methods The clinical significance of PRMT3 in pancreatic cancer was studied by database analysis. The PRMT3 protein level of human pancreatic tumors was detected by immunoblotting and immunohistochemical staining. PRMT3-associated proteins and the methylation sites on the proteins were investigated using mass spectrometry. Seahorse Bioscience analyzed the metabolic reprogramming. Combination index analysis and xenograft animal model were conducted to explore the effects of combination of inhibitors of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and oxidative phosphorylation on tumor growth. Results We found that the expression of PRMT3 is upregulated in pancreatic cancer, and its expression is associated with poor survival. We identified GAPDH as a PRMT3-binding protein and demonstrated that GAPDH is methylated at R248 by PRMT3 in vivo. The methylation of GAPDH by PRMT3 enhanced its catalytic activity while the mutation of R248 abolished the effect. In cells, PRMT3 overexpression triggered metabolic reprogramming and enhanced glycolysis and mitochondrial respiration simultaneously in a GAPDH-dependent manner. PRMT3-overexpressing cancer cells were addicted to GAPDH-mediated metabolism and sensitive to the inhibition of GAPDH and mitochondrial respiration. The combination of inhibitors of GAPDH and oxidative phosphorylation induced a synergistic inhibition on cellular growth in vitro and in vivo. Conclusion Our results suggest that PRMT3 mediates metabolic reprogramming and cellular proliferation through methylating R248 of GAPDH, and double blockade of GAPDH and mitochondrial respiration could be a novel strategy for the treatment of PRMT3-overexpressing pancreatic cancer. Electronic supplementary material The online version of this article (10.1186/s13045-019-0769-7) contains supplementary material, which is available to authorized users.
- Published
- 2019
19. Pyruvate kinase M2 fuels multiple aspects of cancer cells: from cellular metabolism, transcriptional regulation to extracellular signaling
- Author
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Wen-Chun Hung and Ming-Chuan Hsu
- Subjects
0301 basic medicine ,Cancer Research ,Pyruvate Kinase ,Review ,Biology ,PKM2 ,medicine.disease_cause ,Exosomes ,Models, Biological ,lcsh:RC254-282 ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Neoplasms ,medicine ,Extracellular ,Transcriptional regulation ,Animals ,Humans ,Regulation of gene expression ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Cell biology ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cancer cell ,Molecular Medicine ,Signal transduction ,Carcinogenesis ,Pyruvate kinase ,Signal Transduction - Abstract
Originally identified as a metabolic enzyme that catalyzes the transfer of a phosphate group from phosphoenolpyruvate (PEP) to ADP in the glycolytic pathway, pyruvate kinase M2-type (PKM2) has been shown to exhibit novel biological activities in the nucleus and outside the cells. Although cell-based studies reveal new non-canonical functions of PKM2 in gene transcription, epigenetic modulation and cell cycle progression, the importance of these non-canonical functions in PKM2-mediated tumorigenesis is still under debate because studies in genetically modified mice do not consistently echo the findings observed in cultured cancer cells. In addition to regulation of gene expression, the existence of PKM2 in exosomes opens a new venue to study the potential role of this glycolytic enzyme in cell-cell communication and extracellular signal initiation. In this review, we briefly summarize current understanding of PKM2 in metabolic switch and gene regulation. We will then emphasize recent progress of PKM2 in extracellular signaling and tumor microenvironment reprogramming. Finally, the discrepancy of some PKM2’s functions in vitro and in vivo, and the application of PKM2 in cancer detection and treatment will be discussed.
- Published
- 2018
20. Orchestration of H3K27 methylation: mechanisms and therapeutic implication
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Li-Tzong Chen, Ming-Chuan Hsu, Wen-Chun Hung, and Mei-Ren Pan
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0301 basic medicine ,Review ,Biology ,Methylation ,Histones ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Histone H3 ,Heterochromatin ,Histone H2A ,Histone methylation ,Animals ,Humans ,Histone code ,Gene Silencing ,Cancer epigenetics ,Gene mutation ,Molecular Biology ,Epigenomics ,Histone Demethylases ,Pharmacology ,Lysine ,fungi ,EZH2 ,Histone-Lysine N-Methyltransferase ,Cell Biology ,Polycomb repression complex 2 ,Cell biology ,030104 developmental biology ,Biochemistry ,Histone methyltransferase ,Epigenetic drugs ,Histone Methyltransferases ,Molecular Medicine ,Histone modification ,Protein Processing, Post-Translational - Abstract
Histone proteins constitute the core component of the nucleosome, the basic unit of chromatin. Chemical modifications of histone proteins affect their interaction with genomic DNA, the accessibility of recognized proteins, and the recruitment of enzymatic complexes to activate or diminish specific transcriptional programs to modulate cellular response to extracellular stimuli or insults. Methylation of histone proteins was demonstrated 50 years ago; however, the biological significance of each methylated residue and the integration between these histone markers are still under intensive investigation. Methylation of histone H3 on lysine 27 (H3K27) is frequently found in the heterochromatin and conceives a repressive marker that is linked with gene silencing. The identification of enzymes that add or erase the methyl group of H3K27 provides novel insights as to how this histone marker is dynamically controlled under different circumstances. Here we summarize the methyltransferases and demethylases involved in the methylation of H3K27 and show the new evidence by which the H3K27 methylation can be established via an alternative mechanism. Finally, the progress of drug development targeting H3K27 methylation-modifying enzymes and their potential application in cancer therapy are discussed.
- Published
- 2017
21. Enhanced PCF Protocols for Real-time Multimedia Services over 802.11 Wireless Networks.
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Ming-Chuan Hsu and Yaw-Chung Chen
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- 2006
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- View/download PDF
22. Alteration of Epigenetic Modifiers in Pancreatic Cancer and Its Clinical Implication
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Wen-Chun Hung, Li-Tzong Chen, Yu-Hsuan Hung, Ming-Chuan Hsu, and Mei-Ren Pan
- Subjects
0301 basic medicine ,pancreatic cancer ,SWItch/Sucrose Non-Fermentable (SWI/SNF) complex ,lcsh:Medicine ,Review ,Abdominal cavity ,Synthetic lethality ,Disease ,medicine.disease_cause ,epigenetic regulation ,03 medical and health sciences ,0302 clinical medicine ,Pancreatic cancer ,Histone methylation ,medicine ,Epigenetics ,histone methylation ,business.industry ,lcsh:R ,General Medicine ,medicine.disease ,synthetic lethality ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Cancer research ,Pancreas ,business ,Carcinogenesis - Abstract
The incidence of pancreatic cancer has considerably increased in the past decade. Pancreatic cancer has the worst prognosis among the cancers of the digestive tract because the pancreas is located in the posterior abdominal cavity, and most patients do not show clinical symptoms for early detection. Approximately 55% of all patients are diagnosed with pancreatic cancer only after the tumors metastasize. Therefore, identifying useful biomarkers for early diagnosis and screening high-risk groups are important to improve pancreatic cancer therapy. Recent emerging evidence has suggested that genetic and epigenetic alterations play a crucial role in the molecular aspects of pancreatic tumorigenesis. Here, we summarize recent progress in our understanding of the epigenetic alterations in pancreatic cancer and propose potential synthetic lethal strategies to target these genetic defects to treat this deadly disease.
- Published
- 2019
23. Additional file 3: of Protein arginine methyltransferase 3-induced metabolic reprogramming is a vulnerable target of pancreatic cancer
- Author
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Ming-Chuan Hsu, Tsai, Ya-Li, Chia-Hsien Lin, Mei-Ren Pan, Yan-Shen Shan, Tsung-Yen Cheng, Cheng, Skye, Li-Tzong Chen, and Hung, Wen-Chun
- Subjects
fungi - Abstract
Figure S2. Change of the metabolites in nucleotide metabolism. The bars/lines represent relative areas of each metabolite in GFP- (blue) and GFP-PRMT3 (red)-overexpressing PANC-1 cells, respectively. N.D., not detected. (PDF 184 kb)
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- 2019
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24. Additional file 7: of Protein arginine methyltransferase 3-induced metabolic reprogramming is a vulnerable target of pancreatic cancer
- Author
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Ming-Chuan Hsu, Tsai, Ya-Li, Chia-Hsien Lin, Mei-Ren Pan, Yan-Shen Shan, Tsung-Yen Cheng, Cheng, Skye, Li-Tzong Chen, and Hung, Wen-Chun
- Abstract
Figure S6. Advanced severe immunodeficiency (ASID) mice were housed under standard conditions. pLK0.1- and sh-PRMT3-overexpressing Miapaca-2 cells (1 × 107) were suspended in 50 μl PBS mixed with 30 μl Matrige and subcutaneously injected into the left flank of the mice. Tumor burden was monitored with digital calipers twice per week. Two weeks after injection, tumors were harvested and tumor weight was measured. Apoptosis of tumor tissues was analyzed using terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. The percentage of cell death was determined by counting the number of TUNEL-positive cells in three independent fields of different slides using ImageJ software. The results showed that PRMT3 knockout suppressed tumor growth and increased cell apoptosis. Data represented mean ± SEM. Obtained from 5 mice in each group. (PDF 1917 kb)
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- 2019
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25. Additional file 1: of Protein arginine methyltransferase 3-induced metabolic reprogramming is a vulnerable target of pancreatic cancer
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Ming-Chuan Hsu, Tsai, Ya-Li, Chia-Hsien Lin, Mei-Ren Pan, Yan-Shen Shan, Tsung-Yen Cheng, Cheng, Skye, Li-Tzong Chen, and Hung, Wen-Chun
- Abstract
Table S1. PRMT3-associated proteins identified from mass spectrometry. (DOCX 36 kb)
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- 2019
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26. Additional file 6: of Protein arginine methyltransferase 3-induced metabolic reprogramming is a vulnerable target of pancreatic cancer
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Ming-Chuan Hsu, Tsai, Ya-Li, Chia-Hsien Lin, Mei-Ren Pan, Yan-Shen Shan, Tsung-Yen Cheng, Cheng, Skye, Li-Tzong Chen, and Hung, Wen-Chun
- Abstract
Figure S5. The combination of oligomycin and heptelidic acid significantly suppresses the growth of PRMT3-overexpressing cancer cells. Cell proliferation of tumor tissues was measured by Ki67 staining, and the images were captured by a microscope. The percentage of Ki67 staining was determined by counting the number of Ki67 positive cells in three independent fields. Quantitative result of Ki67 staining was analyzed. Data represented mean ± SEM. Obtained from 5 mice in each group. *p
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- 2019
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27. Additional file 4: of Protein arginine methyltransferase 3-induced metabolic reprogramming is a vulnerable target of pancreatic cancer
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Ming-Chuan Hsu, Tsai, Ya-Li, Chia-Hsien Lin, Mei-Ren Pan, Yan-Shen Shan, Tsung-Yen Cheng, Cheng, Skye, Li-Tzong Chen, and Hung, Wen-Chun
- Subjects
fungi - Abstract
Figure S3. Change of the metabolites in metabolism of coenzymes. The bars/lines represent relative areas of each metabolite in GFP- (blue) and GFP-PRMT3 (red)-overexpressing PANC-1 cells, respectively. N.D., not detected. (PDF 492 kb)
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- 2019
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28. Additional file 2: of Protein arginine methyltransferase 3-induced metabolic reprogramming is a vulnerable target of pancreatic cancer
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Ming-Chuan Hsu, Tsai, Ya-Li, Chia-Hsien Lin, Mei-Ren Pan, Yan-Shen Shan, Tsung-Yen Cheng, Cheng, Skye, Li-Tzong Chen, and Hung, Wen-Chun
- Subjects
fungi - Abstract
Figure S1. Change of the metabolites in branched chain and aromatic amino acids metabolism. The bars/lines represent relative areas of each metabolite in GFP- (blue) and GFP-PRMT3 (red)-overexpressing PANC-1 cells, respectively. N.D., not detected. (PDF 229 kb)
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- 2019
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29. Additional file 5: of Protein arginine methyltransferase 3-induced metabolic reprogramming is a vulnerable target of pancreatic cancer
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Ming-Chuan Hsu, Tsai, Ya-Li, Chia-Hsien Lin, Mei-Ren Pan, Yan-Shen Shan, Tsung-Yen Cheng, Cheng, Skye, Li-Tzong Chen, and Hung, Wen-Chun
- Abstract
Figure S4. The inhibition of PRMT3 suppresses ECAR and OCR levels. (a–c) L3.6pl, HPDE, and Capan-2 cells were treated with SGC707 (100 μM) for 48 h. The ECAR and OCR levels were measured with Seahorse XF24 Flux analyzer. Error bars, SEM. n = 3. (PDF 3078 kb)
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- 2019
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30. The histone methyltransferase G9a as a therapeutic target to override gemcitabine resistance in pancreatic cancer
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Li-Tzong Chen, Mei-Ren Pan, Ming Chuan Hsu, Chi Wen Luo, Yan Shen Shan, and Wen Chun Hung
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Male ,0301 basic medicine ,endocrine system diseases ,Pancreatic stellate cell ,Deoxycytidine ,Receptors, Interleukin-8A ,Metastasis ,Mice ,0302 clinical medicine ,Cell Movement ,Histocompatibility Antigens ,Neoplasm Metastasis ,RNA, Small Interfering ,Histone Demethylases ,Pancreatic Stellate Cells ,LGR5 ,Middle Aged ,Extracellular Matrix ,Gene Expression Regulation, Neoplastic ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Neoplastic Stem Cells ,Female ,Research Paper ,medicine.drug ,Antimetabolites, Antineoplastic ,pancreatic stellate cell ,03 medical and health sciences ,Cell Line, Tumor ,Pancreatic cancer ,medicine ,Animals ,Humans ,Neoplasm Invasiveness ,Interleukin 8 ,Autocrine signalling ,Aged ,drug resistance ,business.industry ,Gene Expression Profiling ,Interleukin-8 ,Histone-Lysine N-Methyltransferase ,medicine.disease ,Gemcitabine ,lysine demethylase ,Pancreatic Neoplasms ,HEK293 Cells ,030104 developmental biology ,Drug Resistance, Neoplasm ,Immunology ,Cancer cell ,Cancer research ,business - Abstract
Gemcitabine (GEM) resistance is a critical issue for pancreatic cancer treatment. The involvement of epigenetic modification in GEM resistance is still unclear. We established a GEM-resistant subline PANC-1-R from the parental PANC-1 pancreatic cancer cells and found the elevation of various chromatin-modifying enzymes including G9a in GEM-resistant cells. Ectopic expression of G9a in PANC-1 cells increased GEM resistance while inactivation of G9a in PANC-1-R cells reduced it. Challenge of PANC-1 cells with GEM increased the expression of stemness markers including CD133, nestin and Lgr5 and promoted sphere forming activity suggesting chemotherapy enriched cancer cells with stem-like properties. Inhibition of G9a in PANC-1-R cells reduced stemness and invasiveness and sensitized the cells to GEM. We revealed interleukin-8 (IL-8) is a downstream effector of G9a to increase GEM resistance. G9a-overexpressing PANC-1-R cells exhibited autocrine IL-8/CXCR1/2 stimulation to increase GEM resistance which could be decreased by anti-IL-8 antibody and G9a inhibitor. IL-8 released by cancer cells also activated pancreatic stellate cell (PSC) to increase GEM resistance. In orthotopic animal model, GEM could not suppress tumor growth of PANC-1-R cells and eventually promoted tumor metastasis. Combination with G9a inhibitor and GEM reduced tumor growth, metastasis, IL-8 expression and PSC activation in animals. Finally, we showed that overexpression of G9a correlated with poor survival and early recurrence in pancreatic cancer patients. Collectively, our results suggest G9a is a therapeutic target to override GEM resistance in the treatment of pancreatic cancer.
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- 2016
31. Protein Arginine Methyltransferase 3-Induced Metabolic Reprogramming Is a Vulnerable Target of Pancreatic Cancer
- Author
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Li-Tzong Chen, Ming Chuan Hsu, Wen Chun Hung, Ya Li Tsai, Skye Hung Chun Cheng, Chia-Hsien Lin, Tsung Yen Cheng, Yan Shen Shan, and Mei-Ren Pan
- Subjects
biology ,business.industry ,Cancer ,Methylation ,medicine.disease ,Downregulation and upregulation ,Pancreatic tumor ,Pancreatic cancer ,Cancer cell ,medicine ,Cancer research ,biology.protein ,Glycolysis ,business ,Glyceraldehyde 3-phosphate dehydrogenase - Abstract
Background: The biological function of protein arginine methyltransferase 3 (PRMT3) is not well known because very few physiological substrates of PRMT3 have been identified to date. Methods: The clinical significance of PRMT3 in pancreatic cancer was studied by database analysis. The PRMT3 protein level in human pancreatic tumors was detected by immunoblotting. PRMT3-associated proteins and the methylation sites on the proteins were investigated using mass spectrometry. Capillary electrophoresis time-of-flight mass spectrometry and seahorse bioscience were performed to analyze metabolic reprogramming. Combination index analysis and xenograft animal model were conducted to explore the effects of combination of inhibitors of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and oxidative phosphorylation on tumor growth. Findings: We find the expression of PRMT3 is upregulated in pancreatic cancer, and its expression is associated with poor survival. We further demonstrate that GAPDH is methylated at R248 by PRMT3 in vivo. The methylation of GAPDH by PRMT3 enhances its catalytic activity while the mutation of R248 abolishes the effect. In cells, PRMT3 overexpression triggers metabolic reprogramming and enhances glycolysis and mitochondrial respiration simultaneously in a GAPDH-dependent manner. PRMT3-overexpressing cancer cells are addicted to GAPDH-mediated metabolism and sensitive to the inhibition of GAPDH and mitochondrial respiration. The combination of inhibitors of GAPDH and oxidative phosphorylation induces a synergistic inhibition on cellular growth in vitro and in vivo. Interpretation: Our results suggest PRMT3-induced metabolic reprogramming is a vulnerable target of pancreatic cancer. Funding Statement: This work was supported by the grants from the Ministry of Science and Technology (MOST-103-2314-B-037-075; MOST-104-2314-B-037-004; MOST-105-2314-B-037-001; MOST-107-2320-B-400-006-MY3 to M.-R.P. and W.-C.H. and MOST-106-2321-B-400-007 to L.-T.C.). This study was also supported by the grant from National Research Institutes (NHRI-107A1-CACO-02181811 to Y.-S.S.) and the Yen-Hsu Education Foundation to W.-C.H. Declaration of Interests: The authors have no conflicts of interest to declare. Ethics Approval Statement: Human pancreatic tumor tissues were obtained from patients undergoing surgical resection at Koo Foundation Sun Yat-Sen Cancer Center (Taipei, Taiwan) and National Cheng Kung University Hospital (Tainan, Taiwan) under the guidelines approved by the Institution Review Board at National Health Research Institutes. Written informed consent was obtained from each patient. All animal experiments were approved by Animal Care Committee of National Health Research Institutes.
- Published
- 2018
32. Tyrosine 370 phosphorylation of ATM positively regulates DNA damage response
- Author
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Mien Chie Hung, Ying Nai Wang, Shih Shin Chang, K. Kian Ang, Martin F. Lavin, Satoshi Nakajima, Chien Chia Cheng, Leizhen Wei, Chung-Hsuan Chen, Hong Jen Lee, Li Lan, Wei Chao Chang, Hsin Wei Liao, Guang Peng, Shiaw Yih Lin, and Ming Chuan Hsu
- Subjects
Cell cycle checkpoint ,DNA Repair ,DNA damage ,DNA repair ,Ataxia Telangiectasia Mutated Proteins ,Biology ,chemistry.chemical_compound ,Gefitinib ,Cell Line, Tumor ,Radiation, Ionizing ,medicine ,Humans ,DNA Breaks, Double-Stranded ,Amino Acid Sequence ,Epidermal growth factor receptor ,Phosphorylation ,RNA, Small Interfering ,Molecular Biology ,Checkpoint Kinase 2 ,Tyrosine phosphorylation ,Cell Biology ,ErbB Receptors ,chemistry ,Quinazolines ,Cancer research ,biology.protein ,Tyrosine ,RNA Interference ,Original Article ,HeLa Cells ,Signal Transduction ,medicine.drug - Abstract
Ataxia telangiectasia mutated (ATM) mediates DNA damage response by controling irradiation-induced foci formation, cell cycle checkpoint, and apoptosis. However, how upstream signaling regulates ATM is not completely understood. Here, we show that upon irradiation stimulation, ATM associates with and is phosphorylated by epidermal growth factor receptor (EGFR) at Tyr370 (Y370) at the site of DNA double-strand breaks. Depletion of endogenous EGFR impairs ATM-mediated foci formation, homologous recombination, and DNA repair. Moreover, pretreatment with an EGFR kinase inhibitor, gefitinib, blocks EGFR and ATM association, hinders CHK2 activation and subsequent foci formation, and increases radiosensitivity. Thus, we reveal a critical mechanism by which EGFR directly regulates ATM activation in DNA damage response, and our results suggest that the status of ATM Y370 phosphorylation has the potential to serve as a biomarker to stratify patients for either radiotherapy alone or in combination with EGFR inhibition.
- Published
- 2015
33. Metabolic reprogramming of pancreatic cancer cells by protein arginine methyltransferase 3
- Author
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Wen-Chun Hung, Ming-Chuan Hsu, Ya-Li Tsai, and Li-Tzong Chen
- Subjects
Hepatology ,Endocrinology, Diabetes and Metabolism ,Gastroenterology - Published
- 2019
34. Protein Arginine Methyltransferase 3 Enhances Chemoresistance in Pancreatic Cancer by Methylating hnRNPA1 to Increase ABCG2 Expression
- Author
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Mei-Ren Pan, Chia Hua Tsai, Ya Li Tsai, Pei-Yi Chu, Li-Tzong Chen, Ming Chuan Hsu, Wen Chun Hung, and Yan Shen Shan
- Subjects
RRM ,0301 basic medicine ,Cancer Research ,Abcg2 ,ABCG2 ,lcsh:RC254-282 ,Article ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,Pancreatic cancer ,medicine ,Epigenetics ,hnRNP A1 ,Messenger RNA ,drug resistance ,biology ,Chemistry ,RNA ,Methylation ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,Gemcitabine ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,PRMT3 ,medicine.drug - Abstract
Pancreatic cancer is poorly responsive to chemotherapy due to intrinsic or acquired resistance. Our previous study showed that epigenetic modifying enzymes including protein arginine methyltransferase 3 (PRMT3) are dysregulated in gemcitabine (GEM)-resistant pancreatic cancer cells. Here, we attempt to elucidate the role of PRMT3 in chemoresistance. Overexpression of PRMT3 led to increased resistance to GEM in pancreatic cancer cells, whereas reduction of PRMT3 restored GEM sensitivity in resistant cells. We identified a novel PRMT3 target, ATP-binding cassette subfamily G member 2 (ABCG2), which is known to play a critical role in drug resistance. PRMT3 overexpression upregulated ABCG2 expression by increasing its mRNA stability. Mass spectrometric analysis identified hnRNPA1 as a PRMT3 interacting protein, and methylation of hnRNPA1 at R31 by PRMT3 in vivo and in vitro. The expression of methylation-deficient hnRNPA1-R31K mutant reduced the RNA binding activity of hnRNPA1 and the expression of ABCG2 mRNA. Taken together, this provides the first evidence that PRMT3 methylates the RNA recognition motif (RRM) of hnRNPA1 and promotes the binding between hnRNPA1 and ABCG2 to enhance drug resistance. Inhibition of PRMT3 could be a novel strategy for the treatment of GEM-resistant pancreatic cancer.
- Published
- 2018
35. Corrigendum: Blocking c-Met-mediated PARP1 phosphorylation enhances anti-tumor effects of PARP inhibitors
- Author
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Yi, Du, Hirohito, Yamaguchi, Yongkun, Wei, Jennifer L, Hsu, Hung-Ling, Wang, Yi-Hsin, Hsu, Wan-Chi, Lin, Wen-Hsuan, Yu, Paul G, Leonard, Gilbert R, Lee, Mei-Kuang, Chen, Katsuya, Nakai, Ming-Chuan, Hsu, Chun-Te, Chen, Ye, Sun, Yun, Wu, Wei-Chao, Chang, Wen-Chien, Huang, Chien-Liang, Liu, Yuan-Ching, Chang, Chung-Hsuan, Chen, Morag, Park, Philip, Jones, Gabriel N, Hortobagyi, and Mien-Chie, Hung
- Subjects
Article - Abstract
Poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as promising therapeutics for many diseases, including cancer, in clinical trials1. One PARP inhibitor, olaparib (Lynparza™, AstraZeneca), was recently approved by the FDA to treat ovarian cancer with BRCA mutations. BRCA1 and BRCA2 play essential roles in repairing DNA double strand breaks, and a deficiency of BRCA proteins sensitizes cancer cells to PARP inhibition2,3. Here we show that receptor tyrosine kinase c-Met associates with and phosphorylates PARP1 at Tyr907. Phosphorylation of PARP1 Tyr907 increases PARP1 enzymatic activity and reduces binding to a PARP inhibitor, thereby rendering cancer cells resistant to PARP inhibition. Combining c-Met and PARP1 inhibitors synergized to suppress growth of breast cancer cells in vitro and xenograft tumor models. Similar synergistic effects were observed in a lung cancer xenograft tumor model. These results suggest that PARP1 pTyr907 abundance may predict tumor resistance to PARP inhibitors, and that treatment with a combination of c-Met and PARP inhibitors may benefit patients bearing tumors with high c-Met expression who do not respond to PARP inhibition alone.
- Published
- 2016
36. Extracellular PKM2 induces cancer proliferation by activating the EGFR signaling pathway
- Author
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Ming-Chuan, Hsu, Wen-Chun, Hung, Hirohito, Yamaguchi, Seung-Oe, Lim, Hsin-Wei, Liao, Chia-Hua, Tsai, and Mien-Chie, Hung
- Subjects
Original Article - Abstract
Pyruvate kinase is a key enzyme in the glycolytic pathway that converts phosphoenolpyruvate to pyruvate, and the M2 isoform of pyruvate kinase (PKM2) is associated with cancer. PKM2 has been reported to function independently of its pyruvate kinase activity, which is crucial for cancer cell proliferation. Moreover, there is growing evidence indicating that dimeric PKM2 is released from tumor cells into the circulation of cancer patients. However, the role of secreted PKM2 in cancer is not well understood. Here, we found that the phosphorylation level of epidermal growth factor receptor (EGFR) significantly increased upon the exposure of cells to the recombinant PKM2 protein. In addition, secreted PKM2 induces EGFR phosphorylation and activates the EGFR downstream signaling in triple-negative breast cancer cells. In contrast, knocking down PKM2 decreased EGFR phosphorylation. Moreover, expression of R399E mutant PKM2, which has been reported to preferentially form a dimer, enhanced EGFR phosphorylation, cellular transformation, and cell proliferation more strongly than the wild-type PKM2. Thus, our study revealed a novel function of extracellular PKM2 in the promoting cancer cell proliferation through EGFR activation.
- Published
- 2016
37. G9a orchestrates PCL3 and KDM7A to promote histone H3K27 methylation
- Author
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Li-Tzong Chen, Ming-Chuan Hsu, Mei-Ren Pan, and Wen-Chun Hung
- Subjects
0301 basic medicine ,Jumonji Domain-Containing Histone Demethylases ,Transcription, Genetic ,Biology ,Methylation ,Article ,03 medical and health sciences ,Epigenetics of physical exercise ,Cell Line, Tumor ,Histocompatibility Antigens ,Histone methylation ,Humans ,Regulation of gene expression ,Multidisciplinary ,fungi ,EZH2 ,Nuclear Proteins ,Histone-Lysine N-Methyltransferase ,Cadherins ,DNA-Binding Proteins ,Gene Expression Regulation, Neoplastic ,Pancreatic Neoplasms ,030104 developmental biology ,Histone methyltransferase ,DNA methylation ,Cancer research ,biology.protein ,Demethylase ,Ectopic expression ,Transcription Factors - Abstract
Methylation of histone H3-lysine 9 (H3K9) and H3K27 by the methyltransferase G9a and polycomb repressive complex 2 (PRC2) inhibits transcription of target genes. A crosstalk between G9a and PRC2 via direct physical interaction has been shown recently. Here, we demonstrate an alternative mechanism by which G9a promotes H3K27 methylation. Overexpression of G9a increases both H3K9 and H3K27 methylation, reduces E-cadherin expression and induces epithelial-mesenchymal transition in PANC-1 pancreatic cancer cells. Conversely, the depletion of G9a or ectopic expression of methyltransferase-dead G9a in G9a-overexpressing gemcitabine-resistant PANC-1-R cells exhibits opposite effects. G9a promotes H3K27 methylation of the E-cadherin promoter by upregulating PCL3 to increase PRC2 promoter recruitment and by downregulating the H3K27 demethylase KDM7A to silence E-cadherin gene. The depletion of PCL3 or overexpression of KDM7A elevated expression of E-cadherin in PANC-1-R cells while ectopic expression of PCL3 or knockdown of KDM7A downregulated E-cadherin in PANC-1 cells. Collectively, we provide evidence that G9a orchestrates the dynamic balance within histone-modifying enzymes to regulate H3K27 methylation and gene expression.
- Published
- 2015
38. Bcr-Abl oncogene stimulates jab1 expression via cooperative interaction of β-catenin and STAT1 in chronic myeloid leukemia cells
- Author
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Wen-Chun Hung, Kuei-Ting Yang, Ming-Chung Wang, Ming-Chuan Hsu, and Jing-Yi Chen
- Subjects
Physiology ,Morpholines ,Clinical Biochemistry ,Fusion Proteins, bcr-abl ,Down-Regulation ,Antineoplastic Agents ,Biology ,Piperazines ,Transcription Factor 4 ,Cell Line, Tumor ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,hemic and lymphatic diseases ,Humans ,Enzyme Inhibitors ,Promoter Regions, Genetic ,Transcription factor ,beta Catenin ,Flavonoids ,Oncogene ,Basic Helix-Loop-Helix Leucine Zipper Transcription Factors ,COP9 Signalosome Complex ,Akt/PKB signaling pathway ,Intracellular Signaling Peptides and Proteins ,Myeloid leukemia ,Cell Biology ,Oncogene Protein v-akt ,Pyrimidines ,STAT1 Transcription Factor ,Imatinib mesylate ,Chromones ,Benzamides ,Imatinib Mesylate ,Cancer research ,Ectopic expression ,Chromatin immunoprecipitation ,Peptide Hydrolases ,Transcription Factors ,K562 cells - Abstract
Jab1, a co-activator of AP-1 transcription factor and the fifth subunit of the COP9 signalosome, mediates degradation of the tumor suppressor p53 and p27(Kip1) and functions as a tumor promoter in different types of human cancer. In this study, we show that inhibition of Bcr-Abl oncogene by imatinib induces down-regulation of Jab1 in Bcr-Abl-positive K562, Ku812, and MEG01 leukemia cells suggesting Bcr-Abl may regulate Jab1 expression. Promoter deletion and mutation analysis indicate the Tcf-4/β-catenin and STAT1 binding sites located between the -405/-223 region of the human Jab1 promoter are important for the activation of Jab1 by Bcr-Abl. Double mutation of these two sites reverses the inhibitory effect of imatinib. Chromatin immunoprecipitation assay verifies the binding of β-catenin and STAT1 to human Jab1 promoter. Ectopic expression of dominant-negative Tcf-4 mutant significantly attenuates Jab1 expression while over-expression of β-catenin and STAT1 cooperatively up-regulates Jab1 promoter activity and mRNA expression. Our results also demonstrate that the AKT signaling pathway is involved in the regulation of Jab1 by Bcr-Abl because the AKT inhibitor LY294002 but not the ERK inhibitor PD98059 reduces Jab1 promoter activity and mRNA expression. Taken together, our results suggest that Bcr-Abl stimulates Jab1 expression via the cooperative interaction of β-catenin and STAT1 in leukemia cells.
- Published
- 2011
39. AB108. P082. Role of epigenetic modifying enzymes in the chemoresistance of pancreatic cancer
- Author
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Ming-Chuan Hsu, Li-Tzong Chen, and Wen-Chun Hung
- Subjects
chemistry.chemical_classification ,Endocrinology ,Enzyme ,Oncology ,chemistry ,Endocrinology, Diabetes and Metabolism ,Pancreatic cancer ,Internal Medicine ,medicine ,Cancer research ,Epigenetics ,Biology ,medicine.disease - Published
- 2018
40. KEAP1 E3 Ligase-Mediated Downregulation of NF-κB Signaling by Targeting IKKβ
- Author
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Hsu Ping Kuo, Ann Chi Lin, Yi Du, Chia Wei Li, Mien Chie Hung, Chun Te Chen, Chien-Chen Lai, Ya Hui Chang, Mo Liu, Long Yuan Li, Weiya Xia, Shih-Feng Tsai, Qingqing Ding, Tsai Lien Liao, Chao Kai Chou, Dung Fang Lee, Jia Shen, Longfei Huo, and Ming Chuan Hsu
- Subjects
DNA Copy Number Variations ,RBX1 ,Gene Expression ,Neovascularization, Physiologic ,Breast Neoplasms ,IκB kinase ,Kaplan-Meier Estimate ,Transfection ,Article ,Cell Line ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Downregulation and upregulation ,Ubiquitin ,Cell Line, Tumor ,Neoplasms ,Animals ,Humans ,Protein Interaction Domains and Motifs ,RNA, Small Interfering ,Molecular Biology ,030304 developmental biology ,0303 health sciences ,Kelch-Like ECH-Associated Protein 1 ,biology ,Tumor Necrosis Factor-alpha ,Interleukin-8 ,Intracellular Signaling Peptides and Proteins ,NF-kappa B ,Transcription Factor RelA ,Ubiquitination ,Cell Biology ,NFKB1 ,Cullin Proteins ,KEAP1 ,3. Good health ,Ubiquitin ligase ,Cell biology ,I-kappa B Kinase ,030220 oncology & carcinogenesis ,Mutation ,biology.protein ,Female ,Carrier Proteins ,Cullin ,Protein Binding ,Signal Transduction - Abstract
IkappaB kinase beta (IKKbeta) is involved in tumor development and progression through activation of the nuclear factor (NF)-kappaB pathway. However, the molecular mechanism that regulates IKKbeta degradation remains largely unknown. Here, we show that a Cullin 3 (CUL3)-based ubiquitin ligase, Kelch-like ECH-associated protein 1 (KEAP1), is responsible for IKKbeta ubiquitination. Depletion of KEAP1 led to the accumulation and stabilization of IKKbeta and to upregulation of NF-kappaB-derived tumor angiogenic factors. A systematic analysis of the CUL3, KEAP1, and RBX1 genomic loci revealed a high percentage of genome loss and missense mutations in human cancers that failed to facilitate IKKbeta degradation. Our results suggest that the dysregulation of KEAP1-mediated IKKbeta ubiquitination may contribute to tumorigenesis.
- Published
- 2009
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41. The ZNF304-integrin axis protects against anoikis in cancer
- Author
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Tyler J. Moss, Pinar Kanlikilicer, Mien Chie Hung, Sunila Pradeep, Alexandra Gol-Chambers, Paloma Monroig, Prahlad T. Ram, Nermin Kahraman, Selanere Mangala, Keith Baggerly, Cristina Ivan, Geoffrey Bartholomeusz, Ming Chuan Hsu, George A. Calin, Burcu Aslan, Susan L. Tucker, Archana S. Nagaraja, Anil K. Sood, Guillermo N. Armaiz Pena, Rajesha Rupaimoole, Enrique Fuentes-Mattei, Cristian Rodriguez-Aguayo, Erkan Yuca, Ozgur Ozkayar, Gabriel Lopez-Berestein, Huamin Wang, Vianey Gonzalez-Villasana, Sherry Y. Wu, Hee Dong Han, and Bulent Ozpolat
- Subjects
medicine.medical_specialty ,Integrin beta Chains ,Integrin ,General Physics and Astronomy ,Article ,General Biochemistry, Genetics and Molecular Biology ,Metastasis ,Focal adhesion ,Cell Movement ,Cell Line, Tumor ,Internal medicine ,medicine ,Humans ,Gene silencing ,Anoikis ,Gene Silencing ,Paxillin ,Cell Proliferation ,Ovarian Neoplasms ,Multidisciplinary ,biology ,Carcinoma ,General Chemistry ,medicine.disease ,Gene Expression Regulation, Neoplastic ,Endocrinology ,Cancer cell ,biology.protein ,Cancer research ,Female ,Transcription Factors ,Proto-oncogene tyrosine-protein kinase Src - Abstract
Ovarian cancer is a highly metastatic disease, but no effective strategies to target this metastatic process currently are known. Here, an integrative computational analysis of The Cancer Genome Atlas ovarian cancer dataset coupled with experimental validation identified a novel zinc finger transcription factor ZNF304 as one of the key factors for ovarian cancer metastasis. High tumoral ZNF304 expression was associated with poor overall survival in ovarian cancer patients. Through reverse phase protein array analysis, we demonstrated that ZNF304 promotes multiple proto-oncogenic pathways important for cell survival, migration, and invasion. ZNF304 transcriptionally regulates β1 integrin, which subsequently regulates Src/focal adhesion kinase and paxillin and prevents anoikis. In vivo delivery of ZNF304 siRNA by a novel dual assembly nanoparticle led to sustained gene silencing for 14 days, increased anoikis, and reduced tumor growth in orthotopic mouse models of ovarian cancer. Taken together, ZNF304 is a novel transcriptional regulator of β1 integrin, promotes cancer cell survival, and protects against anoikis in ovarian cancer.
- Published
- 2015
42. HER-2/neu Represses the Metastasis Suppressor RECK via ERK and Sp Transcription Factors to Promote Cell Invasion
- Author
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Hui-Chiu Chang, Wen-Chun Hung, and Ming-Chuan Hsu
- Subjects
Threonine ,MAPK/ERK pathway ,Transcription, Genetic ,Receptor, ErbB-2 ,Hydroxamic Acids ,Biochemistry ,Mice ,Neoplasm Metastasis ,Extracellular Signal-Regulated MAP Kinases ,Promoter Regions, Genetic ,Membrane Glycoproteins ,Reverse Transcriptase Polymerase Chain Reaction ,Histone deacetylase inhibitor ,Transfection ,Up-Regulation ,Gene Expression Regulation, Neoplastic ,Sp3 Transcription Factor ,Matrix Metalloproteinase 9 ,Protein Binding ,Signal Transduction ,medicine.drug ,Chromatin Immunoprecipitation ,DNA, Complementary ,Sp1 Transcription Factor ,medicine.drug_class ,Blotting, Western ,Genetic Vectors ,Down-Regulation ,Biology ,GPI-Linked Proteins ,Sp3 transcription factor ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Immunoprecipitation ,Neoplasm Invasiveness ,Metastasis suppressor ,Molecular Biology ,Cell Nucleus ,Sp1 transcription factor ,Binding Sites ,DNA ,Cell Biology ,Molecular biology ,Histone Deacetylase Inhibitors ,Trichostatin A ,Protein Biosynthesis ,NIH 3T3 Cells ,Chromatin immunoprecipitation ,Gene Deletion - Abstract
Matrix metalloproteinase (MMP) inhibitory proteins may negatively regulate MMP activity to suppress tumor metastasis. In this study, we demonstrate that the HER-2/neu oncogene inhibits the expression of the MMP inhibitor RECK to promote cell invasion. RECK was inhibited via transcriptional repression in B104-1-1 cells, which express constitutively active HER-2/neu. Overexpression of HER-2/neu in NIH/3T3 or HaCaT cells also suppressed RECK expression. Deletion and mutation assays showed that HER-2/neu repressed RECK via the Sp1-binding site localized in the -82/-71 region from the translational start site. DNA affinity precipitation and chromatin immunoprecipitation assays indicated that binding of Sp1 and Sp3 to this consensus site was increased in B104-1-1 cells. We also found that HER-2/neu inhibited RECK via the ERK signaling pathway. Sp1 proteins phosphorylated at Thr453 and Thr739 by ERK bound preferentially to the RECK promoter, and this binding was reversed by HER-2/neu and ERK inhibitors. Furthermore, our data indicate that HER-2/neu obviously increased HDAC1 binding to the Sp1-binding site localized in the -82/-71 region of the RECK promoter. The histone deacetylase inhibitor trichostatin A reversed HER-2/neu-induced inhibition of RECK. HER-2/neu activation was associated with increased MMP-9 secretion and activation. Re-expression of RECK in HER-2/neu-overexpressing cells inhibited MMP-9 secretion and cell invasion. Taken together, our results suggest that HER-2/neu induces the binding of Sp proteins and HDAC1 to the RECK promoter to inhibit RECK expression and to promote cell invasion. Restoration of RECK provides a novel strategy for the inhibition of HER-2/neu-induced metastasis.
- Published
- 2006
43. Correction: Corrigendum: Blocking c-Met–mediated PARP1 phosphorylation enhances anti-tumor effects of PARP inhibitors
- Author
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Gilbert R. Lee, Ye Sun, Yi Hsin Hsu, Yi Du, Ming-Chuan Hsu, Chien Liang Liu, Katsuya Nakai, Wen-Hsuan Yu, Mien Chie Hung, Wan Chi Lin, Hung-Ling Wang, Yongkun Wei, Hirohito Yamaguchi, Chung-Hsuan Chen, Wen-Chien Huang, Chun-Te Chen, Mei-Kuang Chen, Gabriel N. Hortobagyi, Yun Wu, Paul G. Leonard, Wei Chao Chang, Jennifer L. Hsu, Yuan-Ching Chang, Philip H. Jones, and Morag Park
- Subjects
inorganic chemicals ,0301 basic medicine ,Antitumor activity ,C-Met ,Chemistry ,Blocking (radio) ,Poly ADP ribose polymerase ,macromolecular substances ,General Medicine ,environment and public health ,General Biochemistry, Genetics and Molecular Biology ,enzymes and coenzymes (carbohydrates) ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,PARP1 ,Cancer research ,bacteria ,Phosphorylation - Abstract
Corrigendum: Blocking c-Met–mediated PARP1 phosphorylation enhances anti-tumor effects of PARP inhibitors
- Published
- 2016
44. The tumor suppressor RECK interferes with HER-2/Neu dimerization and attenuates its oncogenic signaling
- Author
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Ming-Chuan Hsu, Ming-Fen Hou, Wen-Chun Hung, and Kun-Jing Hong
- Subjects
MAPK/ERK pathway ,medicine.medical_specialty ,Matrix metalloproteinase inhibitor ,Receptor, ErbB-2 ,Biophysics ,Down-Regulation ,Breast Neoplasms ,GPI-Linked Proteins ,Biochemistry ,Medical Records ,Metastasis ,law.invention ,Cell Line ,Structural Biology ,law ,Internal medicine ,Cell Line, Tumor ,Genetics ,medicine ,Humans ,Immunoprecipitation ,Metastasis suppressor ,RNA, Messenger ,Phosphorylation ,RECK ,Molecular Biology ,Cell Proliferation ,Neoplasm Staging ,HER-2/Neu ,Chemistry ,Autophosphorylation ,HEK 293 cells ,Cell Biology ,medicine.disease ,Recombinant Proteins ,Matrix metalloproteinase ,Gene Expression Regulation, Neoplastic ,Protein Transport ,Endocrinology ,Lymphatic Metastasis ,Cancer research ,Suppressor ,Ectopic expression ,Female ,Protein Multimerization ,Signal Transduction - Abstract
Our previous study demonstrates that HER-2/Neu oncogene inhibits a matrix metalloproteinase inhibitor and tumor metastasis suppressor RECK to promote metastasis. Conversely, the effect of RECK on the oncogenic function of HER-2/Neu is unknown. Ectopic expression of RECK in 293T cells and HER-2/Neu-overexpressing breast cancer cells shows that RECK and HER-2/Neu are co-localized and these two proteins can be co-immunoprecipitated. RECK inhibits HER-2/Neu receptor dimerization and autophosphorylation, which causes reduction of ERK and AKT kinase activity and down-regulation of HER-2/Neu target genes. RECK expression is reduced in 58.8% of breast cancer tissues and is associated with lymph node invasion supporting its anti-metastatic role. Collectively, we provide the first evidence that RECK can negatively regulate oncogenic activity of HER-2/Neu by inhibiting receptor dimerization.Structured summaryHER-2/Neu physically interacts with HER-2/Neu by blue native page (View interaction)HER-2/Neu physically interacts with RECK by coimmunoprecipitation (View interaction)HER-2/Neu and RECK colocalize by fluorescence microscopy (View Interaction 1, 2)HER-2/Neu physically interacts with RECK by anti bait coimmunoprecipitation (View interaction)
- Published
- 2010
45. RNA helicase A is a DNA-binding partner for EGFR-mediated transcriptional activation in the nucleus
- Author
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Weiya Xia, Long Yuan Li, Qingqing Ding, Yung Luen Yu, Longfei Huo, Chang Hai Tsai, Tzu Hsuan Huang, Sheng-Chieh Hsu, Mien Chie Hung, Ming Chuan Hsu, Ying Nai Wang, Chien-Chen Lai, Wei Chao Chang, Yan Wang, and Chung-Hsuan Chen
- Subjects
Regulation of gene expression ,Cell Nucleus ,Transcriptional Activation ,Gene knockdown ,Multidisciplinary ,Active Transport, Cell Nucleus ,Promoter ,Breast Neoplasms ,DNA ,Biology ,Biological Sciences ,RNA Helicase A ,Molecular biology ,ErbB Receptors ,Transactivation ,Gene Expression Regulation ,Transcription (biology) ,Gene expression ,Humans ,Cyclin D1 ,Promoter Regions, Genetic ,Gene ,RNA Helicases ,HeLa Cells ,Protein Binding - Abstract
EGF induces the translocation of EGF receptor (EGFR) from the cell surface to the nucleus where EGFR activates gene transcription through its binding to an AT-rich sequence (ATRS) of the target gene promoter. However, how EGFR, without a DNA-binding domain, can bind to the gene promoter is unclear. In the present study, we show that RNA helicase A (RHA) is an important mediator for EGFR-induced gene transactivation. EGF stimulates the interaction of EGFR with RHA in the nucleus of cancer cells. The EGFR/RHA complex then associates with the target gene promoter through binding of RHA to the ATRS of the target gene promoter to activate its transcription. Knockdown of RHA expression in cancer cells abrogates the binding of EGFR to the target gene promoter, thereby reducing EGF/EGFR-induced gene expression. In addition, interruption of EGFR–RHA interaction decreases the EGFR-induced promoter activity. Consistently, we observed a positive correlation of the nuclear expression of EGFR, RHA, and cyclin D1 in human breast cancer samples. These results indicate that RHA is a DNA-binding partner for EGFR-mediated transcriptional activation in the nucleus.
- Published
- 2010
46. Focused ultrasound thermal therapy system with ultrasound image guidance and temperature measurement feedback
- Author
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Ming-Chuan Hsu, Kao-Han Lin, Yung-Yaw Chen, Hsu Chan, Sun-Yi Young, and Win-Li Lin
- Subjects
Hot Temperature ,Materials science ,Movement ,Ultrasonic Therapy ,Acoustics ,Transducers ,Servomotor ,Interference (wave propagation) ,Temperature measurement ,Imaging phantom ,Motion ,Sonication ,Electric Power Supplies ,Coincident ,Thermocouple ,Humans ,Ultrasonics ,Computer vision ,Phantoms, Imaging ,business.industry ,Temperature ,Equipment Design ,Motion control ,Transducer ,Artificial intelligence ,business ,Algorithms - Abstract
In this study, we developed a focused ultrasound (FUS) thermal therapy system with ultrasound image guidance and thermocouple temperature measurement feedback. Hydraulic position devices and computer-controlled servo motors were used to move the FUS transducer to the desired location with the measurement of actual movement by linear scale. The entire system integrated automatic position devices, FUS transducer, power amplifier, ultrasound image system, and thermocouple temperature measurement into a graphical user interface. For the treatment procedure, a thermocouple was implanted into a targeted treatment region in a tissue-mimicking phantom under ultrasound image guidance, and then the acoustic interference pattern formed by image ultrasound beam and low-power FUS beam was employed as image guidance to move the FUS transducer to have its focal zone coincident with the thermocouple tip. The thermocouple temperature rise was used to determine the sonication duration for a suitable thermal lesion as a high power was turned on and ultrasound image was used to capture the thermal lesion formation. For a multiple lesion formation, the FUS transducer was moved under the acoustic interference guidance to a new location and then it sonicated with the same power level and duration. This system was evaluated and the results showed that it could perform two-dimensional motion control to do a two-dimensional thermal therapy with a small localization error 0.5 mm. Through the user interface, the FUS transducer could be moved to heat the target region with the guidance of ultrasound image and acoustic interference pattern. The preliminary phantom experimental results demonstrated that the system could achieve the desired treatment plan satisfactorily.
- Published
- 2008
47. Overexpression of Jab1 in hepatocellular carcinoma and its inhibition by peroxisome proliferator-activated receptor{gamma} ligands in vitro and in vivo
- Author
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Chao-Cheng Huang, Wen-Chun Hung, Ming-Chuan Hsu, Hui-Chiu Chang, and Tsung-Hui Hu
- Subjects
Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Carcinoma, Hepatocellular ,Mice, Nude ,Biology ,In Vitro Techniques ,Ligands ,Gene Expression Regulation, Enzymologic ,chemistry.chemical_compound ,Mice ,RNA interference ,Internal medicine ,medicine ,Animals ,Humans ,Receptor ,Aged ,Mice, Inbred BALB C ,COP9 Signalosome Complex ,Liver Neoplasms ,Intracellular Signaling Peptides and Proteins ,Troglitazone ,Middle Aged ,Blot ,Gene Expression Regulation, Neoplastic ,PPAR gamma ,Endocrinology ,Oncology ,chemistry ,Cell culture ,Cancer research ,Ectopic expression ,Female ,Growth inhibition ,Chromatin immunoprecipitation ,Neoplasm Transplantation ,medicine.drug ,Peptide Hydrolases - Abstract
Purpose: Jun activation domain-binding protein 1 (Jab1) is the fifth subunit of the COP9 signalosome and exhibits oncogenic activity. We investigated Jab1 expression in hepatocellular carcinoma (HCC) tissues and cell lines and tested the effect of peroxisome proliferator-activated receptor γ (PPARγ) ligands on Jab1 expression. Experimental Design: Jab1 expression in HCC tissues and cell lines was studied by real-time reverse transcription-PCR, immunohistochemical staining, and Western blotting. Promoter activity and chromatin immunoprecipitation assays were done to address the inhibition of Jab1 promoter by PPARγ ligands. RNA interference was used to clarify PPARγ ligand-induced inhibition of Jab1. Anticancer and Jab1-suppressing activity of PPARγ ligands was tested in nude mice. Results: Jab1 was detected in the nucleus and cytoplasm of HCC tissues and 37% (37 of 99) of tissues exhibited Jab1 overexpression. Jab1 expression correlated with sex and hepatitis C virus infection, whereas it was negatively associated with hepatitis B virus infection. Additionally, Jab1 was overexpressed in HCC cell lines. PPARγ ligands troglitazone and rosiglitazone down-regulated Jab1 expression in HCC cells, and troglitazone directly suppressed Jab1 promoter activity by inhibiting Sp1- and Tcf4-mediated transcription. This suppression was mediated via both PPARγ-dependent and PPARγ-independent mechanisms. Ectopic expression of Jab1 counteracted troglitazone-induced growth inhibition. Animal studies verified that intratumor or i.p. injection of troglitazone attenuated HCC growth and reduced Jab1 expression in tumor tissues. Conclusions: Our results indicate that Jab1 is overexpressed in HCC and PPARγ ligands may suppress Jab1 to inhibit the proliferation of HCC cells.
- Published
- 2008
48. Embracing Business Context in Pedagogical Simulation Games--A Case with Process Disciplined Project Management
- Author
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Shen-Tzay Huang, Ming-Chuan Hsu, and Wen-Hao Lin
- Subjects
Context model ,Engineering ,Knowledge management ,business.industry ,Context (language use) ,Management information systems ,Multinational corporation ,Situated ,ComputingMilieux_COMPUTERSANDEDUCATION ,Software system ,Project management ,Software engineering ,business ,Software project management - Abstract
The dynamics of business and software engineering in the flattened world poses both challenges and opportunities in terms of pedagogical exploration and innovative experiments. A generic pedagogical scenario is to serve the purpose by incorporating two empiricist approaches in management education to emphasize situated authentic experiences in context. A case contextualized game for software project management discipline is generated, with a teaching case of the multinational textile company, and used in class instruction with statistically positive responses.
- Published
- 2008
49. Jab1 is overexpressed in human breast cancer and is a downstream target for HER-2/neu
- Author
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Chee-Yin Chai, Ming-Feng Hou, Wen-Chun Hung, Wan-Tzu Chen, Hui-Chiu Chang, and Ming-Chuan Hsu
- Subjects
medicine.medical_specialty ,Pathology ,Receptor, ErbB-2 ,Blotting, Western ,Gene Expression ,Breast Neoplasms ,Biology ,Pathology and Forensic Medicine ,Downregulation and upregulation ,Internal medicine ,Cell Line, Tumor ,Coactivator ,Gene expression ,medicine ,Humans ,skin and connective tissue diseases ,Gene knockdown ,Oncogene ,COP9 Signalosome Complex ,Reverse Transcriptase Polymerase Chain Reaction ,Intracellular Signaling Peptides and Proteins ,Cancer ,medicine.disease ,Immunohistochemistry ,Up-Regulation ,Gene Expression Regulation, Neoplastic ,Endocrinology ,Cancer cell ,Cancer research ,Ectopic expression ,Female ,Peptide Hydrolases - Abstract
Jab1 is a coactivator of AP-1 transcription factor and the fifth subunit of the COP9 signalosome. This protein is a potential oncogene and is involved in the mediation of nuclear exportation and degradation of the tumor suppressor p27(Kip1). However, control of Jab1 gene expression and its de-regulation in cancer cells are largely unknown. In this study, we demonstrated that Jab1 is overexpressed in 53 (80.3%) of a series of 66 human breast tumor tissues. In addition, its expression is significantly correlated with HER-2/neu overexpression (P=0.0318). HER-2/neu-overexpressing MDA-MB-453 human breast cancer cells exhibited higher expression of Jab1 than that of MCF-7 breast cancer cells. Promoter activity assay suggested that HER-2/neu oncogene upregulated Jab1 via transcriptional activation. Inhibition of HER-2/neu activity by Herceptin or AG825 significantly attenuated Jab1 expression in HER-2/neu-overexpressing MDA-MB-453 cells. On the contrary, ectopic expression of HER-2/neu stimulated Jab1 expression in MCF-7 cells. Knockdown of Jab1 expression by siRNA resulted in p27(Kip1) upregulation and G1 growth arrest in Jab1-overexpressing MDA-MB-453 cells. Taken together, our results suggest that Jab1 is a downstream target for HER-2/neu and its overexpression is linked with HER-2/neu expression in breast cancer.
- Published
- 2008
50. HER-2/neu transcriptionally activates Jab1 expression via the AKT/beta-catenin pathway in breast cancer cells
- Author
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Wen-Chun Hung, Ming-Chuan Hsu, and Hui-Chiu Chang
- Subjects
Transcriptional Activation ,Cancer Research ,Small interfering RNA ,Receptor, ErbB-2 ,Endocrinology, Diabetes and Metabolism ,Breast Neoplasms ,Biology ,Transfection ,Mice ,Endocrinology ,Gene expression ,Tumor Cells, Cultured ,Animals ,Humans ,RNA, Small Interfering ,Promoter Regions, Genetic ,Transcription factor ,Protein kinase B ,beta Catenin ,Cell Proliferation ,Regulation of gene expression ,Binding Sites ,Akt/PKB signaling pathway ,COP9 Signalosome Complex ,Intracellular Signaling Peptides and Proteins ,Molecular biology ,Gene Expression Regulation, Neoplastic ,Oncogene Protein v-akt ,Oncology ,Cancer cell ,NIH 3T3 Cells ,Signal transduction ,TCF Transcription Factors ,Peptide Hydrolases ,Signal Transduction - Abstract
Jab1 is a co-activator of activating protein-1 (AP-1) transcription factor and the fifth subunit of the constitutive photomorphogenesis 9 (COP9) signalosome, which has been shown to mediate nuclear exportation and ubiquitin-dependent degradation of the tumor suppressor p27Kip1. Jab1 is overexpressed in several types of human cancer. However, de-regulation of Jab1 gene expression in cancer cells is largely unclear. In this study, we reported that expression of Jab1 was stimulated by HER-2/neu oncogene via transcriptional activation. Promoter deletion and mutation analysis indicated that HER-2/neu stimulated Jab1 via the T cell factor (TCF) binding site located at the −380/−368 region of the human Jab1 promoter. DNA affinity precipitation assay and chromatin immunoprecipitation assay verified that binding of β-catenin and TCF-4 to this consensus site was increased by HER-2/neu. In addition, dominant-negative mutant of TCF significantly attenuated the stimulatory effect of HER-2/neu. We also demonstrated that HER-2/neu increased β-catenin/TCF-mediated Jab1 expression via the AKT signaling pathway because chemical inhibitor or dominant-negative mutant of AKT effectively attenuated the stimulatory action of HER-2/neu. IGF-I, which is a well-known AKT activator, also up-regulated the expression of Jab1 in NIH/3T3 and MCF-7 cells. Knockdown of Jab1 by small interfering RNA (siRNA) preferentially inhibited proliferation of HER-2/neu-overexpressing breast cancer cells. Taken together, our results suggest that HER-2/neu transcriptionally activates Jab1 expression to promote proliferation of breast cancer cells.
- Published
- 2007
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