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

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.

• Authors: Yi-Hsien Hsieh, Shu-Ching Hsieh, Chien-Hsing Lee, Shun-Fa Yang, Chun-Wen Cheng, Meng-Ju Tang, Chia-Liang Lin, Chu-Liang Lin, Ruey-Hwang Chou
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 33 Pg. 34859-74 (Oct 27 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26472188 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• EMP3 protein, human
• Membrane Glycoproteins
• Phosphatidylinositol 3-Kinase
• Proto-Oncogene Proteins c-akt

Topics

• Aged
• Animals
• Blotting, Western
• Carcinoma, Hepatocellular (metabolism, pathology)
• Cell Proliferation (physiology)
• Female
• Flow Cytometry
• Fluorescent Antibody Technique
• Gene Knockdown Techniques
• Heterografts
• Humans
• Immunoprecipitation
• Liver Neoplasms (metabolism, pathology)
• Male
• Membrane Glycoproteins (metabolism)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Middle Aged
• Neoplasm Invasiveness (pathology)
• Phosphatidylinositol 3-Kinase (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Signal Transduction (drug effects)
• Tissue Array Analysis