Multi-omics landscape analysis reveals the pan-cancer association of arginine biosynthesis genes with tumor immune evasion and therapy resistance.

Background: The metabolism of arginine, a conditionally essential amino acid, plays a crucial role in cancer progression and prognosis. However, a more detailed understanding of the influence of arginine biosynthesis genes in cancer is currently unavailable. Methods: We performed an integrative multi-omics analysis using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases to determine the characteristics of these genes across multiple cancer types. To measure the overall activity of arginine biosynthesis genes in cancer, we calculated arginine biosynthesis scores based on gene expression. Results: Our results indicated that the arginine biosynthesis score was negatively correlated with immune-related pathways, immune infiltration, immune checkpoint expression, and patient prognosis, and single-cell data further clarified that patients with high arginine biosynthesis scores showed a reduced proportion of T and B cells in an immune desert tumor microenvironment and were insensitive to immunotherapy. We also identified several potential drugs through the Cancer Therapeutic Response Portal (CTRP) and Genomics of Drug Sensitivity in Cancer (GDSC) databases that could target arginine biosynthesis genes and potentially improve the response rate to immunotherapy in patients with a high arginine biosynthesis fraction. Conclusion: Overall, our analyses emphasize that arginine biosynthesis genes are associated with immune evasion in several cancers. Targeting these genes may facilitate more effective immunotherapy.

HES4 is a potential biomarker for bladder cancer: a Mendelian randomization study.

Background: Patients with bladder cancer (BLCA) have a poor prognosis and little progress has been made in treatment. Therefore, the purpose of this work was to employ Mendelian randomization (MR) and transcriptome analysis to identify a novel biomarker that could be used to reliably diagnose BLCA. Methods: TCGA-BLCA and GSE121711 datasets were obtained from public databases. Genome-wide association study (GWAS) data of BLCA outcome (373,295 samples containing 9,904,926 single nucleotide polymorphisms) were obtained through the IEU OpenGWAS database. Differentially expressed genes were applied as exposure factors, and MR analysis was performed to identify genes that had a causal relationship with BLCA. Then, the patients were divided into high and low expression groups according to the expression levels of candidate genes, and genes with survival differences were identified. Univariate and multivariate Cox regression were used to investigate the prognostic value of the expression of these genes. A nomogram was constructed based on independent prognostic factors, and we analyzed the functions and pathways associated with the identified genes as well as their relationship with the immune microenvironment. Results: HES4 was identified as a biomarker. HES4 status, age, and stage were identified as independent prognostic factors, and an excellent nomogram was established. Bioinformatic analysis suggested that HES4 might be associated with the activation of the immune response, bone development, and cancer pathways. The BLCA samples were divided into high and low HES4 groups. The stromal score and 33 immune cells were remarkably different between the two groups, with HES4 expression being negatively correlated with macrophages and mast cells, and positively correlated with eosinophils and central memory CD4+ T cells. Finally, HES4 was up-regulated in cancer samples in both TCGA-BLCA and GSE121711 datasets. Conclusion: This study identified HES4 as an independent prognostic factor for BLCA outcome based on MR and transcriptome analysis, which provides useful information for future research on and treatment of BLCA.

Identification of potential biomarkers for progression and prognosis of renal clear cell carcinoma by comprehensive bioinformatics analysis.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is the most common pathological type of renal cell carcinoma (RCC), and effective biomarkers will improve diagnosis and treatment. OBJECTIVE: This study investigated NPEPL1 expression in ccRCC through public databases and clinical samples and assessed its correlation with clinicopathological features and patient prognosis. METHOD: Data from The Cancer Genome Atlas and clinical specimens were gathered, NPEPL1 expression levels were analyzed; a receiver operating characteristic (ROC) curve was used to evaluate the diagnostic value of NPEPL1; and clinicopathological data was used to study the correlations between expression and clinical parameters. NPEPL1's prognostic value was appraised using a Kaplan-Meier (K-M) survival curve, Cox regression analysis, and a nomogram model; Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of differently expressed genes between tissues with high and low NPEPL1 expression were used to estimate the underlying mechanisms involved. RESULTS: NPEPL1 was significantly higher-expressed in ccRCC tissue. ROC analysis showed that NPEPL1 had noteworthy diagnostic efficacy. NPEPL1 expression was closely related to clinicopathological parameters, such as T and M stage. K-M analysis showed that overall survival was significantly shortened with high NPEPL1 expression. Cox regression analysis showed that NPEPL1 expression was an independent risk factor predicting overall survival. The nomogram showed a significantly high clinical value in predicting the 1-, 3-, and 5-year survival probabilities in ccRCC. GO and KEGG enrichment analysis suggested that NPEPL1 may promote the occurrence and development of ccRCC via the Ras signaling and other pathways. CONCLUSION: NPEPL1 expression in ccRCC was higher than that in normal kidney tissues and was significantly associated with advanced clinical stage and poor prognosis. Therefore, NPEPL1 is a promising prognostic biomarker.

A giant neobladder stone with insignificant symptoms: A case report and literature review.

Background: Giant neobladder lithiasis after orthotopic bladder replacement is an infrequent but important long-term complication, which should be diagnosed and treated early. If left untreated, it may eventually lead to irreversible acute kidney injury and seriously affect the quality of life of patients. Here, we present a rare case of a patient who presented with a massive neobladder stone after radical cystectomy done with orthotopic neobladder construction, followed by a challenging stone extraction process. Case presentation: A 70-year-old female patient presented with a massive neobladder stone 14 years after radical cystectomy done with orthotopic neobladder construction. A computed tomography scan showed a large elliptic stone. The patient underwent suprapubic cystolithotomy surgery, which removed her giant-sized stone in the neobladder. The size of the bladder stone that was removed was 13 cm × 11.5 cm × 9 cm, with a total weight of 903 g. To date, the follow-up time of treatment is 4 months, and in our patient, no pain, urinary tract infections, or other abnormalities suggestive of fistula were found. Conclusion: Imaging examination is useful for detecting neobladder lithiasis occurring after orthotopic neobladder construction. Our experience demonstrates that open cystolithotomy is an appropriate therapeutic method for treating the late-stage complication of a giant neobladder stone.

Comprehensive analyses of a tumor-infiltrating lymphocytes-related gene signature regarding the prognosis and immunologic features for immunotherapy in bladder cancer on the basis of WGCNA.

Tumor-infiltrating lymphocyte (TIL) is a class of cells with important immune functions and plays a crucial role in bladder cancer (BCa). Several studies have shown the clinical significance of TIL in predicting the prognosis and immunotherapy efficacy. TIL-related gene module was screened utilizing weighted gene coexpression network analysis. We screened eight TIL-related genes utilizing univariate Cox regression analysis, least absolute shrinkage and selection operator (LASSO) Cox regression analysis, and multivariate Cox regression analysis. Then, we established a TIL-related signature model containing the eight selected genes and subsequently classified all patients into two groups, that is, the high-risk as well as low-risk groups. Gene mutation status, prognosis, immune cell infiltration, immune subtypes, TME, clinical features, and immunotherapy response were assessed among different risk subgroups. The results affirmed that the TIL-related signature model was a reliable predictor of overall survival (OS) for BCa and was determined as an independent risk factor for BCa patients in two cohorts. Moreover, the risk score was substantially linked to age, tumor staging, TNM stage, and pathological grade. And there were different mutational profiles, biological pathways, immune scores, stromal scores, and immune cell infiltration in the tumor microenvironment (TME) between the two risk groups. In particular, immune checkpoint genes' expression was remarkably different between the two risk groups, with patients belonging to the low-risk group responding better to immune checkpoint inhibition (ICI) therapy. In conclusion, our study demonstrates that the TIL-related model was a reliable signature in anticipating prognosis, immune status, and immunotherapy response, which can help in screening patients who respond to immunotherapy.

Hsa_circ_0102485 inhibits the growth of cancer cells by regulating the miR-188-3p/ARID5B/AR axis in prostate carcinoma.

BACKGROUND: Studies have shown that circular RNAs (circRNAs) have significant potential as novel molecular markers for the diagnosis, treatment, and prognosis of prostate carcinoma (PCa). However, the role and mechanism of circRNA hsa_circ_0102485 in PCa remains unclear. MATERIALS & METHODS: The real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to quantify hsa_circ_0102485 expression in PCa. The potential mechanisms and roles of hsa_circ_0102485 in tumor growth were explored using dual-luciferase-reporter and subcutaneous-xenograft assays, rescue experiments, and immunohistochemical staining. Clinical correlations were assessed by tissue-on-a-chip in-situ hybridization and Fisher's exact test. RESULTS: Hsa_circ_0102485 expression was decreased in PCa, and overexpression of hsa_circ_0102485 suppressed the proliferation, metastasis, invasion, and antiapoptotic abilities of PCa cells. MicroRNA 188-3p (MiR-188-3p) is a direct target of hsa_circ_0102485, and cotransfection of hsa_circ_0102485 in PCa cells overexpressing miR-188-3p inhibited its promotive effects. Hsa_circ_0102485 indirectly promotes the expression of AT-rich interaction domain 5B (ARID5B) and androgen receptor (AR) by sponging miR-188-3p and inhibiting PCa cell growth. Correlation analysis showed that hsa_circ_0102485 expression in PCa was not significantly correlated with the age, International Society of Urologic Pathologists (ISUP) grade, Gleason score, or lymph node metastasis status of PCa patients. CONCLUSION: Hsa_circ_0102485 plays an inhibitory role in PCa by regulating the Mir-188-3p/ARID5B/AR axis and may be a potential diagnostic biomarker and therapeutic target for PCa that requires further study.

A Novel Long Non-Coding RNA KMU15 Promotes Growth and Chemoresistance of Bladder Cancer.

BACKGROUND: Chemotherapy constitutes one of the most important adjuvant treatments for bladder cancer. However, many patients usually develop chemoresistance during chemotherapy. At present, lncRNA has been confirmed not only to be involved in tumorigenesis and progression, but also in tumor chemoresistance. However, the relationship between lncRNAs and chemoresistance of bladder cancer have been rarely reported. METHODS: The novel lncRNA-KMU15 was screened by lncRNAs microarray and determination of IC50 in bladder cancer. The expression of KMU15 was evaluated by qRT-PCR. The correlation between KMU15 and clinicopathological parameters was analyzed from clinical cases. The effects of KMU15 on the biological behavior and chemoresistance were investigated by [3H]-TdR incorporation assay and other experiments. The effects of KMU15 on the growth of xenograft tumors and the survival of nude mice under cisplatin were examined in a xenograft mouse model. RESULTS: We confirmed that KMU15 was expressed higher in bladder cancer tissues than paired control tissues. Moreover, the expression of KMU15 was significantly positively correlated with the grade, stage, metastasis, and recurrence of bladder cancer and was significantly negatively correlated with the prognosis. In addition, KMU15 knockdown could significantly inhibit bladder cell proliferation, adhesion, migration, and chemoresistance and promoted apoptosis. Knockdown of KMU15 inhibited the growth of xenografts in nude mice and significantly prolonged the survival of tumor-bearing mice under cisplatin. CONCLUSIONS: The novel lncRNA KMU15, which is highly expressed in bladder cancer tissues, could promote the proliferation and progression and was closely related to the malignant degree of bladder cancer. It could also significantly enhance the chemoresistance of bladder cancer cells. Therefore, it was expected to be a new therapy target for bladder cancer and a potential prognosis biomarker for chemotherapy.