RESUMEN
Background: Bladder cancer (BLCA) is one of the common malignant tumors worldwide. Recent studies have shown that Transcription factor activating protein-2(TFAP2) family proteins plays a bidirectional regulatory role in the process of tumorigenesis versus evolution by regulating the expression of tumor associated genes. However, little is known about the function of distinct TFAP2s proteins in patient with BLCA. Methods: Formalin-fixed paraffin-embedded (FFPE) sample tissues and clinical data of 240 patients with bladder cancer were collected for immunohistochemical analysis. The Human Protein Atlas, Gene Expression Profiling Interactive Analysis (GEPIA), Shiny Methylation Analysis Resource Tool (SMART), Kaplan-Meier plotter, cBioPortal, Metascape, LinkedOmics, TIMER and CIBERSORT were utilized to analyze differential expression, prognostic value, genetic alteration and immune cell infiltration of TFAP2 family in patients with BLCA. Results: Our study found that TFAP2 family proteins are generally expressed higher in BLCA tissues than in normal tissues. However, they show different trends in the growth, metastasis and survival prognosis of BLCA. TFAP2A and TFAP2C was associated with worse clinical stage and prognosis in BLCA patients, while TFAP2B, TFAP2D and TFAP2E showed the opposite trend. Importantly, the functions of the differentially expressed TFAP2s were primarily related to the developmental process, reproductive process, response to stimulus and immune system process, etc. Moreover, TFAP2 family was significantly correlated with the infiltration of six immune cell types and might regulate TAM polarization. Conclusion: TFAP2 family might be an important regulator of immune cell infiltration and a valuable prognostic biomarker in patients with BLCA.
RESUMEN
Background: Tumor-derived exosomes are involved in the process of tumor metastasis and angiogenesis. MicroRNAs (miRNAs) are the most widely investigated factors in exosomes. Therefore, we hope to find a new therapeutic target in bladder cancer (BLCA), which has high incidence rate and mortality. Methods: Exosomal microRNA(miR)-93-5p expression level, downstream target molecules, and biological functions were examined with bioinformatics technology. Exosomes were extracted by sequential differential centrifugation and verified by transmission electron microscopy. The exosomal miR-93-5p on cell proliferation, invasion, and angiogenesis abilities in 5637 and T24 cells was determined by Cell Counting Kit 8 (CCK-8), colony-forming assay, Transwell assay, and vascular ring formation assay. A mouse xenograft model with intratumor injection was adopted to evaluate the correlation between BLCA-derived exosomes and tumor growth in vivo. Results: The results revealed that exosomes play an important role in the biological progression of BLCA, with miR-93-5p being a particularly important molecule. Compared to normal cells, more malignant cells release more exosomal miR-93-5p, and tumor-derived exosomal miR-93-5p could significantly promote cell proliferation, invasion, and angiogenesis in vitro and in vivo. We identified phosphatase and tensin homolog (PTEN) as the most significant target of miR-93-5p in BLCA and human umbilical vein endothelial cells. Conclusions: Our study successfully revealed the biological role and mechanism of BLCA-derived exosomes in tumor progression. Target at tumor exosomes and exosomal miR-93-5p may be an effective treatment in BLCA.