Oncotarget

Research Papers:

Targeting EMP3 suppresses proliferation and invasion of hepatocellular carcinoma cells through inactivation of PI3K/Akt pathway

Yi-Hsien Hsieh _, Shu-Ching Hsieh, Chien-Hsing Lee, Shun-Fa Yang, Chun-Wen Cheng, Meng-Ju Tang, Chia-Liang Lin, Chu-Liang Lin and Ruey-Hwang Chou

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Oncotarget. 2015; 6:34859-34874. https://doi.org/10.18632/oncotarget.5414

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Abstract

Yi-Hsien Hsieh1,2,*, Shu-Ching Hsieh3,*, Chien-Hsing Lee4,5, Shun-Fa Yang3, Chun-Wen Cheng6, Meng-Ju Tang6, Chia-Liang Lin6, Chu-Liang Lin6, Ruey-Hwang Chou7,8

1Department of Biochemistry, School of Medicine, Chung Shan Medical University, Taichung, Taiwan

2Clinical Laboratory, Chung Shan Medical University Hospital, Taichung, Taiwan

3Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan

4Graduate Institute of Medical Sciences, Chang Jung Christian University, Tainan, Taiwan

5Division of Pediatric Surgery, Department of Surgery, Children's Hospital of China Medical University, Taichung, Taiwan

6Institute of Biochemistry, Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan

7Graduate Institute of Cancer Biology and Center for Molecular Medicine, China Medical University, Taichung, Taiwan

8Department of Biotechnology, Asia University, Taichung, Taiwan

*These authors have contributed equally to this work

Correspondence to:

Ruey-Hwang Chou, e-mail: [email protected]

Keywords: epithelial membrane protein-3, proliferation, migration, invasion, hepatocellular carcinoma

Received: June 01, 2015     Accepted: September 30, 2015     Published: October 12, 2015

ABSTRACT

Epithelial membrane protein-3 (EMP3), a typical member of the epithelial membrane protein (EMP) family, is epigenetically silenced in some cancer types, and has been proposed to be a tumor suppressor gene. However, its effects on tumor suppression are controversial and its roles in development and malignancy of hepatocellular carcinoma (HCC) remain unclear. In the present study, we found that EMP3 was highly expressed in the tumorous tissues comparing to the matched normal tissues, and negatively correlated with differentiated degree of HCC patients. Knockdown of EMP3 significantly reduced cell proliferation, arrested cell cycle at G1 phase, and inhibited the motility and invasiveness in accordance with the decreased expression and activity of urokinase plasminogen activator (uPA) and matrix metalloproteinase 9 (MMP-9) in HCC cells. The in vivo tumor growth of HCC was effectively suppressed by knockdown of EMP3 in a xenograft mouse model. The EMP3 knockdown-reduced cell proliferation and invasion were attenuated by inhibition of phosphatidylinositol 3-kinase (PI3K) or knockdown of Akt, and rescued by overexpression of Akt in HCC cells. Clinical positive correlations of EMP3 with p85 regulatory subunit of PI3K, p-Akt, uPA, as well as MMP-9 were observed in the tissue sections from HCC patients. Here, we elucidated the tumor progressive effects of EMP3 through PI3K/Akt pathway and uPA/MMP-9 cascade in HCC cells. The findings provided a new insight into EMP3, which might be a potential molecular target for diagnosis and treatment of HCC.


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