Metformin reverses bFGF-induced epithelial-mesenchymal transition in HCC cells

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.

Bleomycin induces epithelial-to-mesenchymal transition via bFGF/PI3K/ESRP1 signaling in pulmonary fibrosis

“…Notably, bFGF antisense oligonucleotide therapy shows that it can prevent the development of pulmonary fibrosis in animals [38], suggesting that bFGF stimulates lung fibrosis and it is a important target for lung fibrosis therapy. The downstream effectors of bFGF were phosphatidylinositol 3-kinase (PI3K), mitogen-activated kinases, protein kinase B (Akt) and glycogen synthase kinase 3β (AKT/GSK-3β), and PI3K/Akt and AKT/GSK-3β pathways were obviously activated in bFGF-induced EMT [16,39,40], and when PI3K/Akt was blocked, the effects of bFGF on EMT were weakened [41]. Thus, we speculated that the bFGF-PI3K/Akt signaling pathway also play an important role in BLM-induced EMT, which is classified as a non-Smad signaling pathway.…”

“…Moreover, bFGF acts as a potent mitogen that stimulates the proliferation, differentiation and migration of mesenchymal cells [14]. In addition, in both hepatocellular carcinoma (HCC) and prostate cancer cells, bFGF was shown to induce epithelial-mesenchymal transition through the AKT/GSK-3β/Snail signaling pathway [15,16]. Although it has been reported that bFGF can induce EMT, the definite process remains to be elucidated.…”

The Role of AMP-Activated Protein Kinase as a Potential Target of Treatment of Hepatocellular Carcinoma

“…Ferritti et al suggested that metformin suppress the migration and invasion of hepatocellular carcinoma cells dependent on AMPK activation [99]. This effect of metformin was related to its blockade on bFGF-induced Akt/GSK activation, and subsequent Twist1 stabilization [100]. Meanwhile, metformin repressed HCC metastasis through inhibiting tumor angiogenesis.…”

Metformin May Block the Way Breast Cancer Metastasis: A Meta-analysis and Mechanism Review

“…Metformin induced Snail ubiquitination after LKB1 phosphorylation, which helped Snail's interaction with E3 ligase FBXL14 [44]. Furthermore, metformin decreased Twist with obliterating interaction between GSK-3β and Twist via reducing Akt/GSK-3β pathway [45]. mTOR, of which inhibition under metformin therapy mediated suppression of HIF-1α/VEGF-A and p70s6k [46,47], was another downstream molecule of Akt.…”