The clinical and biological significance of TBRG4 expression in prostate cancer

Background Transforming growth factor beta regulator 4 (TBRG4), regulates mitochondrial RNA processing. TBRG4 has been implicated in the progression of several malignancies, but its biological function and clinical relevance in prostate cancer remain unclear. Methods Publicly available data from The Cancer Genome Atlas prostate adenocarcinoma cohort and three Gene Expression Omnibus cohorts were analyzed. Differential expression was assessed independently in TCGA-PRAD, GSE88808, GSE46602, and GSE70768. Progression-free survival (PFS) was evaluated in TCGA-PRAD. External PFS analyses were conducted in GSE70768 and GSE46602 using the publicly available biochemical-recurrence status and corresponding follow-up time. Gain- and loss-of-function experiments were performed in PC3 and DU145 cells, which showed the highest baseline TBRG4 expression among the tested prostate cancer cell lines. A PC3 subcutaneous xenograft was used for in vivo validation. Results TBRG4 was upregulated in the analyzed PCa cohorts and cell lines and was associated with higher Gleason score, prostate-specific antigen level, and pathologic T category. High TBRG4 expression was associated with shorter PFS in TCGA-PRAD in univariable analysis [hazard ratio (HR), 2.138; 95% confidence interval (CI), 1.180–3.872; P = 0.012], but not after multivariable adjustment (HR, 1.411; 95% CI, 0.771–2.582; P = 0.264). TBRG4 overexpression increased colony formation, migration, invasion, and wound closure and was accompanied by decreased E-cadherin and increased N-cadherin and vimentin expression. TBRG4 knockdown produced the opposite effects. High TBRG4 expression was associated with phosphatidylinositol 3-kinase/protein kinase B/mechanistic target of rapamycin pathway enrichment, and TBRG4 manipulation was accompanied by changes in pathway-protein phosphorylation. TBRG4 knockdown also reduced PC3 xenograft growth. Conclusions TBRG4 is upregulated across the evaluated prostate cancer cohorts and is associated with adverse clinicopathological features in TCGA-PRAD. Functionally, TBRG4 supports tumor growth and invasive phenotypes, accompanied by changes in PI3K/AKT/mTOR signaling. Associations between TBRG4 expression and progression-free survival were observed in selected cohorts, suggesting that TBRG4 may represent a prognostic factor in prostate cancer.