Background: Clear cell renal cell carcinoma (ccRCC) accounts for 80% of all kidney cancers and has a poor prognosis. Recent studies have shown that copper-dependent, regulated cell death differs from previously known death mechanisms (apoptosis, ferroptosis, and necroptosis) and is dependent on mitochondrial respiration (Tsvetkov et al., Science, 2022, 375 (6586), 1254–1261). Studies also suggested that targeting cuproptosis may be a novel therapeutic strategy for cancer therapy. In ccRCC, both cuproptosis and lncRNA were critical, but the mechanisms were not fully understood. The aim of our study was to construct a prognostic profile based on cuproptosis-associated lncRNAs to predict the prognosis of ccRCC and to study the immune profile of clear cell renal cell carcinoma (ccRCC).Methods: We downloaded the transcriptional profile and clinical information of ccRCC from The Cancer Genome Atlas (TCGA). Co-expression network analysis, Cox regression method, and least absolute shrinkage and selection operator (LASSO) method were used to identify cuproptosis-associated lncRNAs and to construct a risk prognostic model. In addition, the predictive performance of the model was validated and recognized by an integrated approach. We then also constructed a nomogram to predict the prognosis of ccRCC patients. Differences in biological function were investigated by GO, KEGG, and immunoassay. Immunotherapy response was measured using tumor mutational burden (TMB) and tumor immune dysfunction and rejection (TIDE) scores.Results: We constructed a panel of 10 cuproptosis-associated lncRNAs (HHLA3, H1-10-AS1, PICSAR, LINC02027, SNHG15, SNHG8, LINC00471, EIF1B-AS1, LINC02154, and MINCR) to construct a prognostic prediction model. The Kaplan–Meier and ROC curves showed that the feature had acceptable predictive validity in the TCGA training, test, and complete groups. The cuproptosis-associated lncRNA model had higher diagnostic efficiency compared to other clinical features. The analysis of Immune cell infiltration and ssGSEA further confirmed that predictive features were significantly associated with the immune status of ccRCC patients. Notably, the superimposed effect of patients in the high-risk group and high TMB resulted in shorter survival. In addition, the higher TIDE scores in the high-risk group suggested a poorer outcome for immune checkpoint blockade response in these patients.Conclusion: The ten cuproptosis-related risk profiles for lncRNA may help assess the prognosis and molecular profile of ccRCC patients and improve treatment options, which can be further applied in the clinic.

BackgroundProstate cancer is the most common tumor in men worldwide, seriously threatening the health of older men, and 5-methylcytosine (m5C) RNA modification has been shown to have a significant impact on the development and progression of various tumors. However, as the most critical methyltransferase for m5c RNA modification, the role of the NSUN members (NSUN1-7) in prostate cancer is unclear.MethodsWe obtained sequencing data of genes and related clinical data of prostate cancer from The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) database and analyzed the correlation between NSUN members’ expression and prognosis. we found that NSUN2 was closely implicated in the prognosis of prostate cancer, then verified the expression of NSUN2 in clinical samples, and obtained the correlation between NSUN2 and immune cell infiltration through CIBERSORT algorithm and ESTIMATE method. The relationship between NSUN2 copy number variation and immune cell infiltration was further analyzed in the TIMER database and identified signaling pathways associated with NSUN2 expression by GO, KEGG, and GSEA analysis. Finally, we verified the expression of NSUN2 in prostate cancer cell lines and confirmed the role of NSUN2 on the biological behavior of prostate cancer cells by proliferation and migration-related assays.ResultsNOP2 and NSUN2 were upregulated in prostate tumor tissues. NSUN2 expression is closely associated with tumor prognosis. NSUN2 high expression implies poor clinical features, and the NSUN family is significantly associated with tumor stromal score and immune score. Besides, NSUN2 is associated with a variety of immune infiltrating cells (B cells memory, T cells CD4 memory resting, T cells CD4 memory activated, NK cells resting, and so on). High NSUN2 expression lowers the sensitivity of many chemotherapy drugs, such as docetaxel, doxorubicin, fluorouracil, cisplatin, and etoposide. In prostate cancer, the most common type of mutation in NSUN2 is amplification, and NSUN2 copy number variation is closely associated with NSUN2 expression and immune cell infiltration. GSEA analysis showed that the related genes were mainly enriched in ubiquitin-mediated protein hydrolysis, cell cycle, RNA degradation, endometrial cancer, prostate cancer, p53 signaling pathway, and NSUN2 potentiated the proliferation and migration of prostate cancer cells.ConclusionsNSUN2 is highly expressed in prostate cancer, which contributes to the progression of prostate cancer, and is closely implicated in immune cell infiltration and chemotherapy drugs. NSUN2 is expected to be a prospective marker and a new treatment target for prostate cancer.

Patients diagnosed with prostate cancer often have a poor prognosis and limited treatment options, as the specific pathogenesis remains to be elucidated. Circular RNA (circRNA) is a type of non-coding RNA that interacts with microRNA (miRNA/miR) and transcription factors to regulate gene expression. However, little is known about specific circRNAs that serve roles in the pathogenesis of prostate cancer. Findings of the present study confirmed that circRNA G protein subunit γ 4 (circGNG4) was upregulated in prostate cancer tissues and cell lines. Knockdown of circGNG4 inhibited the malignant behavior of prostate cancer cells. Furthermore, bioinformatics were used to predict targeting interactions between circGNG4 or miR-223 and EYA transcriptional coactivator and phosphatase 3 (EYA3)/c-Myc mRNA. miR-223 inhibited the malignant behavior of prostate cancer cells, while EYA3/c-Myc had the opposite effect. circGNG4 enhanced the expression of EYA3/c-Myc by sponging miR-223 to promote the growth of prostate cancer tumors in vivo. In conclusion, the circGNG4/miR-223/EYA3/c-Myc regulatory pathway promoted the malignant progression of prostate cancer. The results of the present study may provide potential new targets for the diagnosis or treatment of prostate cancer.

BackgroundIn reference to previous studies, necroptosis played an important role in cancer development. Our team decided to explore the potential prognostic values of long non-coding RNAs (lncRNAs) associated with necroptosis in bladder urothelial carcinoma (BLCA) and their relationship with the tumor microenvironment (TME) and the immunotherapeutic response for accurate dose.MethodsTo obtain the required data, bladder urothelial carcinoma transcriptome data were searched from Cancer Genome Atlas (TCGA) (https://portal.gdc.cancer.gov/). We used co-expression analysis, differential expression analysis, and univariate Cox regression to screen out prognostic lncRNAs associated with necroptosis in BLCA. Then the least absolute shrinkage and selection operator (LASSO) was conducted to construct the necroptosis-associated lncRNAs model. Based on this model, we also performed the Kaplan–Meier analysis and time-dependent receiver operating characteristics (ROC) to estimate the prognostic power of risk score. Multivariate and univariate Cox regression analysis were performed to build up a nomogram. Calibration curves, and time-dependent ROC were also conducted to evaluate nomogram. Principal component analysis (PCA) revealed a difference between high- and low-risk groups. In addition, we explored immune analysis, gene set enrichment analyses (GSEA), and evaluation of the half-maximal inhibitory concentration (IC50) in constructed model. Finally, the entire samples were divided into three clusters based on model of necroptosis-associated lncRNAs to further compare immunotherapy in cold and hot tumors.ResultsA model was built up based on necroptosis-associated lncRNAs. The model revealed good consistence between calibration plots and prognostic prediction. The area of 1-, 3-, and 5-year OS under the ROC curve (AUC) were 0.707, 0.679, and 0.675. Risk groups could be helpful for systemic therapy due to the markedly diverse IC50 between risk groups. To our delight, clusters could effectively identify cold and hot tumors, which would be beneficial to accurate mediation. Clusters 2 and 3 were considered the hot tumor, which was more sensitive to immunotherapeutic drugs.ConclusionsThe outcomes of our study suggested that necroptosis-associated lncRNAs could effectively predict patients with BLCA prognosis, which may be helpful for distinguishing the cold and hot tumors and improving individual treatment of BLCA.

Cytoskeleton-associated protein 2-like (CKAP2L), a cell cycle-related protein, is correlated to tumor progression in some tumors. But there were no pan-cancer studies on CKAP2L, and its role in cancer immunotherapy is also unclear. The expression levels, expression activity, genomic alterations, DNA methylation and functions of CKAP2L in various tumors, as well as the associations between CKAP2L expression and patient prognosis, chemotherapy sensitivity, and tumor immune microenvironment, were all analyzed in a comprehensive pan-cancer analysis of CKAP2L by various databases, analysis websites, and R software. The experiments were also conducted to verify the analysis results. In the majority of cancers, CKAP2L expression and activity were markedly elevated. Elevated CKAP2L expression led to poor prognostic outcomes in patients, and is an independent risk factor for most tumors. Elevated CKAP2L causes decreased sensitivity to chemotherapeutic agents. Knockdown of CKAP2L significantly inhibited the proliferation and metastasis capacity of the KIRC cell lines and resulted in cell cycle G2/M arrest. In addition, CKAP2L was closely related to immune subtypes, immune cell infiltration, immunomodulators and immunotherapy markers (TMB, MSI), patients with high CKAP2L expression were more sensitive to immunotherapy in the IMvigor210 cohort. The results indicate that CKAP2L is a pro-cancer gene that serves as a potential biomarker for predicting patient outcomes. By inducing cells to transition from the G2 phase to the M phase, CKAP2L may promote cell proliferation and metastasis. Furthermore, CKAP2L is closely related to the tumor immune microenvironment and can be used as a biomarker to predict tumor immunotherapy.