RESUMO
The mechanism underlying N6-methyladenosine (m6A) modification in bladder cancer (BC) remains elusive. We identified that the RBM15/METTL3 complex enhances m6A modification and promotes the ENO1 protein translation efficiency through its 359A site by depending on YTHDF1 in BC cells. In the tumor microenvironment, TGF-ß effectively stimulates RBM15/METTL3 expression to improve ENO1 mRNA m6A modification through the Smad2/3 pathway. Reduced ENO1 m6A levels hamper tumor proliferation both in vitro and in vivo. Mechanistically, ENO1 augments PCNA protein stability by reducing its K48-linked ubiquitination and thus prevents protein degradation through the endoplasmic reticulum-associated degradation pathway. According to the subsequent experiments, the ENO1 inhibitor significantly reduced tumor proliferation both in vitro and in vivo. Our study highlights the significance of RBM15/METTL3 complex-mediated ENO1 mRNA m6A modification in ENO1 expression. It also reveals a novel mechanism by which ENO1 promotes BC progression, thereby suggesting that ENO1 can be a therapeutic target for BC.
Assuntos
Adenosina , Proliferação de Células , Proteínas de Ligação a DNA , Progressão da Doença , Fosfopiruvato Hidratase , Proteínas de Ligação a RNA , Proteínas Supressoras de Tumor , Ubiquitinação , Neoplasias da Bexiga Urinária , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/tratamento farmacológico , Humanos , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Adenosina/análogos & derivados , Adenosina/metabolismo , Animais , Fosfopiruvato Hidratase/metabolismo , Fosfopiruvato Hidratase/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Camundongos , Metiltransferases/metabolismo , Metiltransferases/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Biossíntese de Proteínas/efeitos dos fármacos , Camundongos Nus , Biomarcadores Tumorais , Antígeno Nuclear de Célula em ProliferaçãoRESUMO
PURPOSE: Myofibroblastic cancer-associated fibroblasts (myCAFs) are important components of the tumor microenvironment closely associated with tumor stromal remodeling and immunosuppression. This study aimed to explore myCAFs marker gene biomarkers for clinical diagnosis and therapy for patients with bladder cancer (BC). MATERIALS AND METHODS: BC single-cell RNA sequencing (scRNA-seq) data were obtained from the National Center for Biotechnology Information Sequence Read Archive. Transcriptome and clinical data were downloaded from The Cancer Genome Atlas and the Gene Expression Omnibus databases. Subsequently, univariate Cox and LASSO (Least Absolute Shrinkage and Selection Operator regression) regression analyses were performed to construct a prognostic signature. Immune cell activity was estimated using single-sample gene set enrichment analysis whilst the TIDE (tumor immune dysfunction and exclusion) method was employed to assess patient response to immunotherapy. The chemotherapy response of patients with BC was evaluated using genomics of drug sensitivity in cancer. Furthermore, Immunohistochemistry was used to verify the correlation between MAP1B expression and immunotherapy efficacy. The scRNA-seq data were analyzed to identify myCAFs marker genes. RESULTS: Combined with bulk RNA-sequencing data, we constructed a two-gene (COL6A1 and MAP1B) risk signature. In patients with BC, the signature demonstrated outstanding prognostic value, immune infiltration, and immunotherapy response. This signature served as a crucial guide for the selection of anti-tumor chemotherapy medications. Additionally, immunohistochemistry confirmed that MAP1B expression was significantly correlated with immunotherapy efficacy. CONCLUSIONS: Our findings revealed a typical prognostic signature based on myCAF marker genes, which offers patients with BC a novel treatment target alongside theoretical justification.
Assuntos
Biomarcadores Tumorais , Fibroblastos Associados a Câncer , Neoplasias da Bexiga Urinária , Humanos , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/imunologia , Neoplasias da Bexiga Urinária/terapia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Prognóstico , Biomarcadores Tumorais/genética , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Masculino , Feminino , Transcriptoma , Resultado do Tratamento , MiofibroblastosRESUMO
Urothelial carcinoma (UC) with testicular metastasis is extremely rare, and its modes of metastasis, prognosis, and treatment are unclear. In this report, we present an extraordinarily rare case of testicular metastasis arising from UC 8 years after surgery. The patient underwent left orchiepididymectomy and received immunotherapy postoperatively. After a 6-month follow-up, there were no signs of recurrence. Moreover, the clinical characteristics, metastasis pattern, and treatment plan were also summarized based on 14 earlier reported cases of UC with testicular metastasis.