Fibroblast activation protein- promotes the growth and migration of lung cancer cells via the PI3K and sonic hedgehog pathways

A characteristic of the epithelial-to-mesenchymal transition in cancer cells is the upregulation of mesenchymal markers. Fibroblast activation protein (FAP) is predominantly expressed by stromal fibroblasts. Previous studies have demonstrated that FAP is also expressed by certain epithelium-derived cancer cells and is involved in the regulation of certain signaling pathways. One of our previous studies showed that FAP promoted the proliferation of breast cancer cells via the phosphatidylinositol-3-kinase (PI3K) signaling pathway. In the present study, the A549 adenocarcinoma (AC) and SK-MES-1 squamous cell carcinoma (SCC) lung cancer cell lines were transfected with FAP. The FAP-expressing SK-MES-1 cells exhibited an increased growth rate, whereas the FAP-expressing A549 cells exhibited a similar growth rate, compared with respective empty vector-transfected control cells. Electric cell-substrate impedance sensing (ECIS)-based attachment and wound-healing assays showed that the overexpression of FAP markedly increased the adhesive and migratory properties of the SK-MES-1 cells but not those of the A549 cells. Additionally, inhibitors of focal adhesion kinase, agonist-induced phospholipase C, neural Wiskott-Aldrich syndrome protein, extracellular signal-regulated kinase, Rho-associated protein kinase, PI3K, and sonic hedgehog (SHH) were used to evaluate the interaction between FAP and signaling pathways. Only the inhibitors of SHH and PI3K inhibited the increased motility of the FAP-expressing SK-MES-1 cells. Western blot analysis confirmed the activation of PI3K/AKT and SHH/GLI family zinc finger 1 signaling in the FAP-expressing SK-MES-1 cells. These results revealed that FAP promoted the growth, adhesion and migration of lung SCC cells. In addition, FAP regulated lung cancer cell function, potentially via the PI3K and SHH pathways. Further investigations are required to examine the role of FAP in lung AC cells.