Upregulation and biological function of transmembrane protein 119 in osteosarcoma

Abstract

Osteosarcoma is suggested to be caused by genetic and molecular alterations that disrupt osteoblast differentiation. Recent studies have reported that transmembrane protein 119 (TMEM119) contributes to osteoblast differentiation and bone development. However, the level of TMEM119 expression and its roles in osteosarcoma have not yet been elucidated. In the present study, TMEM119 mRNA and protein expression was found to be up-regulated in osteosarcoma compared with normal bone cyst tissues. The level of TMEM119 protein expression was strongly associated with tumor size, clinical stage, distant metastasis and overall survival time. Moreover, gene set enrichment analysis (GSEA) of the Gene Expression Omnibus (GEO) GSE42352 dataset revealed TMEM119 expression in osteosarcoma tissues to be positively correlated with cell cycle, apoptosis, metastasis and TGF-β signaling. We then knocked down TMEM119 expression in U2OS and MG63 cells using small interfering RNA, which revealed that downregulation of TMEM119 could inhibit the proliferation of osteosarcoma cells by inducing cell cycle arrest in G0/G1 phase and apoptosis. We also found that TMEM119 knockdown significantly inhibited cell migration and invasion, and decreased the expression of TGF-β pathway-related factors (BMP2, BMP7 and TGF-β). TGF-β application rescued the inhibitory effects of TMEM119 knockdown on osteosarcoma cell migration and invasion. Further in vitro experiments with a TGF-β inhibitor (SB431542) or BMP inhibitor (dorsomorphin) suggested that TMEM119 significantly promotes cell migration and invasion, partly through TGF-β/BMP signaling. In conclusion, our data support the notion that TMEM119 contributes to the proliferation, migration and invasion of osteosarcoma cells, and functions as an oncogene in osteosarcoma. Increased expression of the transmembrane protein 119 (TMEM119) gene is associated with osteosarcoma, the most common type of bone cancer. TMEM119 has a well-established role in bone development. Zhi-Jun Ge at the Affiliated Yixing Hospital of Jiangsu University, China, and colleagues have now shown that TMEM119 can also drive the formation of bone tumors. Not only did human osteosarcoma tissue contain higher levels of TMEM119 protein than control bone tissue, but the levels of TMEM119 correlated with tumor size, metastasis and patient survival. Blocking the expression of the TMEM119 gene in bone cancer cell lines led to a reduction in cell proliferation and migration, and suppressed the formation of tumors in a mouse model of the disease. Together, these findings highlight TMEM119 as a prognostic factor and as a potential target for gene therapy in osteosarcoma.