Abstract
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.
Highlights
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the third-most common cause of cancer mortality [1]
The expression levels of Milk fat globule-EGF factor 8 (MFG-E8) and α-fetoprotein (AFP), a marker of hepatocellular carcinoma (HCC), were both significantly increased in HCC tissues (Figure 1B,C) and the immunofluorescence signals were overlapped in areas of high malignancy (Figure 1B: HCC high)
Prominent MEG-E8 signals were seen in metastatic HCC tissues, but low signals of AFP were detected in these areas (Figure 1B: Meta HCC)
Summary
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the third-most common cause of cancer mortality [1]. Cancers 2020, 12, 403 underlying HCC tumorigenesis and identifying novel therapeutic targets are both of great significance in improving the overall prognosis of patients with HCC. Milk fat globule-EGF factor 8 (MFG-E8) is a glycoprotein initially identified as a component of milk fat globules secreted from mammary epithelial cells [3]. N-terminal EGF-like domain which contains an integrin-binding RGD motif, and two repeated. C-terminal discoidin/F5/8C domains that bind phosphatidylserine [3]. Because phosphatidylserine is exposed on the surfaces of apoptotic cells, MFG-E8 has been studied as an opsonin that mediates clearance of dying cells via integrin-expressing phagocytes [4,5]. We showed that MFG-E8 is secreted from human umbilical cord mesenchymal stem cells and strongly inhibits the activation of hepatic stellate cells, reducing liver fibrosis both in vitro and in vivo [8]
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