miR-628-5p is a Potential Novel Prognosis Biomarker, Associated with Immune Infiltration in Bladder Urothelial Carcinoma.

BACKGROUND: microRNA-628-5p (miR-628-5p) has a significant impact on certain types of cancer. The precise function of miR-628-5p in the context of bladder urothelial carcinoma (BLCA) remains ambiguous. OBJECTIVE: We aimed to investigate the role of miR-628-5p in BLCA. METHODS: The samples were collected from The Cancer Genome Atlas (TCGA). Statistics were employed to evaluate the correlation and predictive significance of miR-628-5p. We analyzed the target genes and regulatory network of miR-628-5p and the correlation between miR-628-5p and immune infiltration. The expression of miR-628-5p in BLCA cells was confirmed by quantitative reverse-transcription PCR (qRT-PCR). RESULTS: miR-628-5p exhibited differential expression across various types of cancer. There was a significant association between high expression of miR-628-5p and primary therapy outcome (p < 0.05). High expression of miR-628-5p was observed to be associated with poorer overall survival (HR: 1.42; 95% CI: 1.06-1.90; p = 0.02), progress free survival (HR: 1.57; 95% CI: 1.17-2.11; p = 0.003), and disease specific survival (HR: 1.83; 95% CI: 1.28-2.62; p = 0.001) in BLCA. miR-628-5p was an independent prognostic factor in BLCA and may be involved in the development of the disease through various pathways, including focal adhesion, ECM-receptor interaction, PI3K-Akt signaling pathway, and MAPK signaling pathway, and among others. miR-628-5p expression was significantly correlated with immune infiltration in BLCA patients. Compared to normal bladder epithelial cells, BLCA cell lines exhibited a significant upregulation of miR-628-5p. CONCLUSION: It is possible that miR-628-5p could serve as a hopeful therapeutic target and prognostic biomarker for individuals with BLCA.

Carbamylated erythropoietin regulates immune responses and promotes long-term kidney allograft survival through activation of PI3K/AKT signaling.

Modulation of alloimmune responses is critical to improving transplant outcome and promoting long-term graft survival. To determine mechanisms by which a nonhematopoietic erythropoietin (EPO) derivative, carbamylated EPO (CEPO), regulates innate and adaptive immune cells and affects renal allograft survival, we utilized a rat model of fully MHC-mismatched kidney transplantation. CEPO administration markedly extended the survival time of kidney allografts compared with the transplant alone control group. This therapeutic effect was inhibited when the recipients were given LY294002, a selective inhibitor of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway or anti-EPO receptor (EPOR) antibody, in addition to CEPO. In vitro, CEPO inhibited the differentiation and function of dendritic cells and modulated their production of pro-inflammatory and anti-inflammatory cytokines, along with activating the PI3K/AKT signaling pathway and increasing EPOR mRNA and protein expression by these innate immune cells. Moreover, after CD4+ T cells were exposed to CEPO the Th1/Th2 ratio decreased and the regulatory T cell (Treg)/Th17 ratio increased. These effects were abolished by LY294002 or anti-EPOR antibody, suggesting that CEPO regulates immune responses and promotes kidney allograft survival by activating the PI3K/AKT signaling pathway in an EPOR-dependent manner. The immunomodulatory and specific signaling pathway effects of CEPO identified in this study suggest a potential therapeutic approach to promoting kidney transplant survival.

Elucidating the molecular pathways and immune system transcriptome during ischemia-reperfusion injury in renal transplantation.

Ischemia reperfusion injury (IRI) is a major challenge for renal transplantation. This study was performed to explore the mechanisms and potential molecular targets involved in renal IRI. In this study, the gene datasets GSE43974 and GSE126805 from the Gene Expression Omnibus database, which include ischemic and reperfused renal specimens, were analyzed to determine differentially expressed genes (DEGs). Gene ontology annotations, Kyoto Encyclopedia of Genes and Genomes analysis, and gene set enrichment analysis were performed to determine the pathways that are significantly enriched during ischemia and reperfusion. We also determined the microenvironment cell types xCell and performed correlation analyses to reveal the relationship between the molecular pathways and microenvironment cell infiltration. We found 77 DEGs (76 up- and 1 downregulated) and 323 DEGs (312 up- and 11 downregulated) in the GSE43974 and GSE126805 datasets, respectively. Similar signaling pathway enrichment patterns were observed between the two datasets. The combined analyses demonstrate that the NOD-like receptor signaling pathway and its two downstream signaling pathways, MAPK and NF-kß, are the major significantly enriched pathways. The xCell analysis identified immune cells that are significantly changed after reperfusion, including hematopoietic stem cells, M2 macrophages, monocytes, Treg cells, conventional dendritic cells, and pro B-cells. Enrichment scores of the NOD-like receptor signaling pathway and its downstream pathways during IRI was significantly correlated with the change levels in class-switched memory B-cell and hematopoietic stem cells in both datasets. These data reveal the important role of the NOD-like receptor signaling pathway during IRI, and the close relationship between this pathway and infiltration of specific immune cell types. Our data provide compelling insights into the pathogenesis and potential therapeutic targets for renal IRI.