Chang Gung Memorial Hospital at

Chiayi, Taiwan

Chang Gung Memorial Hospital at

Chiayi, Taiwan
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Wang S.-S.,Chang Gung University | Wang S.-S.,Chang Gung Memorial Hospital at | Chen L.-W.,Chang Gung Institute of Technology | Chen L.-Y.,Chang Gung University | And 5 more authors.
Virology | Year: 2010

The ORF61 and ORF60 genes of Kaposi's sarcoma-associated herpesvirus (KSHV) encode the ribonucleotide reductase large and small subunits, respectively. Here we show that ORF50 protein, a latent-lytic switch transactivator, activates the transcription of these two early-lytic genes through different mechanisms. Activation of the ORF61 promoter by ORF50 protein is dependent on an intact RBP-Jκ-binding site within the identified responsive element and the expression of RBP-Jκ protein in cells. The critical element in the ORF60 promoter in response to ORF50 was mapped to a 40-bp region. Binding of YY1, Sp1/Sp3 or unknown proteins to this element may contribute to repression or activation of the ORF60 promoter. Although ORF50 protein does not directly bind to the ORF61 and ORF60 promoters in vitro, we show the association of ORF50 protein with these two promoters in vivo. Our results provide further insights into the regulatory network of the viral lytic genes in KSHV reactivation. © 2009 Elsevier Inc. All rights reserved.


Chen C.-C.,Chang Gung Memorial Hospital at | Chen C.-C.,Chang Gung Institute of Technology | Chen W.-C.,Chang Gung Memorial Hospital at | Chen W.-C.,Chang Gung Institute of Technology | And 9 more authors.
International Journal of Radiation Oncology Biology Physics | Year: 2010

Purpose: Tumor eradication by chemoradiotherapy for pharyngeal cancer has not been particularly successful. Targeting epithelial growth factor receptor (EGFR) could be a potential treatment strategy providing additional benefits, but only a subset of these tumors gives a clinically significant response to EGFR inhibitors. The aim has been to identify the role of interleukin-6 (IL-6) signaling and its predictive power in the treatment response of pharyngeal cancer. Methods and Materials: Human pharyngeal cancer cell lines, including the hypopharyngeal cancer cell line FaDu and its derived cell line FaDu-C225-R, were selected. Changes in tumor growth, response to treatment, and responsible signaling pathway were investigated in vitro. Furthermore, 95 pharyngeal cancer tissue specimens were analyzed by immunohistochemical staining, and correlations were made between levels of IL-6, IL-6 receptor (IL-6R), p-AKT, and p-STAT3 expression and the clinical outcome of patients. Results: In vitro, either extrinsic IL-6 stimulation of cancer cells or intrinsically activated IL-6 signaling detected in FADu-C225-R cells results in resistance to irradiation and EGFR inhibitor. Blocking IL-6 signaling attenuated aggressive tumor behavior and sensitized the cells to treatments. The responsible mechanisms included decreased p-STAT3, less nuclear translocation of EGFR, and subsequently attenuated epithelial-mesenchymal transition. Regarding clinical data, staining of p-STAT3 and IL-6 was significantly linked with lower response rates to treatments and shorter survival in pharyngeal cancer patients. Conclusions: IL-6 and p-STAT3 may be significant predictors of pharyngeal carcinoma, and regulating IL-6 signaling can be considered a promising therapeutic approach. © 2010 Elsevier Inc. All rights reserved.

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