RESUMEN
SLFN11 is abnormally expressed and associated with survival outcomes in various human cancers. However, the role of SLFN11 in clear cell renal cell carcinoma (ccRCC) remains unclear. This study aimed to investigate the clinical value and potential functions of SLFN11 in ccRCC. Comprehensive bioinformatics analyses were performed using online databases. Quantitative real-time PCR (qPCR) and western blotting were used to validate the expression data. CCK8, flow cytometry analysis, and EdU staining were performed to determine the level of cell proliferation. Flow cytometry analysis was also used to detect cell apoptosis. Wound-healing assay and Transwell assays were performed to assess cell migration and invasion capability, respectively. SLFN11 was overexpressed and was an independent prognostic factor in ccRCC. SLFN11 knockdown inhibited cell proliferation, migration, and invasion and promoted apoptosis. Functional and pathway enrichment analyses suggested that SLFN11 may have an impact on tumorigenesis in ccRCC through regulation of the inflammatory response, the PI3K/AKT signaling pathway and other effectors. Furthermore, SLFN11 knockdown inhibited the phosphorylation of the PI3K/AKT signaling pathway and could be activated by 740 Y-P. Finally, we demonstrated that miR-183 may specifically target SLFN11, and miR-183 expression was correlated with predicted survival. SLFN11 may play a critical role in ccRCC progression and may serve as a novel prognostic biomarker in ccRCC.
Asunto(s)
Carcinoma de Células Renales , Carcinoma , Neoplasias Renales , MicroARNs , Humanos , Carcinoma de Células Renales/genética , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Neoplasias Renales/genética , Transducción de Señal , MicroARNs/genética , Proteínas NuclearesRESUMEN
A satisfactory cure rate for renal cell carcinoma (RCC) is difficult to achieve through traditional immunotherapy. RCC has a relatively high spontaneous regression rate due to tumor immune escape. However, tumorderived exosomes (TEXs), which effectively carry tumorassociated antigens (TAAs) and trigger stronger antigenspecific tumor immunity against autologous tumors than against other tumors, have been widely viewed as attractive potential vaccines for tumor treatment, although improvements are needed. Therefore, in our study, we determined whether RenCa cellderived exosome (RDE)stimulated CD8+ T cells exert a stronger specific cytotoxic effect on autologous tumor cells than on other types of tumor cells through the Fas ligand (FasL)/Fas signaling pathway, and whether the combination of RDEstimulated CD8+ T cells with GMCSF and IL12 enhances the anticancer effect. The results showed that RDEs were isolated, as expected, and promoted an increased percentage of CD8+/CD4+ T cells. RDEstimulated CD8+ T cells also more effectively facilitated cytotoxicity against RenCa cells when combined with GMCSF and IL12 in vitro. Furthermore, immunization with RDEs restrained the growth of RenCa tumors in mouse models, and facilitated the stimulation of a stronger specific cytotoxic CD8+ T cell response via the FasL/Fas signaling pathway in vitro. However, these results were observed less frequently for other types of tumor cells after treatment with RDEs, suggesting that RDEs depend on their antigen specificity to trigger antitumor immune responses. These findings revealed that RDEstimulated CD8+ T cells combined with GMCSF and IL12 can more effectively exert a stronger cytotoxic effect than RDEs alone and that RDEs can induce immunization more effectively against renal cortical adenocarcinoma than against other types of cancer. Therefore, according to our study, exosomes are promising potential vaccines, and the combination of exosomestimulated CD8+ T cells with GMCSF and IL12 may be a novel strategy for the treatment of RCC.