Rationale: Siglec15 is an emerging target for normalization cancer immunotherapy. However, pan-cancer anti-Siglec15 treatment is not yet validated and the potential role of Siglec15 in bladder cancer (BLCA) remains elusive. Methods: We comprehensively evaluated the expression pattern and immunological role of Siglec15 using pan-cancer analysis based on RNA sequencing data obtained from The Cancer Genome Atlas. We then systematically correlated Siglec15 with immunological characteristics in the BLCA tumor microenvironment (TME), including immunomodulators, cancer immunity cycles, tumor-infiltrating immune cells (TIICs), immune checkpoints, and T cell inflamed score. We also analyzed the role of Siglec15 in predicting the molecular subtype and the response to several treatment options in BLCA. Our results were validated in several public cohorts as well as our BLCA tumor microarray cohort, the Xiangya cohort. We developed an immune risk score (IRS), validated it, and tested its ability to predict the prognosis and response to cancer immunotherapy. Results: We found that Siglec15 was specifically overexpressed in the TME of various cancers. We hypothesize that Siglec15 designs a non-inflamed TME in BLCA based on the evidence that Siglec15 negatively correlated with immunomodulators, TIICs, cancer immunity cycles, immune checkpoints, and T cell inflamed score. Bladder cancer with high Siglec15 expression was not sensitive to cancer immunotherapy, but exhibited a higher incidence of hyperprogression. High Siglec15 levels indicated a luminal subtype of BLCA characterized by lower immune infiltration, lower response to cancer immunotherapy and neoadjuvant chemotherapy, but higher response to anti-angiogenic therapy and targeted therapies such as blocking Siglec15, β-catenin, PPAR-γ, and FGFR3 pathways. Notably, a combination of anti-Siglec15 and cancer immunotherapy may be a more effective strategy than monotherapy. IRS can accurately predict the prognosis and response to cancer immunotherapy. Conclusions: Anti-Siglec15 immunotherapy might be suitable for BLCA treatment as Siglec15 correlates with a non-inflamed TME in BLCA. Siglec15 could also predict the molecular subtype and the response to several treatment options.
Background Depicting the heterogeneity and functional characteristics of the tumor microenvironment (TME) is necessary to achieve precision medicine for bladder cancer (BLCA). Although classical molecular subtypes effectively reflect TME heterogeneity and characteristics, their clinical application is limited by several issues. Methods In this study, we integrated the Xiangya cohort and multiple external BLCA cohorts to develop a novel 5-methylcytosine (5mC) regulator-mediated molecular subtype system and a corresponding quantitative indicator, the 5mC score. Unsupervised clustering was performed to identify novel 5mC regulator-mediated molecular subtypes. The principal component analysis was applied to calculate the 5mC score. Then, we correlated the 5mC clusters (5mC score) with classical molecular subtypes, immunophenotypes, clinical outcomes, and therapeutic opportunities in BLCA. Finally, we performed pancancer analyses on the 5mC score. Results Two 5mC clusters, including 5mC cluster 1 and cluster 2, were identified. These novel 5mC clusters (5mC score) could accurately predict classical molecular subtypes, immunophenotypes, prognosis, and therapeutic opportunities of BLCA. 5mC cluster 1 (high 5mC score) indicated a luminal subtype and noninflamed phenotype, characterized by lower anticancer immunity but better prognosis. Moreover, 5mC cluster 1 (high 5mC score) predicted low sensitivity to cancer immunotherapy, neoadjuvant chemotherapy, and radiotherapy, but high sensitivity to antiangiogenic therapy and targeted therapies, such as blocking the β-catenin, FGFR3, and PPAR-γ pathways. Conclusions The novel 5mC regulator-based subtype system reflects many aspects of BLCA biology and provides new insights into precision medicine in BLCA. Furthermore, the 5mC score may be a generalizable predictor of immunotherapy response and prognosis in pancancers.
BackgroundBladder cancer (BLCA) is one of the most common urinary malignancies with poor prognosis. There is an unmet need to develop novel robust tools to predict prognosis and treatment efficacy for BLCA.MethodsThe hypoxia-related genes were collected from the Molecular Signatures Database. The TCGA-BLCA cohort was downloaded from the Cancer Genome Atlas and then was randomly divided into training and internal validation sets. Two external validation cohorts were gathered from Gene Expression Omnibus. Also, another independent validation cohort (Xiangya cohort) was collected from our hospital. The Cox regression model with the LASSO algorithm was applied to develop the hypoxia risk score. Then, we correlated the hypoxia risk score with the clinical outcomes, the tumor microenvironment (TME) immune characteristics, and the efficacy prediction for several treatments, which included cancer immunotherapy, chemotherapy, radiotherapy, and targeted therapies.ResultsHypoxia risk score was an independent prognostic factor. A high-risk score indicated an inflamed TME based on the evidence that hypoxia risk score positively correlated with the activities of several cancer immunity cycles and the infiltration levels of many tumor-infiltrating immune cells, such as CD8 + T cells, Dendritic cells, and NK cells. Consistently, the hypoxia risk score was positively related to the expression of several immune checkpoints, such as PD-L1, PD-1, CTLA-4, and LAG-3, as well as the T cell inflamed score. Furthermore, the hypoxia risk score positively correlated with the enrichment scores of most immunotherapy-positive gene signatures. Therefore, patients with higher risk score may be more sensitive to cancer immunotherapy. Meanwhile, the hypoxia risk score was positively related to the sensitivities of several chemotherapeutic drugs, including Cisplatin, Docetaxel, Paclitaxel, Bleomycin, Camptothecin, and Vinblastine. Similarly, the enrichment scores for radiotherapy-predicted pathways and EGFR ligands were higher in the high-risk score group. Conversely, the enrichment scores of several immunosuppressive oncogenic pathways were significantly higher in the low-risk score group, such as the WNT-β-catenin network, PPARG network, and FGFR3 network.ConclusionsWe developed and validated a new hypoxia risk score, which could predict the clinical outcomes and the TME immune characteristics of BLCA. In general, the hypoxia risk score may aid in the precision medicine for BLCA.
RNA modification of N6-methyladenosine (m6A) plays critical roles in various biological processes, such as cancer development, inflammation, and the anticancer immune response. However, the role played by a comprehensive m6A modification pattern in regulating anticancer immunity in kidney renal clear cell carcinoma (KIRC) has not been fully elucidated. In this study, we identified two independent m6A modification patterns with distinct biological functions, immunological characteristics, and prognoses in KIRC. Next, we developed an m6A score algorithm to quantify an individual's m6A modification pattern, which was independently validated in external cohorts. The m6A cluster 1 and low m6A score groups were characterized by a hot tumor microenvironment with an increased infiltration level of cytotoxic immune cells, higher tumor mutation burden, higher immune checkpoint expression, and decreased stroma-associated signature enrichment. In general, the m6A cluster 1 and low m6A score groups reflected an inflammatory phenotype, which may be more sensitive to anticancer immunotherapy. The m6A cluster 2 and high m6A score groups indicated a non-inflammatory phenotype, which may not be sensitive to immunotherapy but rather to targeted therapy. In this study, we first identified m6A clusters and m6A scores to elucidate immune phenotypes and to predict the prognosis and immunotherapy response in KIRC, which can guide urologists for making more precise clinical decisions.
BackgroundThe TGF-β pathway plays critical roles in numerous malignancies. Nevertheless, its potential role in prognosis prediction and regulating tumour microenvironment (TME) characteristics require further elucidation in bladder cancer (BLCA).MethodsTGF-β-related genes were comprehensively summarized from several databases. The TCGA-BLCA cohort (training cohort) was downloaded from the Cancer Genome Atlas, and the independent validation cohorts were gathered from Xiangya Hospital (Xinagya cohort) and Gene Expression Omnibus. Initially, we identified differentially expressed TGF-β genes (DEGs) between cancer and normal tissues. Subsequently, univariate Cox analysis was applied to identify prognostic DEGs, which were further used to develop the TGF-β risk score by performing LASSO and multivariate Cox analyses. Then, we studied the role of the TGF-β risk score in predicting prognosis and the TME phenotypes. In addition, the role of the TGF-β risk score in guiding precision treatments for BLCA has also been assessed.ResultsWe successfully constructed a TGF-β risk score with an independent prognostic prediction value. A high TGF-β risk score indicated an inflamed TME, which was supported by the positive relationships between the risk score, enrichment scores of anticancer immunity steps, and the infiltration levels of tumour-infiltrating immune cells. In addition, the risk score positively correlated with the expression of several immune checkpoints and the T cell inflamed score. Consistently, the risk score was positively related to the enrichment scores of most immunotherapy-positive pathways. In addition, the sensitivities of six common chemotherapeutic drugs were positively associated with the risk score. Furthermore, higher risk score indicated higher sensitivity to radiotherapy and EGFR-targeted therapy. On the contrary, patients with low-risk scores were more sensitive to targeted therapies, including the blockade of FGFR3 and WNT-β-catenin networks.ConclusionsWe first constructed and validated a TGF-β signature that could predict the prognosis and TME phenotypes for BLCA. More importantly, the TGF-β risk score could aid in individual precision treatment for BLCA.
Bladder cancer is one of the leading causes of cancer deaths worldwide. Early detection of lymph node metastasis of bladder cancer is essential to improve patients’ prognosis and overall survival. Current diagnostic methods are limited, so there is an urgent need for new specific biomarkers. Non-coding RNA and m6A have recently been reported to be abnormally expressed in bladder cancer related to lymph node metastasis. In this review, we tried to summarize the latest knowledge about biomarkers, which predict lymph node metastasis in bladder cancer and their mechanisms. In particular, we paid attention to the impact of non-coding RNA on lymphatic metastasis of bladder cancer and its specific molecular mechanisms, as well as some prediction models based on imaging, pathology, and biomolecules, in an effort to find more accurate diagnostic methods for future clinical application.
The limited effect of adjuvant therapy for advanced bladder cancer (BCa) leads to a poor prognosis. Increasing evidence has shown that RNA N6-methyladenosine (m 6 A) modification plays important functional roles in tumorigenesis. Nevertheless, the role and mechanism of m6A-modified noncoding RNAs (ncRNAs) in BCa remain largely unknown. Methods: RT-PCR, western blotting and ONCOMINE dataset were used to determine the dominant m 6 A-related enzyme in BCa. M 6 A-lncRNA epitranscriptomic microarray was used to screen candidate targets of METTL14. RT-PCR, MeRIP and TCGA dataset were carried out to confirm the downstream target of METTL14. CHIRP/MS was conducted to identify the candidate proteins binding to lncDBET. RT-PCR, western blotting, RIP and KEGG analysis were used to confirm the target of lncDBET. The levels of METTL14, lncDBET and FABP5 were tested in vitro and in vivo . CCK-8, EdU, transwell and flow cytometry assays were performed to determine the oncogenic function of METTL14, lncDBET and FABP5, and their regulatory networks. Results : We identified that the m 6 A level of total RNA was elevated and that METTL14 was the dominant m6A-related enzyme in BCa. m 6 A modification mediated by METTL14 promoted the malignant progression of BCa by promoting the expression of lncDBET. Upregulated lncDBET activated the PPAR signalling pathway to promote the lipid metabolism of cancer cells through direct interaction with FABP5, thus promoting the malignant progression of BCa in vitro and in vivo . Conclusions : Our study establishes METTL14/lncDBET/FABP5 as a critical oncogenic axis in BCa.
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