Growth Differentiation Factor 15 Promotes Progression of Esophageal Squamous Cell Carcinoma via TGF-β Type II Receptor Activation

OBJECTIVES: Growth differentiation factor 15 (GDF15), which is derived from tumor-associated macrophages (TAM) and cancer cells, promotes progression of esophageal squamous cell carcinomas (ESCC). However, its role in the ESCC microenvironment remains unclear. Here, we examined the effects of GDF15 on ESCC cell lines and tissues. METHODS: Western blotting, MTS, and Transwell migration/invasion assays were used to evaluate cell signaling, proliferation, and migration/invasion, respectively, in ESCC cell lines treated with recombinant human GDF15 (rhGDF15). ESCC cell lines were administered a TGF-betaRI/II inhibitor (LY2109761), small interfering RNA against TGF-beta type II receptor (TGF-betaRII), or neutralizing antibody against TGF-betaRII to study the role of TGF-betaRII in mediating the effects of rhGDF15. The localization of GDF15 and TGF-betaRII in ESCC cell lines was observed by immunofluorescence. TGF-betaRII expression in ESCC tissues was analyzed by immunohistochemistry, and the relationship between clinicopathological factors and prognosis in ESCC patients was evaluated. RESULTS: rhGDF15 increased levels of phosphorylated Akt, Erk1/2, and TGF-betaRII in ESCC cell lines. Inhibition/knockdown of TGF-betaRII suppressed rhGDF15-induced activation of Akt and Erk1/2 and enhancement of cellular proliferation, migration, and invasion. Immunofluorescence revealed that TGF-betaRII and GDF15 were colocalized in ESCC cell lines. High TGF-betaRII expression in ESCC tissues, as determined by immunohistochemistry, correlated with depth of invasion and increased number of infiltrating TAMs. ESCC patients with high TGF-betaRII expression showed a tendency toward poor prognosis. CONCLUSIONS: GDF15 promotes ESCC progression by increasing cellular proliferation, migration, and invasion via TGF-betaRII signaling.