Abstract
Metformin had exerted important inhibitory effects in multiple cancers. However, the correlation between metformin and hepatocellular carcinoma (HCC) metastasis, and the relevant mechanisms are still unclear. By quantitative proteomics analysis technique, we found metformin could suppress FGF signalling significantly. In FGF signalling basic fibroblast growth factor (bFGF) is a crucial member, it initially binds to its receptors, the complex of bFGF and receptors activate FGF signallings, and promote many cancers progressions. When treating HCC cell lines HepG2 and Huh7 with bFGF, we observed the cells exhibited epithelial mesenchymal transition (EMT) and these cells metastasis potential was enhanced dramaticlly. However, when treating with metformin and bFGF together, EMT and metastasis induced by bFGF could be inhibited in these cells. Furthermore, bFGF could activate AKT/GSK-3β signalling, sequentially decrease the interaction between GSK-3β and Twist1 and decrease ubiquitination of Twist1 leading to Twist1 degradation reducing. While metformin could repress the bFGF-mediated activation in AKT/GSK-3β signalling, inhibition on interaction between GSK-3β and Twist1, enhancement of Twist1 stability. Taken together, our findings suggested that metformin had prominent negative effects on bFGF-induced EMT and metastasis in HCC cells.
Highlights
Liver cancer has been the second leading cause of cancer-related mortality for a long time throughout the world, and approximately 50% of the total number of new cases and deaths is from China [1]
The Ingenuity Pathway Analysis (IPA) tool was further adopted for grouping the proteins into networks and canonical pathways to determine the pathways influenced by metformin in Hepatocellular carcinoma (HCC)
As epithelial mesenchymal transition (EMT) plays an important role in metastasis, we wondered whether metformin could suppress the fibroblast growth factors (FGFs) signalling pathway stimulated by basic fibroblast growth factor (bFGF) in HCC EMT
Summary
Liver cancer has been the second leading cause of cancer-related mortality for a long time throughout the world, and approximately 50% of the total number of new cases and deaths is from China [1]. The incidence and mortality of liver cancer have decreased in China, it is still the leading cause of death and the most common cancer in men younger than 60 years of age [2]. Despite many emerging therapies, such as transarterial chemoembolization, radioembolization, radiofrequency ablation and molecular targeted therapy, surgical excision is still the main therapeutic strategy in HCC, but the rate of recurrence after surgical resection of HCC is approximately 50-70%. One of the main reasons for this is the high rate of intrahepatic and/or extrahepatic metastasis [4]. Developing new techniques or medicines to prevent metastasis will clearly benefit the treatment of HCC
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