Ju Ming Wang

Publications (39) View all

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  Available from: Ju Ming Wang

  Article: Direct interaction of C/EBPδ and Sp1 at the GC-enriched promoter region synergizes the IL-10 gene transcription in mouse macrophage

  Ben-Tzu Chiang, Yi-Wen Liu, Ben-Kuen Chen, Ju-Ming Wang, Wen-Chang Chang
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  ABSTRACT: We previously reported that LPS activates the transcription of the IL-10 gene through the Sp1 and C/EBP binding sites and indicated that Sp1, C/EBPβ and C/EBPδ can coactivate the IL-10 gene expression in mouse macrophage cells [Liu Y.-W., Tseng H.-P., Chen L.-C., Chen B.-K., Chang W.-C. J. Immunol. 171: 821–828, 2003]. In the present report, we demonstrated the direct physical interaction between C/EBPδ and Sp1, and also mapped the interaction domains of these two proteins. C/EBPδ binds to Sp1 via its basic region leucine zipper domain. The C-terminus of Sp1 was also the major region interacting with C/EBPδ. However, both glutamine- and serine/threonine-rich homologus regions of Sp1 also interacted with C/EBPδ. The binding of Sp1 and C/EBPδ as a complex to the Sp1 binding site on the promoter of IL-10 was further confirmed by using the DNA affinity precipitation assay. By using Sp1-deficient SL2 cells, we also found that the overexpressions of C/EBPδ and Sp1 synergically activate the transcriptional activity of IL-10 gene. Taken together, our present results revealed a novel mechanism of a superactivation of Sp1 by C/EBPδ via a direct interaction between these two transcription factors leading to the activation of the IL-10 gene in mouse macrophage cells.
  Journal of Biomedical Science 04/2012; 13(5):621-635. · 2.01 Impact Factor
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  Available from: Ju Ming Wang

  Article: In vivo positron emission tomography imaging of protease activity by generation of a hydrophobic product from a noninhibitory protease substrate.

  Chih-Hung Chuang, Kuo-Hsiang Chuang, Hsin-Ell Wang, Steve R Roffler, Jen-taie Shiea, Shey-Cherng Tzou, Ta-Chun Cheng, Chien-Han Kao, Shih-Yen Wu, Wei-Lung Tseng, Chiu-Min Cheng, Ming-Feng Hou, Ju-Ming Wang, Tian-Lu Cheng
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  ABSTRACT: To develop an imaging technology for protease activities in patients that could help in prognosis prediction and in design of personalized, protease-based inhibitors and prodrugs for targeted therapy. Polyethylene glycol (PEG) was covalently attached to the N-terminus of a hydrophilic peptide substrate (GPLGVR) for matrix metalloproteinase (MMP) to increase hydrophilicity. PEG-peptide was then linked to a hydrophobic tetramethylrhodamine (TMR) domain and labeled with (18)F to form a PEG-peptide-(18)F-TMR probe. Specific cleavage of the probe by MMP2 was tested in vitro by matrix-assisted laser desorption/ionization-time-of-flight (MALDI-TOF). In vivo imaging of MMP2-expressing tumors was evaluated by micro-PET. The hydrophobic TMR fragment (948 Da) was specifically generated by MMP2 enzymes and MMP-expressing HT1080 cells but not control MCF-7 cells. MMP-expressing HT1080 cells and tumors selectively accumulated the hydrolyzed, hydrophobic TMR fragment at sites of protease activity. Importantly, we found that (18)F-labeled probe ((18)F-TMR) preferentially localized in HT1080 tumors but not control MCF-7 tumors as shown by micro-PET. Uptake of the probe in HT1080 tumors was 18.4 ± 1.9-fold greater than in the MCF-7 tumors 30 minutes after injection. These results suggest that the PEG-peptide-(18)F-TMR probe displays high selectivity for imaging MMP activity. This strategy successfully images MMP expression in vivo and may be extended to other proteases to predict patient prognosis and to design personalized, protease-based inhibitors and prodrug-targeted therapies.
  Clinical Cancer Research 01/2012; 18(1):238-47. · 7.74 Impact Factor
• Article: EGFR nuclear import in gallbladder carcinoma: nuclear phosphorylated EGFR upregulates iNOS expression and confers independent prognostic impact.

  Chien-Feng Li, Fu-Ming Fang, Ju-Ming Wang, Ching-Cherng Tzeng, Hui-Chun Tai, Yu-Ching Wei, Shau-Hsuan Li, Yuan-Ting Lee, Yu-Hui Wang, Shih-Chen Yu, Yow-Ling Shiue, Patrick Yu-Wei Chu, Wen-Ling Wang, Li-Tzong Chen, Hsuan-Ying Huang
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  ABSTRACT: The understanding of epidermal growth factor receptor (EGFR) deregulation in carcinogenesis remains incomplete. We investigated the implications of EGFR gene status and EGFR nuclear translocation in gallbladder carcinoma (GBCA). Subcellular localization of EGFR and phosphorylated EGFR (pEGFR) was analyzed by fractional immunoblotting and confocal immunofluorescence in GBCA cell lines. pEGFR binding to iNOS promoter was assessed by chromatin immunoprecipitation with iNOS promoter activity evaluated by luciferase assay. EGFR, pEGFR, and iNOS were immunohistochemically assessable for localization and level in the training set of 104 GBCAs on tissue microarrays, with 76 cases analyzed for EGFR gene by chromogenic in situ hybridization (CISH) and mutant-enriched PCR targeting exons 19 and 21. The prognostic impact of nuclear pEGFR (N-pEGFR) immunoexpression was reaffirmed on whole sections of 58 GBCAs in the test set. Nuclear expression of EGFR and pEGFR was substantiated in vitro with augmented activity of iNOS promoter elicited by pEGFR binding upon EGF treatment. Despite no mutation, EGFR amplification, identified in 11 cases (15%) by CISH, strongly correlated with cytoplasmic EGFR expression (P < 0.001) but not with disease-specific survival (DSS). Immunoexpression of nuclear EGFR (N-EGFR), cytoplasmic pEGFR, and N-pEGFR was strongly related to that of iNOS (all ≤0.005). N-pEGFR independently predicted worse DSS in both training (P = 0.0468, HR = 2.024) and test sets (P = 0.0223, HR = 5.573). N-EGFR and N-pEGFR express in GBCA, conferring clinical aggressiveness partly through iNOS transactivation. Lacking response-predicting mutation, EGFR gene status, albeit amplified in 15% of GBCA, is neither related to nuclear EGFR translocation nor prognostically useful.
  Annals of Surgical Oncology 07/2011; 19(2):443-54. · 4.17 Impact Factor
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  Available from: Ju Ming Wang

  Article: CCAAT/enhancer-binding protein delta mediates tumor necrosis factor alpha-induced Aurora kinase C transcription and promotes genomic instability.

  Sin-Rong Wu, Chien-Feng Li, Liang-Yi Hung, A-Mei Huang, Joseph T Tseng, Jen-Hui Tsou, Ju-Ming Wang
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  ABSTRACT: Epidemiologic and clinical research indicates that chronic inflammation increases the risk of certain cancers, possibly through chromosomal instability. However, the mechanism of inflammation-dependent chromosomal instability associated with tumorigenesis is not well characterized. The transcription factor CCAAT/enhancer-binding protein δ (C/EBPδ, CEBPD) is induced by tumor necrosis factor α (TNFα) and expressed in chronically inflamed tissue. In this study, we show that TNFα promotes aneuploidy. Loss of CEBPD attenuated TNFα-induced aneuploidy, and CEBPD caused centromere abnormality. Additionally, TNFα-induced CEBPD expression augmented anchorage-independent growth. We found that TNFα induced expression of aurora kinase C (AURKC) through CEBPD, and that AURKC also causes aneuploidy. Furthermore, high CEBPD expression correlated with AURKC expression in inflamed cervical tissue specimens. These data provide insight into a novel function for CEBPD in inducing genomic instability through the activation of AURKC expression in response to inflammatory signals.
  Journal of Biological Chemistry 06/2011; 286(33):28662-70. · 4.77 Impact Factor
• Article: The tumour suppressor C/EBPδ inhibits FBXW7 expression and promotes mammary tumour metastasis.

  Kuppusamy Balamurugan, Ju-Ming Wang, Hsin-Hwa Tsai, Shikha Sharan, Miriam Anver, Robert Leighty, Esta Sterneck
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  ABSTRACT: Inflammation and hypoxia are known to promote the metastatic progression of tumours. The CCAAT/enhancer-binding protein-δ (C/EBPδ, CEBPD) is an inflammatory response gene and candidate tumour suppressor, but its physiological role in tumourigenesis in vivo is unknown. Here, we demonstrate a tumour suppressor function of C/EBPδ using transgenic mice overexpressing the Neu/Her2/ERBB2 proto-oncogene in the mammary gland. Unexpectedly, this study also revealed that C/EBPδ is necessary for efficient tumour metastasis. We show that C/EBPδ is induced by hypoxia in tumours in vivo and in breast tumour cells in vitro, and that C/EBPδ-deficient cells exhibit reduced glycolytic metabolism and cell viability under hypoxia. C/EBPδ supports CXCR4 expression. On the other hand, C/EBPδ directly inhibits expression of the tumour suppressor F-box and WD repeat-domain containing 7 gene (FBXW7, FBW7, AGO, Cdc4), encoding an F-box protein that promotes degradation of the mammalian target of rapamycin (mTOR). Consequently, C/EBPδ enhances mTOR/AKT/S6K1 signalling and augments translation and activity of hypoxia-inducible factor-1α (HIF-1α), which is necessary for hypoxia adaptation. This work provides new insight into the mechanisms by which metastasis-promoting signals are induced specifically under hypoxia.
  The EMBO Journal 11/2010; 29(24):4106-17. · 9.20 Impact Factor