Bladder cancer-derived exosomal KRT6B promotes invasion and metastasis by inducing EMT and regulating the immune microenvironment

Abstract

Background Tumour-derived exosomes have recently been shown to participate in the formation and progression of different cancer processes, including tumour microenvironment remodelling, angiogenesis, invasion, metastasis, and drug resistance. However, the function and mechanism of exosome-encapsulated nucleic acids and proteins in bladder cancer remain unclear. This study aimed to investigate the effects of tumour-derived exosomes on the tumorigenesis and development of bladder cancer. Methods In this study, gene expression profiles and clinical information were collected from The Cancer Genome Atlas (TCGA) database and two independent Gene Expression Omnibus (GEO) datasets. The nucleic acids and proteins encapsulated in bladder cancer-derived exosomes were obtained from the ExoCarta database. Based on these databases, the expression patterns of exosomal mRNAs and proteins and the matched clinicopathological characteristics were analysed. Furthermore, we carried out a series of experiments to verify the relevant findings. Results A total of 7280 differentially expressed mRNAs were found in TCGA data, of which 52 mRNAs were shown to be encapsulated in bladder cancer-derived exosomes. Survival analysis based on the UALCAN database showed that among the top 10 upregulated and the top 10 downregulated exosomal genes, only the expression of KRT6B had a statistically significant effect on the survival of bladder cancer patients. Additionally, clinical correlation analysis showed that the elevated level of KRT6B was highly associated with bladder cancer stage, grade, and metastasis status. GSEA revealed that KRT6B was involved not only in epithelial–mesenchymal transition-related pathways but also in the immune response in bladder cancer. Ultimately, our experimental results were also consistent with the bioinformatic analysis. Conclusion KRT6B, which can be detected in bladder cancer-derived exosomes, plays an important role in the epithelial–mesenchymal transition and immune responses in bladder cancer. Further research will enable its potentially prognostic marker and therapeutic target for bladder cancer.

Identification of Specific Genes for Adenocarcinoma and Squamous Cell of Lung Carcinoma by Bioinformatics Analysis

“…Furthermore, genes KRT6B, SPRR1B and KRT14 which are enriched in LUSC network modules, are associated with the increased risk of cancer. KRT6B, plays an important role in the epithelial-mesenchymal transition and immune responses in bladder cancer (25). Inaddition, KRT6B has been detected as a biomarker for the progression of chronic gastritis to early gastric cancer (26).…”

Role of exosomes in non-small cell lung cancer and EGFR-mutated lung cancer

“…EMT weakens the strong adhesion between differentiated epithelial cells, allowing cancer cells to achieve individual or collective motility, which makes EMT an intuitive mechanism for tumor metastasis initiation (107)(108)(109). Exosomes can be involved in the EMT effect of tumor cells (110)(111)(112).…”

The Biological Effect of Small Extracellular Vesicles on Colorectal Cancer Metastasis

“…Many studies have demonstrated that during the progression of many types of cancer such as lung, bladder, and liver cancer, tumor-associated sEVs carry and release a variety of active components such as miRNAs, proteins, and circRNAs into the surrounding cells. This further promotes the metastasis of tumor cells by causing EMT of the recipient cells through various pathways [ 24 , 48 , 49 ]. In addition, sEVs affect the EMT of recipient cells and play an important role in CRC metastasis ( Table 2 ).…”

“…Several studies have shown that differential expression of sEV content is closely associated with CRC metastasis and plays an important role in the multi-step and multi-linked metastatic process [ 20 , 21 , 22 ]. Tumor-associated sEVs promote tumor cell metastasis and xenotropic colonization through various mechanisms such as influencing tumor cells to undergo EMT, suppressing tumor immunity, promoting generation of the pre-metastatic ecological niche, and increasing vascular leakage [ 23 , 24 , 25 ]. Other mechanisms are summarized in Figure 1 .…”