Chronic TGFβ stimulation promotes the metastatic potential of lung cancer cells by Snail protein stabilization through integrin β3-Akt-GSK3β signaling

Abstract

Chronic exposure to TGFβ, a frequent occurrence for tumor cells in the tumor microenvironment, confers more aggressive phenotypes on cancer cells by promoting their invasion and migration while at the same time increasing their resistance to the growth-inhibitory effect of TGFβ. In this study, a transdifferentiated (TD) A549 cell model, established by chronically exposing A549 cells to TGFβ, showed highly invasive phenotypes in conjunction with attenuation of Smad-dependent signaling. We show that Snail protein, the mRNA expression of which strongly correlates with a poor prognosis in lung cancer patients, was highly stable in TD cells after TGFβ stimulation. The increased protein stability of Snail in TD cells correlated with elevated inhibitory phosphorylation of GSK3β, resulting from the high Akt activity. Notably, integrin β3, whose expression was markedly increased upon sustained exposure to TGFβ, was responsible for the high Akt activity as well as the increased Snail protein stability in TD cells. Consistently, clinical database analysis on lung cancer patients revealed a negative correlation between overall survival and integrin β3 mRNA levels. Therefore, we suggest that the integrin β3-Akt-GSK3β signaling axis plays an important role in non-canonical TGFβ signaling, determining the invasive properties of tumor cells chronically exposed to TGFβ.

Prognostic value of high-expression of miR-17-92 cluster in various tumors: evidence from a meta-analysis

“…It was previously reported that miR-18-mediated low-expression of target gene TGF-β intimately contributed to prolonged survival of glioblastoma multiforme (GBM) patients 55 . Similarly, miR-19 could exhibit modulatory effect on GSK-3β/β-catenin axis, down-regulated target gene GSK-3β could promote the metastatic potential of lung cancer cells, revealing a poor survival outcome for cancer patients 56 , 57 . Besides, miR-20a was able to suppress the hepatocellular cancer cell proliferation and migration by directly targeted RUNX3, while clinical evidences have proved that RUNX3 was negatively associated with tumor progression, lymph node metastasis and poor prognosis 58 , 59 .…”

Crosstalk between cancer and immune cells: Role of tumor‐associated macrophages in the tumor microenvironment

“…As previously reported, TGF-β promotes breast cancer cells motility and metastasis by upregulating the gene expression of integrins. 128,129 Another example is in hepatoma carcinoma environment, TGF-β enhanced cell migration and invasion by increasing the gene expression of chemokine receptors. 130 In conclusion, the promotion of TGF-β signaling on tumor development lies largely on the increased angiogenesis, decreased immune performance and more regular extra-cellular architecture.…”

Precancerous niche (PCN), a product of fibrosis with remodeling by incessant chronic inflammation

“…The inhibition of heat-shock protein 27 (HSP27), highly expressed in fibrotic foci of idiopathic pulmonary fibrosis (IPF), results in Snail degradation followed by inhibition of TGF-b1 induced cell transition [75]. TGF-b1 stabilizes Snail and is associated with increased integrin b3 with consequent high Akt activity and elevated inhibitory phosphorylation of GSK-3b [76,77].…”