TGF-β is associated with poor prognosis and promotes osteosarcoma progression via PI3K/Akt pathway activation

Abstract

ABSTRACT Transforming growth factor beta (TGF-β) is a multifunctional cytokine with important functions in cell proliferation and differentiation. TGF-β is highly expressed in several types of cancers and promotes tumor invasion and metastasis. However, the role of TGF-β in osteosarcoma progression is poorly understood. In the present study, we found that TGF-β is highly expressed in osteosarcoma cells and tissues, and is associated with high Ennecking stage (P = 0.033), metastasis, and recurrence. TGF-β-knockdown osteosarcoma cell lines were established using siRNA (si-TGF-β). Cells transfected with si-TGF-β exhibited significantly reduced proliferation, migration/invasion, and colony formation abilities, and increased levels of cell apoptosis. In addition, si-TGF-β treatment reduced spheroid size, the ratio of CD133-positive cells, and expression of SOX-2, Nanog, and Oct-3/4 in osteosarcoma cells. Mechanistically, PI3K/mTOR phosphorylation is inhibited by TGF-β knockdown. Pretreatment with 25 µM LY294002, a PI3K-specific inhibitor, further enhanced the si-TGF-β-induced suppression of osteosarcoma progression. Taken together, these results reveal a novel role for TGF-β in osteosarcoma progression and modulation of stemness-related traits and indicate that TGF-β may be of value as a therapeutic target for the treatment of osteosarcoma.