Xingxing Tang

Introduction: To investigate the diagnostic and prognostic value of commonly used immunohistochemical markers regarding high-grade disease, muscle-invasion bladder cancer (MIBC) and survival in bladder cancer. Methods: A total of 477 patients diagnosed with bladder cancer at Peking University Cancer Hospital between 2009 and 2024 were included. The immunohistochemical markers included CK7, CK20, GATA3, Uroplakin 3, CK5/6, P40, P63, Syn, CD56, CGA, Vimentin, S100, LCA, Ki67, P53, Her2, EGFR, PD-L1, PD-1 tumor, PD-1 stroma, and Pan-TRK. Logistic analyses were used to determine the diagnostic value of the markers for high-grade disease and MIBC. Cox regression analyses were used to determine the prognostic value of the markers for survival. Results: We found Ki67 positivity (p < 0.001) and Her2 positivity (p = 0.001) might have an association with high-grade disease, while no marker demonstrated diagnostic value for MIBC. Patients with CK7 positivity (p = 0.012), Uroplakin 3 positivity (p = 0.004), and PD-1 (stroma) positivity (p = 0.037) had better overall survival (OS) than those with negative expression, while Cox regression analyses showed only CK7 positivity (p = 0.025) and Uroplakin 3 positivity (p = 0.008) had prognostic value for better OS. However, considering there were only 2 CK7-negative patients, the sample size might be insufficient to demonstrate its prognostic value. Conclusions: These results suggest that Ki67 positivity and Her2 positivity might have association with high-grade disease, and Uroplakin 3 positivity might have prognostic value for better OS. However, these conclusions require further clarification through larger-scale studies in the future.

Bladder cancer is one of the most common malignancies of the urinary system. Identifying new potential therapeutic targets and exploring molecular mechanisms are crucial for improving treatment and prognosis. The hyperpolarization-activated cyclic nucleotide-gated (HCN) channel 2, known to play a key role in various physiological and pathological processes, has an unclear function and mechanism of action in bladder cancer. We employed bioinformatics analysis and immunohistochemistry to assess the role of HCN2 in bladder cancer, integrating in vitro and in vivo models to evaluate the impact of HCN2 on cell behavior. Molecular interactions were characterized using immunoprecipitation, chromatin immunoprecipitation, and dual-luciferase reporter assays. Our investigation revealed a significant upregulation of HCN2 in bladder cancer tissues, which was predictive of a poorer clinical outcome. Functionally, HCN2 knockdown in bladder cancer impeded cell proliferation, induced apoptosis, and curtailed migration and invasion. Mechanistically, the overexpression of HCN2 contributed to the translocation of the REST transcription factor into the nucleus and facilitated its binding to the BGN promoter for transcriptional activation of its expression. This regulatory mechanism was shown to suppress ferroptosis, a form of regulated cell death, thereby enhancing the proliferative and tumorigenesis of bladder cancer cells. This study uncovers the novel mechanism by which HCN2 regulates ferroptosis via the REST-BGN axis, affecting bladder cancer cell behavior, and provides new perspectives and strategies for future clinical treatment.

Disitamab Vedotin has shown good therapeutic efficacy against bladder cancer. Although its mechanism is clear, the regulation of gene expression in bladder cancer cells by Disitamab Vedotin is not fully understood. We searched the GEO database and identified the GSE237789 dataset, in which researchers treated the bladder cancer cell line SW780 with Disitamab Vedotin and performed high-throughput transcriptome sequencing. Compared with the control SW780 cells, the expression levels of the vast majority of genes (16,223/16,390, 98.98%) in Disitamab Vedotin-treated SW780 cells remained unchanged. Only one hundred fifty-nine genes (0.97%) were upregulated, and eight genes (0.05%) were downregulated. Enrichment analysis results showed that the related differentially expressed genes (DEGs) were mainly enriched in the TNF signaling pathway, NF-κB signaling pathway, and other pathways. Protein–protein interaction analysis revealed that 10 genes, TNF, IL1B, IL1A, CXCL8, CXCL1, CCL2, MMP9, ICAM1, CXCL10, and CCL20, had the highest connectivity, and all of these genes belong to the TNF signaling pathway. These results suggest that the TNF signaling pathway is the key pathway regulated by Disitamab Vedotin in bladder cancer cells, which may represent a stress response of bladder cancer cells to Disitamab Vedotin.

Background/Objectives: Procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1 (PLOD1) is known as an enhancer of collagen fiber deposition and cross-linking stability. However, there is limited information on its function in tumors. In this study, we aimed to elucidate the function and potential mechanism of action of PLOD1 across cancers. Methods: We assessed the pan-cancer expression, mutation, methylation and prognostic value of PLOD1 through multiple online databases. In addition, we performed correlation analyses of its immunological features, as well as functional assessment analyses of PLOD1. Finally, we assessed the effect of PLOD1 knockdown on bladder tumor cells using in vitro experiments. Results: Our findings suggest that PLOD1 is aberrantly expressed in multiple cancer types, accompanied by a poor prognosis. Epigenetic alterations in PLOD1 are highly heterogeneous across a wide range of tumors, and aberrant methylation and copy number variants correlate with a poor prognosis. In the tumor microenvironment, PLOD1 expression correlated positively with the infiltration level of various immunosuppressive cells (e.g., monocytes, macrophages and tumor-associated fibroblasts) and negatively with immune-killing cells (e.g., CD8⁺ T cells, B cells and CD4⁺ T cells). In addition, PLOD1 expression was associated with immune checkpoints and immunomodulatory genes. Finally, in vitro experiments demonstrated that knockdown of PLOD1 reduced the proliferation, migration and antiapoptotic abilities of T24 cells. Conclusions: The results of this study demonstrate that PLOD1 is a potential oncogene and prognostic biomarker in pan-cancer; tumor tissues with high PLOD1 expression reveal a relatively immunosuppressive tumor microenvironment.

(1) Background: CREB-binding protein (CBP) is a key transcriptional coactivator of androgen receptors (AR). We conducted this study to investigate the effects of CBP on AR expression and proliferation in benign prostatic hyperplasia (BPH) prostate epithelial cells. (2) Methods: By analyzing a published data set, we found that CBP was closely related to the gene expression of AR in prostate cells. We enrolled 20 BPH patients who underwent transurethral resection of the prostate (TURP) in Peking University First Hospital in 2022, and analyzed the expressions of CBP and AR in BPH prostate tissues. Then, we used ICG-001 and shRNA to inhibit CBP in prostate epithelial cells (BPH-1 cells and RWPE-1 cells), and conducted immunofluorescence, cell viability assay, flow cytometry analysis, and Western blot to analyze the effects of CBP on AR expression and proliferation in prostate epithelial cells. We also studied the interaction between CBP and AR through a co-immunoprecipitation assay. (3) Results: CBP is consistent with AR in expression intensity in prostate tissues. Inhibiting CBP decreases AR expression, and induces proliferation inhibition, apoptosis, and cell cycle arrest in BPH prostate epithelial cells. The co-immunoprecipitation assay showed that CBP binds with AR to form transcription complexes in prostate epithelial cells. (4) Conclusions: Inhibiting CBP decreases AR expression and inhibits proliferation in benign prostate epithelial cells. CBP may be a potential target to affect AR expression and the proliferation of prostate epithelial cells in BPH.

Background: Metastasis suppressor 1 (MTSS1) is a multi-functional cytoskeletal protein. Recent research showed that MTSS1 is a potential tumor suppressor in many types of cancer cells, including kidney and bladder cancer cells. However, the clinical implication of MTSS1 in human bladder uroepithelium cell carcinoma (BUCC) and its potential in suppressing BUCC tumorigenesis remains undetermined. In the present study, the expression of MTSS1 in human BUCC tissue samples, and correlations between MTSS1 and pathological grade and stage of the tumors were examined in BUCC specimens. The function of MTSS1 in BUCC progression was explored. Materials and Methods: The mRNA and protein expression of MTSS1 were examined in 68 BUCC tissue samples with matching adjacent normal bladder tissues using quantitative real-time PCR and western blotting. Furthermore, the bladder cancer cell line 5637 was used to determine the anticancer effect of MTSS1. Results: Lower MTSS1 mRNA expression was recorded in BUCC tissues compared to normal bladder tissues. A lower MTSS1 mRNA level was observed in tumors with high clinical stage and with high pathological nuclear grade. Likewise, MTSS1 protein expression in normal bladder tissue was significantly higher than that in BUCC tissue. The protein level of MTSS1 significantly negatively correlated with clinical stage and pathological nuclear grade of BUCC. Cumulative survival curves indicated that MTSS1 expression was negatively correlated with survival time: patients with a high level of MTSS1 had significantly longer survival time than those with a low level of MTSS1 (p<0.001). Overexpression of MTSS1 reduced BUCC cell proliferation, cell-cycle progression and colony formation, but had no influence on BUCC cell apoptosis. Conclusion: Overexpression of MTSS1 suppresses BUCC development, providing a novel perspective for BUCC tumorigenesis and a potential therapeutic target for BUCC.