Background Ankylosing spondylitis (AS) is a chronic inflammatory arthritis. Upregulation of microRNA (miR)-92b-3p is associated with enhanced osteoblastic differentiation. The current study sought to investigate the functional mechanism of miR-92b-3p in osteogenic differentiation of AS fibroblasts. Methods First, fibroblasts were isolated from AS and non-AS patients and cultured. Next, cell morphology was observed, cell proliferation was assessed and the vimentin expression pattern was determined. Alkaline phosphatase (ALP) activity and levels of osteogenic markers RUNX2, OPN, OSX, and COL I were additionally measured, followed by determination of miR-92b-3p and TOB1 levels. The binding site of miR-92b-3p and TOB1 was predicted, and their target relationship was validated. Lastly, miR-92b-3p inhibitor, si-TOB1, and the BMP/Smad signaling pathway inhibitor LDN193189 were delivered into AS fibroblasts to evaluate the osteogenic differentiation of AS fibroblasts and the activation of the BMP/Smad pathway. Results miR-92b-3p was highly expressed in AS fibroblasts. AS fibroblasts showed enhanced osteogenic differentiation and proliferation, while inhibition of miR-92b-3p suppressed osteogenic differentiation and proliferation of AS fibroblasts. miR-92b-3p targeted TOB1, and TOB1 was poorly expressed in AS fibroblasts. The concurrent downregulation of TOB1 and inhibition of miR-92b-3p elevated the levels of RUNX2, OPN, OSX, and COL I and ALP activity and further enhanced the proliferation of AS fibroblasts. The BMP/Smad pathway was activated in AS fibroblasts. Silencing miR-92b-3p could inhibit the activation of the BMP/Smad pathway by upregulating TOB1. Inhibition of the BMP/Smad pathway reduced the number of calcified nodules and hindered the osteogenic differentiation and proliferation of AS fibroblasts. Conclusion Our findings highlighted that silencing miR-92b-3p inhibited the osteogenic differentiation and proliferation of AS fibroblasts by upregulation of TOB1 and inhibition of the BMP/Smad pathway. Graphical abstract
Objective This work focused on investigating the relation of centromeric protein A (CENPA) gene expression with prognosis of papillary renal cell carcinoma (PRCC). Methods We obtained data from PRCC cases in TCGA. Thereafter, CENPA levels between the paired PRCC and matched non-carcinoma samples were analyzed by Wilcoxon rank-sum test, while the relations of clinicopathological characteristics with CENPA level were examined by logistic regression and Wilcoxon rank-sum test. The prognostic value of CENPA was assessed by plotting the receiver operating feature curve (ROC) and calculating the value of area under curve (AUC). In addition, relations between clinicopathological characteristics and PRCC survival were analyzed through Kaplan–Meier (KM) and Cox regression analyses. After dividing the total number of patients into the trial cohort and the validation cohort in a ratio of 7:3, we constructed a nomogram in trial cohort according to multivariate Cox regression results for predicting how CENPA affected patient survival and used the calibration curve to verify its accuracy in both cohorts. We also determined CENPA levels within cancer and matched non-carcinoma samples through immunohistochemistry (IHC). Finally, we utilized functional enrichment for identifying key pathways related to differentially expressed genes (DEGs) between PRCC cases with CENPA up-regulation and down-regulation. Results CENPA expression enhanced in PRCC tissues compared with healthy counterparts (P < 0.001). CENPA up-regulation was related to pathological TNM stage and clinical stage (P < 0.05). Meanwhile, the ROC curves indicated that CENPA had a remarkable diagnostic capacity for PRCC, and the expression of CENPA can significantly improve the predictive accuracy of pathological TNM stage and clinical stage for PRCC. As revealed by KM curves, PRCC cases with CENPA up-regulation were associated with poor survival compared with those with CENPA down-regulation (Risk ratio, RR = 3.07, 95% CI: 1.58–5.97, P = 0.001). In the meantime, univariate as well as multivariate analysis showed an independent association of CENPA with overall survival (OS, P < 0.05) and the nomogram demonstrated superior predictive ability in both cohorts. IHC analysis indicated that PRCC cases showed an increased CENPA positive rate compared with controls. As revealed by functional annotations, CENPA was enriched into pathways associated with neuroactive ligand receptor interactions, cytokine receptor interactions, extracellular matrix regulators, extracellular matrix glycoproteins and nuclear matrisome. Conclusion CENPA expression increases within PRCC samples, which predicts dismal PRCC survival. CENPA may become a molecular prognostic marker and therapeutic target for PRCC patients.
The present work aimed to screen biomarkers associated with Chromophobe cell carcinoma of kidney(chrcc)by bioinformatics methods as key genes to predict the prognosis of chrcc.The GSE15641 dataset was acquired from Gene Expression Omnibus(GEO) database, Totally 1153 differentially expressed genes (DEGs) were identified.thereafter, DEGs were detected to carry out Gene Ontology (GO) annotation and Kyoto Encyclopedia of Gene and Genome (KEGG) pathway enrichment analysis. Moreover, the protein-protein interaction (PPI) networks were constructed and visualized using Cytoscape software to identify pivotal genes,including KRAS, EGFR, EHHADH and CCNB2, were obtained, with CCNB2 being identified as the only significant core gene according to Kaplan-Meier (K-M)survival analysis.According to our results, CCNB2 expression was notably higher in The Cancer Genome Atlas(TCGA)-chrcc patients than in normal samples, and the high CCNB2 expression in cancer tissues was associated with adverse clinicopathological factors. The high CCNB2 expression group had markedly poor overall survival(OS) and progression-free interval (PFI) compared with low expression group. Meanwhile, immune infiltration analysis demonstrated a positive correlation between CCNB2 expression and Th2 cells enrichment levels in chrcc patients, and a negative correlation between CCNB2 expression and Cytotoxic cells as well as DC cells. At last, according to the Gene Set Enrichment Analysis(GSEA) enrichment results including CCNB2 gene, there was a significant difference in the classification of hepatocellular carcinoma (HCC) subclass and breast cancer (BC).In the current work, CCNB2 can be considered as a predictive molecular marker and a potential therapeutic target for chrcc.
Objective: This work focused on investigating the relation of centromeric protein A (CENPA) gene expression with prognosis of papillary renal cell carcinoma (PRCC). Methods: We obtained data from PRCC cases in TCGA. Thereafter, CENPA levels between the paired PRCC and matched non-carcinoma samples were analyzed by Wilcoxon rank-and-sum test, while the relations of clinicopathological characteristics with CENPA level were examined by logistic regression and Wilcoxon rank-sum test. The prognostic value of CENPA was assessed by plotting the receiver operating feature curve (ROC) and calculating the value of area under curve (AUC). In addition, relations between clinicopathological features and PRCC survival were analyzed through Kaplan-Meier (KM) and Cox regression analyses. Additionally, we constructed a nomogram according to multivariate Cox regression results for predicting how CENPA affected patient survival. We also determined CENPA levels within cancer and matched non-carcinoma samples through immunohistochemistry (IHC). Finally, we utilized functional enrichment for identifying key pathways related to differentially expressed genes (DEGs) between PRCC cases with CENPA up-regulation and down-regulation. Results: CENPA expression enhanced in PRCC tissues compared with healthy counterparts (P <0.001). CENPA up-regulation was related to clinical stage and pathological TNM stage (P<0.05). Meanwhile, the ROC curve indicated that CENPA had a remarkable diagnostic capacity for PRCC (AUC=0.936). As revealed by KM curve, PRCC cases with CENPA up-regulation were associated with poor survival compared with those with CENPA down-regulation (risk ratio, RR=3.07, 95% CI: 1.58-5.97, P=0.001). In the meantime, univariate as well as multivariate analysis showed an independent association of CENPA with overall survival (OS, P <0.001). IHC analysis indicated that PRCC cases showed an increased CENPA positive rate compared with controls. As revealed by functional annotations, CENPA was enriched into pathways associated with KEGG - NEUROACTIVE - LIGAND - RECEPTOR - INTERACTION, KEGG - CYTOKINE - CYTOKINE - RECEPTOR INTERACTION, NABA - ECM - REGULATORS, NABA - ECM - GLYCOPROTEINS, and NABA - CORE - MATRISOME pathways. Conclusion: CENPA expression increases within PRCC samples, which predicts dismal PRCC survival. CENPA may become a molecular prognostic marker and therapeutic target for PRCC patients.
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