Milk fat globule-EGF factor 8 (MFG-E8) is an anti-inflammatory glycoprotein that mediates a wide spectrum of pathophysiological processes. MFG-E8 has been studied as a key regulator of cancer cell invasion, migration, and proliferation in different tissues and organs. However, potential roles of MFG-E8 in the growth and progression of liver cancer have not been investigated to date. Here, we analyzed 33 human hepatocellular carcinoma (HCC) samples and found that levels of MFG-E8 expression were significantly higher in HCC cells than in normal liver tissues. In addition, our in vitro gain-of-function study in three different HCC cell lines revealed that overexpression of MFG-E8 promoted the proliferation and migration of HCC cells, as determined by RT-qPCR, MTT assays, and wound healing analyses. Conversely, an MFG-E8 loss-of function study showed that proliferation capacity was significantly reduced by MFG-E8 knockdown in HCC cells. Additionally, MFG-E8 activity-neutralizing antibodies profoundly inhibited both migration and proliferation of HCC cells, attenuating their tumorigenic properties. These reductions in migration and proliferation were rescued by treatment of HCC cells with recombinant MFG-E8 protein. Furthermore, an in vivo HCC xenograft study showed that the number of proliferating HCC cells and tumor volume/weight were all significantly increased by MFG-E8 overexpression, compared to control mice. These results clearly show that MFG-E8 plays an important role in HCC progression and may provide a basis for future mechanistic studies and new strategies for the treatment of liver cancer.
Bibliographical noteFunding Information:
This research was supported by the Bio & Medical Technology Development Program of the National Research Foundation funded by the Korean government (Ministry of Science & ICT) (No.2017M3A9B4042581) and the 2018 Announcement of Bio-Industry Core Technology Development Business granted by the Korea Evaluation Institute of industrial Technology (No. 10081266). Acknowledgments: The authors would like to thank the Biobank of Ajou University Hospital and Korea University Guro Hospital, members of Korea Biobank Network [IRB No. # 1040548-KU-IRB-17-166-A-1(E-A-1)] for providing biological specimens used in this study. We also thank the staffs of Gyerim Experimental Animal Resource Center for animal care and technical assistance.
Funding: This research was supported by the Bio & Medical Technology Development Program of the National Research Foundation funded by the Korean government (Ministry of Science & ICT) (No.2017M3A9B4042581) and the 2018 Announcement of Bio-Industry Core Technology Development Business granted by the Korea Evaluation Institute of industrial Technology (No. 10081266).
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- Hepatocellular carcinoma
- Milk fat globule-EGF factor 8
ASJC Scopus subject areas
- Cancer Research