Upregulated lncRNA THRIL/TNF-α Signals Promote Cell Growth and Predict Poor Clinical Outcomes of Osteosarcoma

Onco Targets Ther. 2020 Jan 7;13:119-129. doi: 10.2147/OTT.S235798. eCollection 2020.


Background: The immunosuppressive facet and tumorigenic role of TNF-α have been revealed in osteosarcoma (OS). Long noncoding RNA THRIL is identified to regulate TNF-α expression and participates in immune response. Thus, investigations on the clinical expression pattern of THRIL/TNF-α signal in OS would provide a potential target premise for OS patients.

Methods: We collected OS (n=83), nontumor tissues (n=37) and serum samples (n=83 for OS and n=40 for healthy control) to determine the expressions and clinical significance of THRIL/TNF-α signal. Knockdown of THRIL in OS cell lines MG63 and Saos2 in vitro and in vivo was performed to confirm its function in the development of OS.

Results: Elevated expression of THRIL was associated with increased TNF-α levels in OS tissues and serum samples. Combination of THRIL and TNF-α in tissues showed a more efficient diagnostic value for OS patients than either of them. Moreover, high-expressed THRIL was associated with larger tumor size, advanced Enneking stage and lung metastasis, whereas high TNF-α expression was found in patients with high histologic grade and patients who simultaneously harbor high THRIL and TNF-α showed the worst overall survival and metastasis-free survival. TNF-α signals increased OS cell vitalities in vitro but knockdown of THRIL inhibited TNF-α expressions, leading to impaired cell vitality, increased apoptosis and also downregulated epithelial to mesenchymal transition (EMT) phenotype and the ability of invasion, but these processes were restored by the treatment of TNF-α. The oncogenic role of THRIL/TNF-α signal was also confirmed in the xenograft model of MG63 cells.

Conclusion: Overexpressed THRIL and TNF-α promoted OS progression with efficient diagnostic and prognostic value. THRIL/TNF-α signal supported cell growth and EMT phenotype of OS cells in vitro and in vivo.

Keywords: THRIL; TNF-α; growth; lncRNA; osteosarcoma.

Grant support

This work was supported by Key Discipline Construction Project of Pudong Health Bureau of Shanghai (Grant No. PWZxk2017-18 to TYY) and Discipline Construction Project of Pudong New Area Commission of Health and Family Planning (Grant No. PWYts2018-03 to TYY).