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Carcinogenesis Advance Access published online on January 3, 2008
Carcinogenesis, doi:10.1093/carcin/bgm263
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Down-regulation of HER2 by RIG1 Involves the PI3K/Akt Pathway in Ovarian Cancer Cells

Chien-Chih Ou1, Shih-Chung Hsu2, Yin-Hui Hsieh3, Wan-Ling Tzou3, Tzu-Chao Chuang4,5, Jah-Yao Liu6,* and Ming-Ching Kao3,7,*

1 Graduate Institute of Medical Sciences
3 Graduate Institute of Biochemistry, National Defense Medical Center, Taipei, Taiwan
2 The Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan
4 Department of Chemistry
5 Graduate Institute of Life Sciences, Tamkang University, Tamsui, Taipei, Taiwan
6 Department of Obstetrics & Gynecology, Tri-Service General Hospital, Taipei, Taiwan
7 Graduate Institute of Clinical Medical Science, China Medical University College of Medicine, Taichung, Taiwan

* Corresponding author: Dr. Ming-Ching Kao, Graduate Institute of Clinical Medical Science, China Medical University College of Medicine, No. 91 Hsueh-Shih Road, Taichung, Taiwan 40402, ROC, E-Mail: mckao{at}mail.cmu.edu.tw; or Dr. Jah-Yao Liu, Department of Obstetrics & Gynecology, Tri-Service General Hospital, No. 325, Sec. 2, Cherng-Kung Road, Neihu, Taipei, Taiwan 114, ROC.

Interferon-{gamma} (IFN-{gamma}) is known to down-regulate HER2 oncoprotein (p185HER2 or briefly p185) in prostate cancer cells. We demonstrate that the IFN-{gamma}-induced retinoid-inducible gene 1 (RIG1) acts as a transrepressor of p185. Furthermore, we exhibit that RIG1 down-regulates the activated (phosphorylated) form of p185 and PI3K/Akt and the mammalian target of rapamycin (mTOR), downstream substrates of HER2. We also elucidate that heregulin (HRG) specifically restores the activation of p185 and Akt after their activities are reduced by RIG1. Additionally, expression of vascular endothelial growth factor (VEGF) increases through the HER2 and Akt/mTOR signaling pathways, indicating that VEGF is down-regulated by RIG1 within the cell. These findings suggest that RIG1 plays a role in IFN-{gamma}-mediated therapy by down-regulating p185 and its downstream PI3K/Akt/mTOR/VEGF signaling pathway. These results may provide a new therapeutic mechanism for the clinical use of IFN-{gamma} and RIG1.

Received July 15, 2007; revised October 30, 2007; accepted November 10, 2007.


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