Capsaicin (CAP), a highly selective agonist for transient receptor potential vanilloid type 1 (TRPV1), has been widely reported to exhibit anti-oxidant, anti-inflammation and anticancer activities. Currently, several therapeutic approaches for bladder cancer (BCa) are available, but accompanied by unfavorable outcomes. Previous studies reported a potential clinical effect of CAP to prevent BCa tumorigenesis. However, its underlying molecular mechanism still remains unknown. Our transcriptome analysis suggested a close link among calcium signaling pathway, cell cycle regulation, ROS metabolism and FOXO signaling pathway in BCa. In this study, several experiments were performed to investigate the effects of CAP on BCa cells (5637 and T24) and NOD/SCID mice. Our results showed that CAP could suppress BCa tumorigenesis by inhibiting its proliferation both in vitro and in vivo. Moreover, CAP induced cell cycle arrest at G0/G1 phase and ROS production. Importantly, our studies revealed a strong increase of FOXO3a after treatment with CAP. Furthermore, we observed no significant alteration of apoptosis by CAP, whereas Catalase and SOD2 were considerably upregulated, which could clear ROS and protect against cell death. Thus, our results suggested that CAP could inhibit viability and tumorigenesis of BCa possibly via FOXO3a-mediated pathways.

Bladder cancer (BLCA) is a common malignancy of the urinary system. The gut microbiome produces various metabolites that play functional roles in tumorigenesis and tumor progression. However, the integrative analysis of the gut microbiome and metabolome in BLCA has still been lacking. Thus, the aim of this study was to identify microbial and functional characteristics and metabolites in BLCA in a Chinese population. Metagenomics, targeted metabolomics, bioinformatics, and integrative analysis were used in fecal samples of BLCA patients and healthy individuals. We found gut microbiomes were significantly dysregulated in BLCA patients, including Bifidobacterium, Lactobacillus, Streptococcus, Blautia, and Eubacterium. We also found 11Z-eicosenoic acid, 3-methoxytyrosine, abrine, aniline-2-sulfonate, arachidic acid, conjugated linoleic acids, elaidic acid, glycylleucine, glycylproline, leucyl-glycine, linoelaidic acid, linoleic acid, nicotinamide hypoxanthine dinucleotide, oleic acid, petroselinic acid, and ricinoleic acid to be significantly decreased, while cholesterol sulfate was significantly increased in BLCA patients. Integration of metagenomics and metabolomics revealed interactions between gut microbiota and metabolites and the host. We identified the alterations of gut microbiomes and metabolites in BLCA in a Chinese population. Moreover, we preliminarily revealed the associations between specific gut microbiomes and metabolites. These findings determined potential causative links among gut dysbiosis, dysregulated metabolites, and BLCA.

Background: Transient receptor potential (TRP) channels are involved in various physiological, pathological, and tumorigenesis-related processes. However, only a few studies have comprehensively analyzed TRP family members and their association with prognosis and tumor microenvironment (TME) in various cancers. Thus, in this study, we focused on TRP channels in pan-cancer and screened two typical TRP channels, TRPV4 and TRPC4, as examples. Methods: Based on the latest public databases, we evaluated the expression level and prognostic value of TRP family genes in pan-cancer tissues via various bioinformatic analytical methods, and investigated the relationship between the expression of TRP family genes with TME, stemness score, immune subtype, drug sensitivity, and immunotherapy outcome in pan-cancer tissues. Results: Pan-cancer analysis revealed that the TRP family genes were differentially expressed in tumor and para-carcinoma tissues. A significant correlation existed between the expression of TRP family genes and prognosis. The expression of TRP family genes was significantly correlated with stromal, immune, RNA stemness, and DNA stemness scores in pan-cancer tissues. Our results indicated that the expression of TRP family genes correlated with the sensitivity to various drugs including PLX-4720, SB-590885, and HYPOTHEMYCIN, immunotherapy outcome, and immune-activation-related genes. Immunohistochemical analysis revealed significant differential expression of TRPV4 in bladder and para-carcinoma tissues. Conclusions: Our study elucidated the possible role of TRP family genes in cancer progression and provided insights for further studies on TRP family genes as potential pan-cancer targets to develop diagnostic and therapeutic strategies.

Background: Patients with urothelial bladder carcinoma (UBC) have a poor prognosis and a high risk of progression. Recently, tRNA-derived small RNAs (tsRNAs), a novel type of noncoding RNA, have been identified. In our previous study, we found tiRNA-Gly-GCC-1 was significantly upregulated in UBC tissue and might target the predicted target gene toll-like receptor 4 (TLR4) to play a regulatory role in UBC. Thus, the aim of this study was to identify the functional roles of tiRNA-Gly-GCC-1 and the relationship between tiRNA-Gly-GCC-1 and TLR4. Methods: After lentiviral transfection in 5637 and T24 cell lines, quantitative reverse transcription-PCR, Cell Counting Kit-8, IncuCyte ZOOM™ live cell imaging, flow cytometry, Transwell assays, scratch assay, and luciferase assay were performed. Results: The results showed down-regulation of tiRNA-Gly-GCC-1 inhibits cell proliferation, migration and invasion, promotes cell apoptosis, and affects the cell cycle. Besides, tiRNA-Gly-GCC-1 was found to inhibit TLR4 expression by directly targeting its 3′UTR. Conclusions: Our study demonstrated that tiRNA-Gly-GCC-1 promotes the progression of UBC and directly targets TLR4. This study provides novel insights for future investigations to explore the mechanisms and therapeutic targets for UBC.

Muscle-invasive bladder cancer (MIBC) leads to a large societal burden. Recently, tRNA-derived small RNAs (tsRNAs), a novel type of noncoding RNA (ncRNAs), have been identified. However, the expression patterns and functions of tsRNAs in MIBC have not yet been identified. Here, RNA sequencing, bioinformatics, and quantitative reverse transcription- polymerase chain reaction (qRT-PCR) were used to screen the expression profiles and predict the potential roles of tsRNAs in MIBC. Of 406 tsRNAs differentially expressed in MIBC tissues, 91 tsRNAs were significantly differentially expressed. Then, four candidate tsRNAs, tiRNA-1:34-Val-CAC-2, tiRNA-1:33-Gly-GCC-1, tRF-1:32-Gly-GCC-1, and tRF-+1:T20-Ser-TGA-1, were selected. Next, a bioinformatics analysis showed the potential target genes and tsRNA–mRNA network. The most significant and meaningful terms of gene ontology were the positive regulation of the phosphate metabolic process, lamellipodium, and protein-cysteine S-acyltransferase activity in the biological process, cellular component, and molecular function, respectively. In addition, the top four pathways were predicted by the Kyoto Encyclopedia of Genes and Genomes database (KEGG). Finally, qRT-PCR demonstrated a similar expression pattern compared to sequencing data for the candidate tsRNAs. In short, we find differential expression profiles and predict that tiRNA-1:33-Gly-GCC-1, tRF-1:32-Gly-GCC-1, and tRF-+1:T20-Ser-TGA-1 are very likely to engage in the pathophysiological process of MIBC via regulating the target genes in the key pathways.

Background: Small nucleolar RNAs (snoRNAs) are a new non-coding RNAs (ncRNAs), which have not been widely investigated and are identified to be involved in tumorigenesis. But the function of snoRNAs in BLCA has not been reported yet. Methods: SnoRNAs signature (SNORS) was constructed through LASSO cox regression analysis. Integrated analysis of candidate snoRNAs was performed to detect the correlation between copy number variation (CNV)/DNA methylation/protein/mRNA/alternative splicing (AS). Then we built a nomogram integrating independent prognostic factors to assist the clinical utility. Results: We have screened out 15 prognostic differentially expressed snoRNAs (DESs) and constructed SNORS consisting of 5 candidate snoRNAs which could appropriately stratify patients into low or high SNORS groups with distinct prognosis. Then we found 5 candidate snoRNAs might be regulated by their own CNV and DNA methylation. Moreover, 5 candidate snoRNAs were significantly correlated mRNA and alternative splicing (AS), which might regulate diverse biological process in tumorigenesis, such as “extracellular matrix”, “epithelial–mesenchymal transition (EMT)”, etc. signaling pathways. Furthermore, SNORS was an independent prognostic factor, which was strikingly correlated with clinical outcome. Through inporating with other variables, we have established a predictive nomogram, which was more effectively to predict prognosis than any other variables alone. Conclusion: Our findings first highlighted an important role of snoRNAs in BLCA and established a potential prognostic model which could serve as a biomarker for BLCA.