Oncotarget

Research Papers:

Glypican-3 induces oncogenicity by preventing IGF-1R degradation, a process that can be blocked by Grb10

Wei Cheng, Po-Chun Huang, Hsiao-Mei Chao, Yung-Ming Jeng, Hey-Chi Hsu, Hung-Wei Pan, Wuh-Liang Hwu and Yu-May Lee _

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Oncotarget. 2017; 8:80429-80442. https://doi.org/10.18632/oncotarget.19035

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Abstract

Wei Cheng1,2,3, Po-Chun Huang4,5, Hsiao-Mei Chao6, Yung-Ming Jeng7, Hey-Chi Hsu7, Hung-Wei Pan8, Wuh-Liang Hwu9 and Yu-May Lee4,5,9

1Department of Pathology, Kee-Lung Hospital, Ministry of Health and Welfare, Kee-Lung, Taiwan

2Ching Kuo Institute of Management and Health, Kee-Lung, Taiwan

3National Taipei University of Nursing and Health Sciences, Taipei, Taiwan

4Institute of Biochemical Sciences, National Taiwan University, Taipei, Taiwan

5Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan

6Department of Pathology, Wang Fang Hospital, Taipei Medical University, Taipei, Taiwan

7Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei, Taiwan

8Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan

9Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan

Correspondence to:

Yu-May Lee, email: YML6120@gate.sinica.edu.tw

Keywords: glypican-3, hepatocellular carcinoma, insulin-like growth factor 1 receptor, ubiquitination, growth factor receptor-bound protein 10

Received: February 17, 2017     Accepted: June 18, 2017     Published: July 06, 2017

ABSTRACT

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and is a major cause of cancer-related death worldwide. Previously, we demonstrated that glypican-3 (GPC3) is highly expressed in HCC, and that GPC3 induces oncogenicity and promotes the growth of cancer cells through IGF-1 receptor (IGF-1R). In the present study, we investigated the mechanisms of GPC3-mediated enhancement of IGF-1R signaling. We demonstrated that GPC3 decreased IGF-1-induced IGF-1R ubiquitination and degradation and increased c-Myc protein levels. GPC3 bound to Grb10, a mediator of ligand-induced receptor ubiquitination, and the overexpression of Grb10 blocked GPC3-enhanced IGF-1-induced ERK phosphorylation. GPC3 promoted the growth of NIH3T3 and PLC-PRF-5 cells in serum-free medium but did not promote the growth of IGF-1R negative R- cells. Grb10 overexpression decreased GPC3-promoted cell growth. Therefore, the present study elucidates the mechanisms of GPC3-induced oncogenicity, which may highlight new strategies for the treatment of HCC.


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