Transforming growth factor-beta signals promote progression of squamous cell carcinoma by inducing epithelial-mesenchymal transition and angiogenesis

The molecular mechanisms driving the progression and metastasis of oral squamous cell carcinoma (OSCC) remain largely uncharacterized. Transforming growth factor-beta (TGF-beta) is a key player in tumor progression drawing attention for its important roles in migration, and invasion. Activation of TGF-beta signaling in tumor microenvironment has been observed in various cancer types, however its specific roles in the context of oral cancer progression remain unexplored. In this study, we examined the effect of TGF-beta and SB431542, an inhibitor of TGF-beta type I receptor kinase, on the murine squamous cell carcinoma cells. Incubation of SCCVII squamous cell carcinoma cells with TGF-beta induced the activation of the TGF-beta signaling pathway, as revealed by the upregulated expression of PAI-1 and TMEPAI, and induced epithelial-mesenchymal transition (EMT). Notably, the motility of SCCVII cells was increased upon activation of the TGF-beta signaling pathway. RNA sequencing analyses revealed upregulation of genes related to induction not only of EMT but also of angiogenesis. In consistent with these in vitro results, inhibition of TGF-beta signaling in SCCVII cell-derived primary tumors resulted in suppressed angiogenesis. Furthermore, we have identified 6 candidate factors (ANKRD1, CCBE1, FSTL3, uPA, thrombospondin-1 and integrin beta3), whose expressions are induced by TGF-beta signaling in SCCVII cells, and associated with poor prognosis for patients with head and neck cancer. Present findings highlight the roles of TGF-beta signals in the progression of OSCC via multiple mechanisms including EMT and angiogenesis, and suggest novel therapeutic approach targeting identified TGF-beta targets.