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Carcinogenesis Advance Access originally published online on January 3, 2008
Carcinogenesis 2008 29(2):299-306; 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

Downregulation of HER2 by RIG1 involves the PI3K/Akt pathway in ovarian cancer cells

Chien-Chih Ou, Shih-Chung Hsu1,7, Yin-Hui Hsieh2, Wan-Ling Tsou2, Tzu-Chao Chuang3,4, Jah-Yao Liu5,* and Ming-Ching Kao2,6,*

Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan 114, Republic of China
1 Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan 110, Republic of China
2 Graduate Institute of Biochemistry, National Defense Medical Center, Taipei, Taiwan 114, Republic of China
3 Department of Chemistry and
4 Graduate Institute of Life Sciences, Tamkang University, Tamsui, Taipei, Taiwan 25137, Republic of China
5 Department of Obstetrics & Gynecology, Tri-Service General Hospital, No. 325, Section 2, Cheng-Kung Road, Neihu, Taipei, Taiwan 114, Republic of China
6 Department of Biological Science and Technology, China Medical University College of Life Sciences, No. 91 Hsueh-Shih Road, Taichung, Taiwan 40402, Republic of China
7 Kang-Ning Junior College of Medical Care and Management, Taipei, Taiwan 114, Republic of China

* To whom correspondence should be addressed. Tel: +886 4 22053366 ext. 2206; Fax: +886 4 22070465;Email: mckao{at}mail.cmu.edu.tw Correspondence may also be address to Jah-Yao Liu. Tel: +886 287923100 ext. 12828; Fax: +886 2 27931272;Email: jyliu{at}mail.ndmctsgh.edu.tw

Interferon-{gamma} (IFN-{gamma}) is known to downregulate 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 downregulates the activated (phosphorylated) form of p185 and phosphoinositide-3 kinase (PI3K)/serine/threonine-specific protein kinase (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 downregulated by RIG1 within the cell. These findings suggest that RIG1 plays a role in IFN-{gamma}-mediated therapy by downregulating 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.

Abbreviations: AKT, serine/threonine-specific protein kinase; FACS, fluorescence-activated cell sorter; β-gal, β-galactosidase; HRG, heregulin; IFN-{gamma}, interferon-{gamma}; IRF-1, interferon regulatory factor-1; MAPK, mitogen-activated protein kinase; mRNA, messenger RNA; mTOR, mammalian target of rapamycin; PCR, polymerase chain reaction; PI3K, phosphatidylinositol-3 kinase; RIG1, retinoid-inducible gene 1; siRNA, small interference RNA; STAT1, signal transducers and activators of transcription 1; VEGF, vascular endothelial growth factor

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


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