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Title: HER-2/neu raises SHP-2, stops IFN-{gamma} anti-proliferation in bladder cancer

Abstract

Gene amplification or HER-2/neu protein overexpression signals a poor outcome for bladder cancer patients. We investigated the anti-proliferative effect of IFN-{gamma} in HER-2/neu-transfected human bladder cancer cells (TCC-N5 and TCC-N10). The cells continued growing after IFN-{gamma} stimulation but did not activate the Janus kinase (Jak)/Stat pathway. We found Jak/Stat protein phosphatase in TCC-N5 and TCC-N10 cells with upregulated Src homology 2-containing protein tyrosine phosphatase-2 (SHP-2). After the cells had been treated with AG825, a HER-2/neu-specific inhibitor, SHP-2 expression declined, and Jak2/Stat1 reactivated. Similar results were reported in a mouse bladder cancer cell line, MBT2, with constitutive HER-2/neu overexpression. Further, AG825 pretreatment restored the anti-proliferation activity of IFN-{gamma} in TCC-N5 and TCC-N10 cells. Therefore, the suppression of IFN-{gamma} signaling in HER-2/neu-overexpressing bladder cancer cells might be due to SHP-2 upregulation. The regulation of SHP-2 by HER-2/neu provides a new target for blocking the HER-2/neu oncogenic pathwa000.

Authors:
 [1];  [2];  [1];  [3];  [1];  [4];  [1];  [5]
  1. Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan 704, Taiwan (China)
  2. (China)
  3. Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan (China)
  4. Department of Dentistry, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan (China)
  5. Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan 704, Taiwan (China) and Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan (China) and Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan (China). E-mail: sunnysu@mail.ncku.edu.tw
Publication Date:
OSTI Identifier:
20991315
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 356; Journal Issue: 1; Other Information: DOI: 10.1016/j.bbrc.2007.02.099; PII: S0006-291X(07)00409-3; Copyright (c) 2007 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; BLADDER; CELL PROLIFERATION; GENE AMPLIFICATION; GENE REGULATION; GROWTH; INHIBITION; MICE; NEOPLASMS; PATIENTS; PROTEINS; TYROSINE

Citation Formats

Su, W.-P., Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Tu, I-H., Hu, S.-W., Yeh, H.-H., Shieh, D.-B., Chen, T.-Y., and Su, W.-C. HER-2/neu raises SHP-2, stops IFN-{gamma} anti-proliferation in bladder cancer. United States: N. p., 2007. Web. doi:10.1016/j.bbrc.2007.02.099.
Su, W.-P., Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Tu, I-H., Hu, S.-W., Yeh, H.-H., Shieh, D.-B., Chen, T.-Y., & Su, W.-C. HER-2/neu raises SHP-2, stops IFN-{gamma} anti-proliferation in bladder cancer. United States. doi:10.1016/j.bbrc.2007.02.099.
Su, W.-P., Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Tu, I-H., Hu, S.-W., Yeh, H.-H., Shieh, D.-B., Chen, T.-Y., and Su, W.-C. Fri . "HER-2/neu raises SHP-2, stops IFN-{gamma} anti-proliferation in bladder cancer". United States. doi:10.1016/j.bbrc.2007.02.099.
@article{osti_20991315,
title = {HER-2/neu raises SHP-2, stops IFN-{gamma} anti-proliferation in bladder cancer},
author = {Su, W.-P. and Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan and Tu, I-H. and Hu, S.-W. and Yeh, H.-H. and Shieh, D.-B. and Chen, T.-Y. and Su, W.-C.},
abstractNote = {Gene amplification or HER-2/neu protein overexpression signals a poor outcome for bladder cancer patients. We investigated the anti-proliferative effect of IFN-{gamma} in HER-2/neu-transfected human bladder cancer cells (TCC-N5 and TCC-N10). The cells continued growing after IFN-{gamma} stimulation but did not activate the Janus kinase (Jak)/Stat pathway. We found Jak/Stat protein phosphatase in TCC-N5 and TCC-N10 cells with upregulated Src homology 2-containing protein tyrosine phosphatase-2 (SHP-2). After the cells had been treated with AG825, a HER-2/neu-specific inhibitor, SHP-2 expression declined, and Jak2/Stat1 reactivated. Similar results were reported in a mouse bladder cancer cell line, MBT2, with constitutive HER-2/neu overexpression. Further, AG825 pretreatment restored the anti-proliferation activity of IFN-{gamma} in TCC-N5 and TCC-N10 cells. Therefore, the suppression of IFN-{gamma} signaling in HER-2/neu-overexpressing bladder cancer cells might be due to SHP-2 upregulation. The regulation of SHP-2 by HER-2/neu provides a new target for blocking the HER-2/neu oncogenic pathwa000.},
doi = {10.1016/j.bbrc.2007.02.099},
journal = {Biochemical and Biophysical Research Communications},
number = 1,
volume = 356,
place = {United States},
year = {Fri Apr 27 00:00:00 EDT 2007},
month = {Fri Apr 27 00:00:00 EDT 2007}
}
  • We examined 4{mu}m paraffin-embedded tissue sections from twenty female breast tumors for the presence of HER-2/neu (ERBB2) gene amplification. The study population consisted of ten BRCA1 carriers and ten non-BRCA1 carriers. Carrier status was assessed through linkage analysis. Detection of HER-2/neu gene amplification was performed blinded with respect to BRCA1 status. Forty cells representing at least two different areas of each tumor were analyzed by fluorescence in situ hybridization (FISH) using a HER-2/neu cosmid probe. We did not find any cases which showed the typical HER-2/neu gene amplification profile (homogeneous distribution of cells with > 4 signals per cell). Inmore » half of the cases, small foci that appeared amplified were identified as clusters of cells with > 4 signals. Modifying our analysis to compensate for this, cases were considered to be amplified if nine or more cells out of forty contained over four HER-2/neu signals. For the 10 BRCA1 carrier positive samples, 5 were HER-2/neu amplified and 5 were not. Similarly, of the 10 BRCA1 carrier negative samples, 5 were HER-2/neu amplified and 5 were not. Therefore, we found no statistical correlation between BRCA1 carrier status and amplification of the HER-2/neu gene in the tumors studied.« less
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