Identification and validation of miR-509-5p as a prognosticator for favorable survival in osteosarcoma.

Osteosarcoma (OS) is the most common primary bone cancer diagnosed in children. This study aims to explore the aberrantly expressed miRNAs that are prognostically related and to provide potential biomarkers for the prognosis prediction of OS. The miRNA profiles of OS and adjacent normal controls were obtained from 2 gene expression omnibus cohorts (i.e., GSE28423 and GSE65071). GSE39058 and Therapeutically Applicable Research to Generate Effective Treatments cohorts, which respectively contained 91 and 85 OS samples with both miRNA expression and clinical characteristics, were employed to perform survival and multivariate Cox regression analyses. Lymphocyte infiltration abundance between distinct subgroups was evaluated with the CIBERSORT algorithm and a previously proposed method. Gene set enrichment analysis was used to infer the dysregulated signaling pathways within each subgroup. Of the 31 differentially expressed miRNAs, miR-509-5p (miR-509) was the most significantly prognostic miRNA in the GSE39058 cohort and its high expression was associated with the better OS prognosis (Log-rank P = .008). In the Therapeutically Applicable Research to Generate Effective Treatments validation cohort, the association of high miR-509 expression with favorable survival was also observed (Log-rank P = .014). The results remained still significant even adjusted for clinical confounding factors in multivariate Cox regression models. Further immunology analyses demonstrated that elevated infiltration of lymphocytes, decreased infiltration of immune-suppressive cells, and immune response-related pathways were significantly enriched in patients with miR-509 high expression. Our study suggests that miR-509 may serve as a potential biomarker for evaluating OS prognosis and provides clues for tailoring OS immunotherapy strategies.

Tribbles Pseudokinase 2 Promotes the Proliferation, Migration, and Invasion of Osteosarcoma through Modulating AP4/p21 Pathway.

OBJECTIVE: At present, the efficacy of the clinical treatment of osteosarcoma is limited. We aimed to investigate the role of Tribbles pseudokinase 2 (TRIB2) in the progression of osteosarcoma and the underlying molecular mechanism. MATERIALS AND METHODS: TRIB2 expression in osteosarcoma tissues and cells was measured via western blot analysis and quantitative reverse transcription polymerase chain reaction. Mouse xenograft tumor model was established to investigate the in vivo effect of Tribbles pseudokinase 2 on the development of osteosarcoma. RESULTS: We found that TRIB2 expression was increased in osteosarcoma tissues and cell lines compared with that in tumor adjacent normal tissues and normal bone cell line. Suppressing TRIB2 expression inhibited the proliferation, migration, and invasion of osteosarcoma cells. Mechanistically, TRIB2 interacted with AP4, thereby inhibiting p21 expression at transcriptional level. In a mouse xenograft tumor model, TRIB2 overexpression promoted the growth of osteosarcoma by inhibiting p21 expression, which was reversed by AP4 silence. CONCLUSION: Therefore, targeting TRIB2 may become a potential approach for osteosarcoma treatment.

miR-509-5p Inhibits the Proliferation and Invasion of Osteosarcoma by Targeting TRIB2.

Osteosarcoma (OS) is one of the most common malignant bone tumors in adolescents with a poor prognosis. Though miR-509-5p has been reported as a tumor suppressor in several human cancers, the role of miR-509-5p in OS remains unclear. In this study, our result of real-time PCR (RT-PCR) showed that the expression of miR-509-5p was significantly decreased in OS tissues and cell lines. Overexpression of miR-509-5p significantly suppressed cell proliferation and invasion in OS cell lines. Moreover, we identified tribbles homolog 2 (TRIB2) as the direct target of miR-509-5p. Knockdown of TRIB2 could inhibit the malignant capacity of OS cells. At last, we reported that TRIB2 could inhibit the bioactivity of the tumor suppressor gene p21 via blocking its transcriptional activity. Collectively, our study revealed that miR-509-5p functions as a tumor suppressor by targeting TRIB2 in OS and thus could affect the activity of p21, suggesting that miR-509-5p is a novel preventive intervention for OS patients.