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Abstract Background Bladder cancer (BLCA) is notably associated with advanced age, characterized by its high incidence and mortality among the elderly. Despite promising advancements in models that amalgamate molecular subtypes with treatment and prognostic outcomes, the considerable heterogeneity in BLCA poses challenges to their universal applicability. Consequently, there is an urgent need to develop a new molecular subtyping system focusing on a critical clinical feature of BLCA: senescence. Methods Utilizing unsupervised clustering on the Cancer Genome Atlas Program (TCGA)-BLCA cohort, we crafted a senescence-associated molecular classification and precision quantification system (Senescore). This method underwent systematic validation against established molecular subtypes, treatment strategies, clinical outcomes, the immune tumor microenvironment (TME), relevance to immune checkpoints, and identification of potential therapeutic targets. Results External validations were conducted using the Xiangya cohort, IMvigor210 cohort, and meta-cohort, with multiplex immunofluorescence confirming the correlation between Senescore, immune infiltration, and cellular senescence. Notably, patients categorized within higher Senescore group were predisposed to the basal subtype, showcased augmented immune infiltration, harbored elevated driver gene mutations, and exhibited increased senescence-associated secretory phenotype (SASP) factors expression in the transcriptome. Despite poorer prognoses, these patients revealed greater responsiveness to immunotherapy and neoadjuvant chemotherapy. Conclusions Our molecular subtyping and Senescore, informed by age-related clinical features, accurately depict age-associated biological traits and its clinical application potential in BLCA. Moreover, this personalized assessment framework is poised to identify senolysis targets unique to BLCA, furthering the integration of aging research into therapeutic strategies.

Abstract Immunotherapy resistance in bladder cancer (BLCA) is associated with elevated levels of sialic acid–binding immunoglobulin-like lectin (Siglec15). This protein plays a crucial role in fostering a noninflammatory tumor microenvironment (TME), which is conducive to cancer progression. Our study confirmed that the overexpression of Siglec15 led to a reduction in CD8+ T cell infiltration. This effect was mediated by the downregulation of pro-inflammatory cytokines and chemokines, which in turn exacerbated BLCA malignancy. Furthermore, Siglec15 inhibited the cytotoxicity of effector T cell, contributing to immune evasion. An in vivo study demonstrated that Siglec15 overexpression induced a non-inflammatory TME and promoted resistance to immunotherapy. These findings highlight Siglec15 as a potential therapeutic target for BLCA. By modulating inflammation in the TME and CD8+ T cell function, targeting Siglec15 may offer a novel strategy for overcoming immunotherapy resistance and improving patient outcomes.

Abstract Background Vasculogenic mimicry (VM) is a potential cause of resistance to antiangiogenic therapy and is closely related to the malignant progression of tumors. It has been shown that noncoding RNAs play an important role in the formation of VM in malignant tumors. However, the role of circRNAs in VM of bladder cancer and the regulatory mechanisms are unclear. Methods Firstly, hsa_circ_0000520 was identified to have circular character by Sanger sequencing and Rnase R assays. Secondly, the potential clinical value of hsa_circ_0000520 was explored by quantitative real-time polymerase chain reaction (qRT-PCR) and fluorescence in situ hybridization (FISH) of clinical specimens. Thirdly, the role of hsa_circ_0000520 in bladder cancer invasion, migration, and VM formation was examined by in vivo and in vitro experiments. Finally, the regulatory mechanisms of hsa_circ_0000520 in the malignant progression of bladder cancer were elucidated by RNA binding protein immunoprecipitation (RIP), RNA pulldown, co-immunoprecipitation (co-IP), qRT-PCR, Western blot (WB), and fluorescence co-localization. Results Hsa_circ_0000520 was characterized as a circular RNA and was lowly expressed in bladder cancer compared with the paracancer. Bladder cancer patients with high expression of hsa_circ_0000520 had better survival prognosis. Functionally, hsa_circ_0000520 inhibited bladder cancer invasion, migration, and VM formation. Mechanistically, hsa_circ_0000520 acted as a scaffold to promote binding of UBE2V1/UBC13 to Lin28a, further promoting the ubiquitous degradation of Lin28a, improving PTEN mRNA stability, and inhibiting the phosphorylation of the PI3K/AKT pathway. The formation of hsa_circ_0000520 in bladder cancer was regulated by RNA binding protein QKI. Conclusions Hsa_circ_0000520 inhibits metastasis and VM formation in bladder cancer and is a potential target for bladder cancer diagnosis and treatment.

Abstract Resistance to immunotherapy in bladder cancer has greatly limited its clinical application. Through single-cell sequencing, we determined that ACSM6, an oncogene that is highly expressed in bladder cancer, promotes the abilities of proliferation, cloning, migration, and invasion. The key point is that ACSM6 can also lead to a non-inflammatory immune microenvironment by inhibiting the chemotaxis and tumor killing ability of CD8+ T cells. Survival analysis revealed that high ACSM6 expression was associated with shorter overall survival in the immunotherapy cohort. In summary, ACSM6 is expected to become a novel biomarker for predict bladder cancer progression.

IntroductionFresh Aareca nut fruit for fresh fruit chewing commonly found in green or dark green hues. Despite its economic significance, there is currently insufficient research on the study of color and luster of areca. And the areca nut fruits after bagging showed obvious color change from green to tender yellow. In the study, we tried to explain this interesting variation in exocarp color.MethodsFruits were bagged (with a double-layered black interior and yellow exterior) 45 days after pollination and subsequently harvested 120 days after pollination. In this study, we examined the the chlorophyll and carotenoid content of pericarp exocarp, integrated transcriptomics and metabolomics to study the effects of bagging on the carotenoid pathway at the molecular level.ResultsIt was found that the chlorophyll and carotenoid content of bagged areca nut (YP) exocarp was significantly reduced. A total of 21 differentially expressed metabolites (DEMs) and 1784 differentially expressed genes (DEGs) were screened by transcriptomics and metabolomics. Three key genes in the carotenoid biosynthesis pathway as candidate genes for qPCR validation by co-analysis, which suggested their role in the regulation of pathways related to crtB, crtZ and CYP707A.DiscussionWe described that light intensity may appear as a main factor influencing the noted shift from green to yellow and the ensuing reduction in carotenoid content after bagging.

Abstract Background Prostate cancer (PC) is the most common neoplasm and is the second leading cause of cancer-related deaths in men worldwide. The Hippo tumor suppressor pathway is highly conserved in mammals and plays an important role in carcinogenesis. YAP is one of major key effectors of the Hippo pathway. However, the mechanism supporting abnormal YAP expression in PC remains to be characterized. Methods Western blot was used to measure the protein expression of ATXN3 and YAP, while the YAP target genes were measured by real-time PCR. CCK8 assay was used to detect cell viability; transwell invasion assay was used to measure the invasion ability of PC. The xeno-graft tumor model was used for in vivo study. Protein stability assay was used to detect YAP protein degradation. Immuno-precipitation assay was used to detect the interaction domain between YAP and ATXN3. The ubiquitin-based Immuno-precipitation assays were used to detect the specific ubiquitination manner happened on YAP. Results In the present study, we identified ATXN3, a DUB enzyme in the ubiquitin-specific proteases family, as a bona fide deubiquitylase of YAP in PC. ATXN3 was shown to interact with, deubiquitylate, and stabilize YAP in a deubiquitylation activity-dependent manner. Depletion of ATXN3 decreased the YAP protein level and the expression of YAP/TEAD target genes in PC, including CTGF, ANKRD1 and CYR61. Further mechanistic study revealed that the Josephin domain of ATXN3 interacted with the WW domain of YAP. ATXN3 stabilized YAP protein via inhibiting K48-specific poly-ubiquitination process on YAP protein. In addition, ATXN3 depletion significantly decreased PC cell proliferation, invasion and stem-like properties. The effects induced by ATXN3 depletion could be rescued by further YAP overexpression. Conclusions In general, our findings establish a previously undocumented catalytic role for ATXN3 as a deubiquitinating enzyme of YAP and provides a possible target for the therapy of PC. Video Abstract

PurposePrevious research has shown that bladder cancer has one of the highest incidences of developing a second primary malignancy. So, we designed this study to further examine this risk in light of race and histology.Patients and methodsUsing the surveillance, epidemiology, and end results (SEER) 18 registry, we retrospectively screened patients who had been diagnosed with bladder cancer between 2000 and 2018. We then tracked these survivors until a second primary cancer diagnosis, the conclusion of the trial, or their deaths. In addition to doing a competing risk analysis, we derived standardized incidence ratios (SIRs) and incidence rate ratios (IRRs) for SPMs by race and histology.ResultsA total of 162,335 patients with bladder cancer were included, and during follow-ups, a second primary cancer diagnosis was made in 31,746 of these patients. When the data were stratified by race, SIRs and IRRs for SPMs showed a significant difference: Asian/Pacific Islanders (APIs) had a more pronounced increase in SPMs (SIR: 2.15; p 0.05) than White and Black individuals who had an SIRs of 1.69 and 1.94, respectively; p 0.05. In terms of histology, the epithelial type was associated with an increase in SPMs across all three races, but more so in APIs (IRR: 3.51; 95% CI: 2.11–5.85; p 0.001).ConclusionWe found that race had an impact on both the type and risk of SPMs. Additionally, the likelihood of an SPM increases with the length of time between the two malignancies and the stage of the index malignancy.

BackgroundMicroRNAs, small non-coding RNA molecules with about 22 nucleotides in length, play a significant role in the development of bladder cancer. Previous studies found that miR-616-5p could promote the progress of cancers. However, its role in bladder cancer remains unclear. In the study, we aimed to demonstrate how miR-616-5p impacts the invasion and migration of bladder cancer and its potential downstream targets.MethodsFirstly, qRT-PCR was used to detect the expression of miR-616-5p in normal bladder uroepithelial cell lines and bladder cancer cell lines. Then, chamber–transwell invasion and wound healing migration assays were used to detect the roles of miR-616-5p and NR2C2 in invasion and migration. Subsequently, Western blot was used to evaluate the regulation effects of miR-616-5p and NR2C2. Finally, luciferase assays were performed to manifest the mechanism of miR-616-5p and NR2C2 regulation.ResultsWe found that miR-616-5p was upregulated in bladder cancer, and it could promote the invasion and migration of bladder cancer in vitro. Moreover, we demonstrated that NR2C2 was a downstream target of miR-616-5p. miR-616-5p could inhibit the expression of NR2C2 by binding to the 3′UTR of NR2C2 mRNA. Importantly, patients with a high expression of NR2C2 showed better prognoses in bladder cancer.ConclusionsThis study identifies that miR-616-5p can promote bladder cancer progression via altering the expression of NR2C2. Therefore, identifying miR-616-5p expression levels might be a useful strategy for developing potential therapeutic targets in bladder cancer.

Background: As a transcription factor, Zinc finger protein ZIC2 can interact with various DNAs and proteins. Current studies have shown that ZIC2 plays an oncogene role in various cancers. In this study, we systematically characterize the prevalence and predictive value of ZIC2 expression across multiple cancer types.Methods: We mined several public databases, including Oncomine, the Cancer Genome Atlas (TCGA), cBioPortal, Kaplan-Meier Plotter and PrognoScan to evaluated the differentially expressed ZIC2 between tumor samples and normal control samples in pan-cancner, and then explored the association between ZIC2 expression and patient survival, prognosis and clinicopathologic stage. We also analyzed the relationship between tumor mutation burden (TMB), microsatellite instability (MSI), tumor microenvironment, tumor- and immune-related genes and ZIC2 expression. Finally, we explored the potential signaling pathway mechanism through gene set enrichment analysis (GSEA).Results: ZIC2 expression was higher in most cancer tissues compared with adjacent normal tissues. High ZIC2 expression was associated with worse prognosis and a higher clinicopathologic stage. ZIC2 expression was strongly associated with the TMB, MSI, tumor microenvironment and tumor- and immune-related genes. The GSEA revealed that multiple tumor- and immune-related pathways were differentially enriched in ZIC2 high or low expression phenotype.Conclusion: ZIC2 expression may be a potential prognostic molecular biomarker of poor survival in pan-cancer and may act as an oncogene with a strong effect in the processes of tumorigenesis and progression.