Identification and validation of shared gene signature of kidney renal clear cell carcinoma and COVID-19.

Background: COVID-19 is a severe infectious disease caused by the SARS-CoV-2 virus, and previous studies have shown that patients with kidney renal clear cell carcinoma (KIRC) are more susceptible to SARS-CoV-2 infection than the general population. Nevertheless, their co-pathogenesis remains incompletely elucidated. Methods: We obtained shared genes between these two diseases based on public datasets, constructed a prognostic risk model consisting of hub genes, and validated the accuracy of the model using internal and external validation sets. We further analyzed the immune landscape of the prognostic risk model, investigated the biological functions of the hub genes, and detected their expression in renal cell carcinoma cells using qPCR. Finally, we searched the candidate drugs associated with hub gene-related targets from DSigDB and CellMiner databases. Results: We obtained 156 shared genes between KIRC and COVID-19 and constructed a prognostic risk model consisting of four hub genes. Both shared genes and hub genes were highly enriched in immune-related functions and pathways. Hub genes were significantly overexpressed in COVID-19 and KIRC. ROC curves, nomograms, etc., showed the reliability and robustness of the risk model, which was validated in both internal and external datasets. Moreover, patients in the high-risk group showed a higher proportion of immune cells, higher expression of immune checkpoint genes, and more active immune-related functions. Finally, we identified promising drugs for COVID-19 and KIRC, such as etoposide, fulvestrant, and topotecan. Conclusion: This study identified and validated four shared genes for KIRC and COVID-19. These genes are associated with immune functions and may serve as potential prognostic biomarkers for KIRC. The shared pathways and genes may provide new insights for further mechanistic research and treatment of comorbidities.

CircFSCN1 induces tumor progression and triggers epithelial-mesenchymal transition in bladder cancer through augmentation of MDM2-mediated p53 silencing.

BACKGROUND: Compelling evidences indicated that circular RNA (circRNA) was a novel class of non-coding RNA that played critical and distinct roles in various human cancers. Their roles and underlying mechanisms, however, in bladder cancer (BC) remained largely unknown. METHODS: A novel circRNA derived from oncogene FSCN1, namely circFSCN1, was selected from a microarray analysis. The phenotypic alterations were assessed with functional experiments in vitro and in vivo. RNA immunoprecipitation, RNA pull-down, luciferase reporter assay, and rescue experiments were sequentially proceeded to clarify the interactions among circFSCN1, miR-145-5p, MDM2, and p53. RESULTS: We observed that the expression of circFSCN1 was elevated in BC cell lines and tissues. Next, we validated the fundamental properties of circFSCN1. In the meanwhile, we noticed that elevated circFSCN1 level, pathological T stage, and tumor grade were identified as independent factors associated with cancer-specific survivals of patients with BC，as determined by univariate and multivariable COX regression analyses. Phenotype studies demonstrated the promoting effects of circFSCN1 on the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of BC cells. Mechanistically, we elucidated that circFSCN1, primarily localized in the cytoplasm, upregulated the expression of MDM2, a well-known inhibitor of p53, by directly binding to miR-145-5p. CONCLUSIONS: Elevated circFSCN1 induces tumor progression and EMT in BC via enhancing MDM2-mediated silencing of p53 by sponging miR-145-5p. Targeting circFSCN1, a novel identified target, may be conducive in impeding BC progression and providing survival benefits for patients with BC.

Deciphering the immunological and prognostic features of bladder cancer through platinum-resistance-related genes analysis and identifying potential therapeutic target P4HB.

Objectives: To identify the molecular subtypes and develop a scoring system for the tumor immune microenvironment (TIME) and prognostic features of bladder cancer (BLCA) based on the platinum-resistance-related (PRR) genes analysis while identifying P4HB as a potential therapeutic target. Methods: In this study, we analyzed gene expression data and clinical information of 594 BLCA samples. We used unsupervised clustering to identify molecular subtypes based on the expression levels of PRR genes. Functional and pathway enrichment analyses were performed to understand the biological activities of these subtypes. We also assessed the TIME and developed a prognostic signature and scoring system. Moreover, we analyzed the efficacy of immune checkpoint inhibitors. Then we conducted real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) experiments to detect the expression level of prolyl 4-hydroxylase subunit beta (P4HB) in BLCA cell lines. Transfection of small interference ribonucleic acid (siRNA) was performed in 5637 and EJ cells to knock down P4HB, and the impact of P4HB on cellular functions was evaluated through wound-healing and transwell assays. Finally, siRNA transfection of P4HB was performed in the cisplatin-resistant T24 cell to assess its impact on the sensitivity of BLCA to platinum-based chemotherapy drugs. Results: In a cohort of 594 BLCA samples (TCGA-BLCA, n=406; GSE13507, n=188), 846 PRR-associated genes were identified by intersecting BLCA expression data from TCGA and GEO databases with the PRR genes from the HGSOC-Platinum database. Univariate Cox regression analysis revealed 264 PRR genes linked to BLCA prognosis. We identified three molecular subtypes (Cluster A-C) and the PRR scoring system based on PRR genes. Cluster C exhibited a better prognosis and lower immune cell infiltration compared to the other Clusters A and B. The high PRR score group was significantly associated with an immunosuppressive tumor microenvironment, poor clinical-pathological features, and a poor prognosis. Furthermore, the high PRR group showed higher expression of immune checkpoint molecules and a poorer response to immune checkpoint inhibitors than the low PRR group. The key PRR gene P4HB was highly expressed in BLCA cell lines, and cellular functional experiments in vitro indicate that P4HB may be an important factor influencing BLCA migration and invasion. Conclusion: Our study demonstrates that the PRR signatures are significantly associated with clinical-pathological features, the TIME, and prognostic features. The key PRR gene, P4HB, s a biomarker for the individualized treatment of BLCA patients.

Transcriptome sequencing and single-cell sequencing analysis identify GARS1 as a potential prognostic and immunotherapeutic biomarker for multiple cancers, including bladder cancer.

Background: Glycyl-tRNA synthetase 1 (GARS1) belongs to the aminoacyl-tRNA synthetase family, playing a crucial role in protein synthesis. Previous studies have reported a close association between GARS1 and various tumors. However, the role of GARS1 in human cancer prognosis and its impact on immunology remain largely unexplored. Methods: In this study, we comprehensively analyzed GARS1 expression at the mRNA and protein levels, examined genetic alterations, and assessed its prognostic implications in pan-cancer, with a specific emphasis on the immune landscape. Furthermore, we investigated the functional enrichment of genes related to GARS1 and explored its biological functions using single-cell data. Finally, we conducted cellular experiments to validate the biological significance of GARS1 in bladder cancer cells. Results: In general, GARS1 expression was significantly upregulated across multiple cancer types, and it demonstrated prognostic value in various cancers. Gene Set Enrichment Analysis (GSEA) revealed the association of GARS1 expression with multiple immune regulatory pathways. Moreover, GARS1 exhibited significant correlations with immune infiltrating cells (such as DC, CD8+T cells, Neutrophils, and Macrophages), immune checkpoint genes (CD274, CD276), and immune regulatory factors in tumors. Additionally, we observed that GARS1 could effectively predict the response to anti-PD-L1 therapy. Notably, Ifosfamide, auranofin, DMAPT, and A-1331852 emerged as potential therapeutic agents for GARS1-upregulated tumors. Our experimental findings strongly suggest that GARS1 promotes the proliferation and migration of bladder cancer cells. Conclusion: GARS1 holds promise as a potential prognostic marker and therapeutic target for pan-cancer immunotherapy, offering valuable insights for the development of more precise and personalized approaches to tumor treatment in the future.

The value of EYA1/3/4 in clear cell renal cell carcinoma: a study from multiple databases.

There is evidence from multiple studies that dysregulation of the Eyes Absent (EYA) protein plays multiple roles in many cancers. Despite this, little is known about the prognostic significance of the EYAs family in clear cell renal cell carcinoma (ccRCC). We systematically analyzed the value of EYAs in Clear Cell Renal Cell Carcinoma. Our analysis included examining transcriptional levels, mutations, methylated modifications, co-expression, protein-protein interactions (PPIs), immune infiltration, single-cell sequencing, drug sensitivity, and prognostic values. We based our analysis on data from several databases, including the Cancer Genome Atlas database (TCGA), the Gene Expression Omnibus database (GEO), UALCAN, TIMER, Gene Expression Profiling Interactive Analysis (GEPIA), STRING, cBioPortal and GSCALite. In patients with ccRCC, the EYA1 gene was significantly highly expressed, while the expression of EYA2/3/4 genes showed the opposite trend. The level of expression of the EYA1/3/4 gene was significantly correlated with the prognosis and clinicopathological parameters of ccRCC patients. Univariate and multifactorial Cox regression analyses revealed EYA1/3 as an independent prognostic factor for ccRCC, establishing nomogram line plots with good predictive power. Meanwhile, the number of mutations in EYAs was also significantly correlated with poor overall survival (OS) and progression-free survival (PFS) of patients with ccRCC. Mechanistically, EYAs genes play an essential role in a wide range of biological processes such as DNA metabolism and double-strand break repair in ccRCC. The majority of EYAs members were related to the infiltration of immune cells, drug sensitivity, and methylation levels. Furthermore, our experiment confirmed that EYA1 gene expression was upregulated, and EYA2/3/4 showed low expression in ccRCC. The increased expression of EYA1 might play an important role in ccRCC oncogenesis, and the decreased expression of EYA3/4 could function as a tumor suppressor, suggesting EYA1/3/4 might serve as valuable prognostic markers and potential new therapeutic targets for ccRCC.

Prognostic biomarker DARS2 correlated with immune infiltrates in bladder tumor.

Background: DARS2 is a pivotal member of the Aminoacyl-tRNA synthetases family that is critical for regulating protein translation. However, the biological role of DARS2 in bladder cancer remains elusive. Methods: We analyzed the correlation between DARS2 expression and prognosis, tumor stage, and immune infiltration in bladder cancer using The Cancer Genome Atlas (TCGA) database. We validated findings in clinical samples from The First Affiliated Hospital of Nanchang University and explored the biological functions of DARS2 using cell and animal models. Results: We found DARS2 to be upregulated in bladder cancer, associated with tumor progression and poor prognosis. Immune infiltration analysis suggested that DARS2 may facilitate immune evasion by modulating PD-L1. Cell and animal experiments validated that DARS2 knockdown and overexpress can inhibit or increase cancer cell proliferation, metastasis, tumorigenesis, immune escape, and PD-L1 levels. Conclusions: Our study reveals DARS2 as a potential prognostic biomarker and immunotherapy target in BLCA.

Pathological diagnostic nomograms for predicting malignant histology and unfavorable pathology in patients with endophytic renal tumor.

Purpose: To develop and validate nomograms for pre-treatment prediction of malignant histology (MH) and unfavorable pathology (UP) in patients with endophytic renal tumors (ERTs). Methods: We retrospectively reviewed the clinical information of 3245 patients with ERTs accepted surgical treatment in our center. Eventually, 333 eligible patients were included and randomly enrolled into training and testing sets in a ratio of 7:3. We performed univariable and multivariable logistic regression analyses to determine the independent risk factors of MH and UP in the training set and developed the pathological diagnostic models of MH and UP. The optimal model was used to construct a nomogram for MH and UP. The area under the receiver operating characteristics (ROC) curves (AUC), calibration curves and decision curve analyses (DCA) were used to evaluate the predictive performance of models. Results: Overall, 172 patients with MH and 50 patients with UP were enrolled in the training set; and 74 patients with MH and 21 patients with UP were enrolled in the validation set. Sex, neutrophil-to-lymphocyte ratio (NLR), R score, N score and R.E.N.A.L. score were the independent predictors of MH; and BMI, NLR, tumor size and R score were the independent predictors of UP. Single-variable and multiple-variable models were constructed based on these independent predictors. Among these predictive models, the malignant histology-risk nomogram consisted of sex, NLR, R score and N score and the unfavorable pathology-risk nomogram consisted of BMI, NLR and R score performed an optimal predictive performance, which reflected in the highest AUC (0.842 and 0.808, respectively), the favorable calibration curves and the best clinical net benefit. In addition, if demographic characteristics and laboratory tests were excluded from the nomograms, only the components of the R.E.N.A.L. Nephrometry Score system were included to predict MH and UP, the AUC decreased to 0.781 and 0.660, respectively (P=0.001 and 0.013, respectively). Conclusion: In our study, the pathological diagnostic models for predicting malignant and aggressive histological features for patients with ERTs showed outstanding predictive performance and convenience. The use of the models can greatly assist urologists in individualizing the management of their patients.

Novel circular RNA circ_0086722 drives tumor progression by regulating the miR-339-5p/STAT5A axis in prostate cancer.

Recent studies validate that circular RNAs have played critical regulatory functions in cancer biology. However, their contribution to prostate cancer (PCa) remained largely unclear. Our study aimed to explore the regulatory function and underlying mechanisms of circ_0086722 in PCa. The circ_0086722 levels in PCa tissues and cell lines were detected through qRT-PCR. In vivo and in vitro experiments were performed to evaluate the functions of circ_0086722 in PCa. Subsequently, the underlying mechanisms of circ_0086722 were explored with qRT-PCR, RNA immunoprecipitation, miRNA pull-down, and luciferase reporter assay experiments. Results revealed that circ_0086722 was highly expressed in PCa tissues and cell lines. Furthermore, high levels of circ_0086722 were positively correlated with pT3 stage, higher specimen Gleason score (>7), and worse biochemical recurrence-free survivals of PCa patients. Then, functional experiments revealed that circ_0086722 accelerated PCa proliferation and progression. Moreover, we demonstrated that circ_0086722 could mechanistically relieve the repressive effects of miR-339-5p on its target STAT5A, which facilitates PCa development. In conclusion, our findings revealed that circ_0086722 drives PCa development via the miR-339-5p/STAT5A axis, and it may function as a potential prognostic biomarker or therapeutic target for PCa treatment. Further studies with large sample sizes and sufficiently long follow-up periods are necessary to confirm the predictive role of circ_0086722 for the prognosis of PCa patients.

LncRNA SNHG17 aggravated prostate cancer progression through regulating its homolog SNORA71B via a positive feedback loop.

Prostate cancer (PC) is a prevalent male malignancy with high occurrence rate. Recent studies have showed that small nucleolar host genes (SNHGs) and their homolog small nucleolar RNAs (snoRNAs) elicit regulatory functions in carcinogenesis. Present study aimed to investigate the role of SNHG17 and its homolog SNORA71B in PC. Function of SNHG17 and SNORA71B in PC is detected by CCK-8, colony formation, flow cytometry analysis of apoptosis, and transwell migration assay. The mechanism whereby SNHG17 regulated SNORA71B was detected by RIP, pulldown, ChIP, and luciferase reporter assays. Results depicted that transcript 6 of SNHG17 and SNORA71B were upregulated in PC. Knockdown of SNHG17 or SNORA71B weakened proliferation, invasion, migration, and epithelial-to-mesenchymal transition (EMT) and strengthened apoptosis. Mechanistically, SNHG17 and SNORA71B were transcriptionally activated by signal transducer and activator of transcription 5A (STAT5A). SNHG17 positively regulated SNORA71B in PC cell lines and other cell lines. SNHG17 sponged miR-339-5p to upregulate STAT5A and therefore to cause transactivation of SNORA71B. Rescue experiments delineated that SNORA71B was required for the regulation of SNHG17 on PC. Moreover, SNHG17 silence hindered tumorigenesis of PC in vivo. In conclusion, current study first revealed that lncRNA SNHG17 aggravated prostate cancer progression through regulating its homolog SNORA71B via a positive feedback loop, which might do help to the pursuit of better PC treatment.