MFG-E8 overexpression promotes colorectal cancer progression via AKT/MMPs signalling

Abstract

Several studies have revealed that MFG-E8 (milk fat globule-epidermal growth factor 8) is related to tumour development and progression. However, the relationship between MFG-E8 expression and metastasis in colorectal cancer patients and the role of MFG-E8 in colorectal cancer invasion and progression remain unknown. In this study, we performed immunohistochemistry and quantitative real-time polymerase chain reaction to assess MFG-E8 expression in colorectal cancer and adjacent non-cancerous tissues. Colorectal cancer RNAseq data from The Cancer Genome Atlas project were downloaded and MFG-E8 expression was analysed. Gene set enrichment analysis was performed for gene ontology and pathway analysis associated with MFG-E8 expression. For in vitro studies, we used lentivirus-mediated MFG-E8 RNA interference and commercialized recombinant human MFG-E8 to investigate its role in colorectal cancer cell growth, migration and invasion. It seems that MFG-E8 was overexpressed in advanced colorectal cancer tissues compared with early-stage colorectal cancer tissues and adjacent non-cancerous tissues. Correlation analysis revealed that MFG-E8 expression was significantly related to plasma membrane invasion, lymph node metastasis, distant metastasis and tumour-node-metastasis stage. Survival analysis revealed that high MFG-E8 expression predicted a poorer prognosis than low MFG-E8 expression group both in our colorectal cancer cohort and The Cancer Genome Atlas colorectal cancer cohort. In vitro study suggested that MFG-E8 knockdown can suppress the growth of colorectal cancer cells without affecting the expression of the proliferation-related gene Ki67. MFG-E8 knockdown also suppressed colorectal cancer cell migration and invasion, a change accompanied by MMP-2 and MMP-9 downregulation. Moreover, MFG-E8 knockdown induced a shift from mesenchymal makers to epithelial makers, while pretreatment with rhMFG-E8 had the opposite effect. The effect of MFG-E8 on colorectal cancer cell migration, invasion and epithelial-to-mesenchymal was partially dependent on the PI3K/AKT signalling pathway. These findings provide a better understanding of the molecular mechanism underlying colorectal cancer progression and suggest a predictive role for MFG-E8 in colorectal cancer metastasis and prognosis.

Immunoregulatory influence of abundant MFG‐E8 expression by esophageal cancer treated with chemotherapy

“…Our study also showed that the RFS and OS of the high MFG‐E8 expression group were significantly worse than those of the low‐expression group. These findings are consistent with the previous reports …”

“…We examined MFG‐E8 expression in human esophageal squamous cell carcinoma using IHC staining and found that some of the cells abundantly express MFG‐E8, as shown in other types of cancer . As the IHC staining of the samples showed that the expression of MFG‐E8 was more abundant in cancer cells than in macrophages or other stromal cells, MFG‐E8 from cancer cells appears to play an important role in the tumor microenvironment.…”

“…Such expression has been found to be associated with tumor proliferation, epithelial‐mesenchymal transition, cell migration, M2 macrophage polarization, and the induction of Tregs . However, there are limited reports that clarified its prognostic impact on cancer patients . Furthermore, although MFG‐E8 is predicted to affect the balance of the expression of tumor‐infiltrating lymphocytes such as CD8 + T cells and Tregs, this relationship and its influence on survival are yet to be revealed.…”

“…[15][16][17][18][19] However, there are limited reports that clarified its prognostic impact on cancer patients. 16,20 Furthermore, although MFG-E8 is predicted to affect the balance of the expression of tumor-infiltrating lymphocytes such as CD8 + T cells and Tregs, 14 Table 1). The precise regimen is described elsewhere.…”

Thymol inhibits cell migration and invasion by downregulating the activation of PI3K/AKT and ERK pathways in human colon cancer cells

“…Invasion and migration have been acknowledged as the most lethal attributes of solid tumors and account for the majority of metastases [17]. Tumor cells have the ability to migrate from the original site to the blood and lymph, and invade surrounding or distant tissues, causing metastasis.…”