Identification of MUC1-C as a Target for Suppressing Progression of Head and Neck Squamous Cell Carcinomas.

The MUC1-C protein is aberrantly expressed in adenocarcinomas of epithelial barrier tissues and contributes to their progression. Less is known about involvement of MUC1-C in the pathogenesis of squamous cell carcinomas (SCC). Here, we report that the MUC1 gene is upregulated in advanced head and neck SCCs (HNSCC). Studies of HNSCC cell lines demonstrate that the MUC1-C subunit regulates expression of (i) RIG-I and MDA5 pattern recognition receptors, (ii) STAT1 and IFN regulatory factors, and (iii) downstream IFN-stimulated genes. MUC1-C integrates chronic activation of the STAT1 inflammatory pathway with induction of the ∆Np63 and SOX2 genes that are aberrantly expressed in HNSCCs. In extending those dependencies, we demonstrate that MUC1-C is necessary for NOTCH3 expression, self-renewal capacity, and tumorigenicity. The findings that MUC1 associates with ∆Np63, SOX2 and NOTCH3 expression by single-cell RNA sequencing analysis further indicate that MUC1-C drives the HNSCC stem cell state and is a target for suppressing HNSCC progression. SIGNIFICANCE: This work reports a previously unrecognized role for MUC1-C in driving STAT1-mediated chronic inflammation with the progression of HNSCC and identifies MUC1-C as a druggable target for advanced HNSCC treatment.

Prognostic value of preoperative combined neutrophil, monocyte, and lymphocyte scores in patients with renal cell carcinoma undergoing laparoscopic nephrectomy: A retrospective study.

BACKGROUND: In a multi-institutional clinical study, we assessed the prognostic significance of a novel indicator preoperative peripheral blood immune (PBIS) scores that combined ratios of preoperative lymphocyte, monocyte, and neutrophil of renal cell carcinoma (RCC) patients undergoing laparoscopic nephrectomy. METHODS: Between January 2014 and December 2019, 438 patients with RCC were retrospectively analyzed in three centers. We used X-tile software to obtain the optimum cut-off values for neutrophils, monocytes, and lymphocytes to classify the patients. To assess the relationship between PBIS score and overall survival (OS), and cancer-specific survival (CSS) in patients with RCC by Kaplan-Meier survival curves and Cox regression analyses. In addition, predictive OS and CSS nomograms were constructed. The discriminative ability of nomogram and predictive performance accuracy were verified with consistency index (C-index), calibration curves, receiver operating curve (ROC) curves, decision curve analysis (DCA) curves, and time-dependent ROC curves. RESULTS: The optimum cutoff values for monocytes, lymphocytes, and neutrophils were 0.46, 1.01, and 4.50, respectively. We divided patients into four subgroups according to PBIS scores, which were significantly associated with M-stage (p = 0.008), T-stage (p < 0.001), N-stage (p = 0.006), and AJCC stage (p < 0.001). Multivariate Cox regression analysis revealed that RCC patients with lower PBIS scores showed a worse postoperative prognosis and served as an independent predictor of OS (p = 0.002) and CSS (p < 0.001). Ultimately, the nomograms based on PBIS scores demonstrated excellent predictive performance for OS (C-index: 0.770) and CSS (C-index: 0.828) through the analysis of calibration curves, ROC curves, DCA curves, and time-dependent ROC curves. CONCLUSION: PBIS score served as novel and effective predictor to accurately predict OS and CSS in patients with RCC receiving laparoscopic nephrectomy.

Single-cell combined bioinformatics analysis: construction of immune cluster and risk prognostic model in kidney renal clear cells based on CD8+ T cell-associated genes.

BACKGROUND: Kidney cancer is an immunogenic solid tumor, characterized by high tumor burden and infiltration of CD8+ T cells. Although immunotherapy targeting the PD1/CTLA-4 axis has demonstrated excellent clinical efficacy, clinical outcomes in most patients are poor. METHODS: We used the RNA sequencing data from the GEO database for KIRC GSE121636 and normal kidney tissue GSE131685, and performed single-cell analysis for cluster identification, pathway enrichment, and CD8+ T cell-associated gene identification. Subsequently, the significance of different CD8+ T-cell associated gene subtypes was elucidated by consensus clustering, pathway analysis, mutated gene analysis, and KIRC immune microenvironment analysis in the TCGA-KIRC disease cohort. Single gene analysis identified LAG3 as the most critical CD8+ T-cell-associated gene and its function was verified by cell phenotype and immunohistochemistry in KIRC. RESULTS: In the present study, CD8+ T-cell associated genes in KIRC were screened, including GZMK, CD27, CCL4L2, FXYD2, LAG3, RGS1, CST7, DUSP4, CD8A, and TRBV20-1 and an immunological risk prognostic model was constructed (risk score = - 0.291858656434841*GZMK - 0.192758342489394*FXYD2 + 0.625023643446193*LAG3 + 0.161324477181591*RGS1 - 0.380169045328895*DUSP4 - 0.107221347575037*TRBV20-1). LAG3 was identified and proved as the most critical CD8+ T cell-associated gene in KIRC. CONCLUSION: We proposed and constructed an immunological risk prognostic model for CD8+ T cell-associated genes and identified LAG3 as a pivotal gene for KIRC progression and CD8+ T-cell infiltration. The model comprehensively explained the immune microenvironment and provided novel immune-related therapeutic targets and biomarkers in KIRC.

Lycopene intake and the risk of erectile dysfunction in US adults: NHANES 2001-2004.

BACKGROUND: Erectile dysfunction is a condition with a high incidence among adult men. Lycopene has been shown to lower blood glucose and reduce weight in diabetic patients because of its antioxidant and anti-inflammatory properties. However, the association between lycopene and the incidence of erectile dysfunction is unclear. OBJECTIVE: The aim of this study was to examine the dietary lycopene intake and its association with erectile dysfunction risk in the US population. MATERIALS AND METHODS: We investigated the lycopene intake of adult participants with complete information on clinical variables from the National Health and Nutrition Examination Survey between 2001 and 2004. Dose-response curve analysis was applied to explore the association between lycopene intake and erectile dysfunction. Logistic regression models were used to adjust for confounders. Different ethnicities, body mass index level, hypertension status, diabetes status, and smoking status were analyzed as subgroups. Propensity score matching was employed to eliminate the effects of potential confounders to confirm the reliability of the results. RESULTS: A total of 3265 participants with lycopene consumption data were included in our study, including 931 individuals with erectile dysfunction and 2334 without erectile dysfunction during National Health and Nutrition Examination Survey 2001-2004. We found more consumption of lycopene in the non-erectile dysfunction group than in the erectile dysfunction group. Dose-response curve analysis revealed a significant negative association between lycopene intake and erectile dysfunction prevalence. After adjusting for age, race, cigarette smoking, body mass index, annual family income, education, physical activity, hypertension, diabetes, depression, and testosterone level, we found that increased lycopene intake reduced the odds ratio of erectile dysfunction. Low lycopene intake was positively related to erectile dysfunction in almost all subgroups, especially in Mexican American, non-Hispanic white, body mass index <25, hypertension positive, diabetes mellitus negative, and smoke negative. Furthermore, the results were confirmed in the 1:1 matched group. CONCLUSION: Our national data suggest that lower dietary lycopene intake is positively associated with an increased risk of erectile dysfunction in US men.

Cisplatin induces acute kidney injury by downregulating miR-30e-5p that targets Galnt3 to activate the AMPK signaling pathway.

Cisplatin nephrotoxicity is an etiological factor for acute kidney injury (AKI). MicroRNA (miRNA) expression is dysregulated in cisplatin-induced AKI (cAKI) although the underlying mechanisms are unclear. A cAKI model was established by intraperitoneally injecting cisplatin, and key miRNAs were screened using high-throughput miRNA sequencing. The functions of key miRNAs were determined using the cell viability, live/dead, reactive oxygen species (ROS), and 5-ethynyl-2'-deoxyuridine (EdU) proliferation assays. Additionally, the macrophage membrane was wrapped around a metal-organic framework (MOF) loaded with miRNA agomir to develop a novel composite material, macrophage/MOF/miRNA agomir nanoparticles (MMA NPs). High-throughput miRNA sequencing revealed that miR-30e-5p is a key miRNA that is downregulated in cAKI. The results of in vitro experiments demonstrated that miR-30e-5p overexpression partially suppressed the cisplatin-induced or lipopolysaccharide (LPS)-induced downregulation of cell viability, proliferation, upregulation of ROS production, and cell death. Meanwhile, the results of in vivo and in vitro experiments demonstrated that MMA NPs alleviated cAKI by exerting anti-inflammatory effects. Mechanistically, cisplatin downregulates the expression of miR-30e-5p, and the downregulated miR-30e-5p can target Galnt3 to activate the adenosine 5'-monophosphate activated protein kinase (AMPK) signaling pathway, which promotes the progression of AKI. Our study found that miR-30e-5p is a key downregulated miRNA in cAKI. The downregulated miR-30e-5p promotes AKI progression by targeting Galnt3 to activate the AMPK signaling pathway. The newly developed MMA NPs were found to have protective effects on cAKI, suggesting a potential novel strategy for preventing cAKI.

GAD1 contributes to the progression and drug resistance in castration resistant prostate cancer.

BACKGROUND: Prostate cancer is currently the second most lethal malignancy in men worldwide due to metastasis and invasion in advanced stages. Studies have revealed that androgen deprivation therapy can induce stable remission in patients with advanced prostate cancer, although most patients will develop castration-resistant prostate cancer (CRPC) in 1-2 years. Docetaxel and enzalutamide improve survival in patients with CRPC, although only for a short time, eventually patients develop primary or secondary resistance, causing disease progression or biochemical relapse. METHODS: The gene expression profiles of docetaxel-sensitive or -resistant prostate cancer cell lines, namely GSE33455, GSE36135, GSE78201, GSE104935, and GSE143408, were sequentially analyzed for differentially expressed genes and progress-free interval significance. Subsequently, the overall survival significance and clinic-pathological features were analyzed by the R package. The implications of hub genes mutations, methylation in prostate cancer and the relationship with the tumor immune cell infiltration microenvironment were assessed with the help of cBioPortal, UALCAN and TISIDB web resources. Finally, effects of the hub genes on the progression and drug resistance in prostate cancer were explored using reverse transcription-polymerase chain reaction (RT-PCR), immunohistochemistry, cell phenotype, and drug sensitivity. RESULT: Glutamate decarboxylase 1 (GAD1) was tentatively identified by bioinformatic analysis as an hub gene for the development of drug resistance, including docetaxel and enzalutamide, in prostate cancer. Additionally, GAD1 expression, mutation and methylation were significantly correlated with the clinicopathological features and the tumor immune microenvironment. RT-PCR, immunohistochemistry, cell phenotype and drug sensitivity experiments further demonstrated that GAD1 promoted prostate cancer progression and decreased the therapeutic effect of docetaxel or enzalutamide. CONCLUSION: This research confirmed that GAD1 was a hub gene in the progression and development of drug resistance in prostate cancer. This helped to explain prostate cancer drug resistance and provides new immune-related therapeutic targets and biomarkers for it.

LMNTD2-AS1 regulates immune cell infiltration and promotes prostate cancer progression by targeting FUS to regulate NRF2 signal pathway.

Numerous studies have demonstrated that long non-coding RNAs (lncRNAs) play crucial roles in tumor progression. This study aimed to identify lncRNAs associated with overall survival (OS) and progression-free interval (PFI) in prostate cancer (PCa) patients and to elucidate the driving mechanisms and functions of these lncRNAs. We utilized the TCGA database to screen for lncRNAs linked with OS and PFI. KM survival analysis, ROC curve analysis, and Cox survival analysis were employed to assess the prognostic significance of lncRNAs in PCa patients. We conducted a loss-of-function assay to explore the role of lncRNAs in PCa. Correlation analysis was performed to study the relationship between lncRNAs and immune cell infiltration. Lasso regression analysis was performed to screen proteins which might interact with lncRNAs, while rescue experiments verified the integrity of the signaling pathway. LMNTD2-AS1 was found to be the only lncRNA in PCa patients associated with both OS and PFI with significantly elevated levels in PCa. Elevated LMNTD2-AS1 expression was significantly linked to advanced stage, grade, primary treatment outcomes, residual tumors, and Gleason scores in PCa patients. Moreover, multivariate Cox regression analysis revealed that high LMNTD2-AS1 expression independently predicted PFI in PCa patients. The AUC of LMNTD2-AS1 for predicting 3-year OS and 5-year OS in PCa patients was 0.877 and 0.807, respectively, while for 3-year PFI and 5-year PFI it was 0.751 and 0.727, respectively. Overexpression of LMNTD2-AS1 correlated with infiltration of neutrophils, macrophages, pDC, NK CD56bright cells, and other immune cells. Furthermore, FUS and NRF2 are both potential binding proteins and related signaling pathways downstream of LMNTD2-AS1. Functional experiments demonstrated that LMNTD2-AS1 knockdown significantly inhibited migration, invasion, and proliferation of PCa cells while overexpression of FUS was found to rescue the functional inhibition caused by LMNTD2-AS1 knockdown. LMNTD2-AS1 functions as an oncogene in PCa, influencing patient prognosis and the immune microenvironment; it may regulate immune cell infiltration and promote PCa progression by interacting with the NRF2 signaling pathway via FUS binding.

M6A-mediated-upregulation of lncRNA BLACAT3 promotes bladder cancer angiogenesis and hematogenous metastasis through YBX3 nuclear shuttling and enhancing NCF2 transcription.

Lymphatic metastasis is recognized as the leading manner of metastasis in bladder cancer (BLCa), but hematogenous metastasis accounts for a majority of cancer-associated deaths. The past two decades have witnessed tremendous attention in long non-coding RNAs (lncRNAs), which are a new hope for the development of targeted drug therapy for metastatic cancers; however, the underlying mechanism of lncRNAs involved in BLCa hematogenous metastasis remains to be elucidated. Here, we identified BLCa-associated transcript 3 (BLACAT3), a lncRNA, which was aberrantly upregulated in BLCa and corelated with poor prognosis of patients with muscle-invasive bladder cancer. Methodologically, m6A epitranscriptomic microarray, RNA sequencing and mass spectrometry (MS) were used to screen the key molecules of the regulatory axis. Functional assays, animal models and clinical samples were used to explore the roles of BLACAT3 in BLCa in vitro and in vivo. Mechanistically, m6A modification contributes to BLACAT3 upregulation by stabilizing RNA structure. BLACAT3 recruits YBX3 to shuttle into the nucleus, synergistically enhances NCF2 transcription, and promotes BLCa angiogenesis and hematogenous metastasis by activating downstream NF-κB signaling. Our findings will develop prognosis prediction tools for BLCa patients and discover novel therapeutic biological targets for metastatic BLCa.

Cuproptosis-related LINC01711 promotes the progression of kidney renal clear cell carcinoma.

This study utilized The Cancer Genome Atlas (TCGA) database to identify cuproptosis-related long non-coding RNAs (CRlncRNAs) in patients with kidney renal clear cell carcinoma (KIRC) which was further applied to construct risk signatures. All KIRC patients were divided into the training and the validation sets at a ratio of 7:3. Lasso regression analysis identified two prognosis-associated CRlncRNAs (LINC01204 and LINC01711), and prognostic risk signatures were constructed in both the training and the validation sets. Kaplan-Meier survival curves showed that patients with high-risk scores had significantly shorter overall survival (OS) than those with low-risk scores both in both the training and the validation sets. The area under the curve (AUC) of the prognostic nomogram generated based on age, grade, stage and risk signature to predict the 1-, 3- and 5-year OS were 0.84, 0.81 and 0.77, respectively, and the calibration curves also showed the high accuracy of the nomogram. In addition, we constructed the LINC01204/LINC01711-miRNA-mRNA ceRNA network graph. Finally, we experimentally investigated the function of LINC01711 by knocking down LINC01711 and revealed that knockdown of LINC01711 inhibited the proliferation, migration and invasion of KIRC cells. Hence, in this study, we developed a signature of prognostic risk-associated CRlncRNAs that could accurately predict the prognosis of KIRC patients and constructed a related ceRNA network to shed light on the mechanistic study of KIRC. LINC01711 might serve as a potential biomarker for the early diagnosis and prognosis of KIRC patients.

piRNA-1742 promotes renal cell carcinoma malignancy by regulating USP8 stability through binding to hnRNPU and thereby inhibiting MUC12 ubiquitination.

Accumulating studies have confirmed that PIWI-interacting RNAs (piRNAs) are considered epigenetic effectors in cancer. We performed piRNA microarray expression analysis on renal cell carcinoma (RCC) tumor tissues and paired normal tissues and performed a series of in vivo and in vitro experiments to explore piRNAs associated with RCC progression and investigate their functional mechanisms. We found that piR-1742 was highly expressed in RCC tumors and that patients with high piR-1742 expression had a poor prognosis. Inhibition of piR-1742 significantly reduced tumor growth in RCC xenograft and organoid models. Mechanistically, piRNA-1742 regulates the stability of USP8 mRNA by binding directly to hnRNPU, which acts as a deubiquitinating enzyme that inhibits the ubiquitination of MUC12 and promotes the development of malignant RCC. Subsequently, nanotherapeutic systems loaded with piRNA-1742 inhibitors were found to effectively inhibit the metastasis and growth of RCC in vivo. Therefore, this study highlights the functional importance of piRNA-related ubiquitination in RCC and demonstrates the development of a related nanotherapeutic system, possibly contributing to the development of therapeutic approaches for RCC.

Physical activity can influence the relationship between ethylene oxide and risk of kidney stones: A cross-sectional study from the NHANES 2013-2016.

Ethylene oxide (EO) is known to cause inflammatory damage, and suitable physical activity can reportedly affect the risk of kidney stones. In this study, we aimed to investigate the relationship between EO and kidney stones and whether physical activity can potentially influence the relationship between EO and kidney stones. Overall, 3,336 adult participants were included; of them, 330 (9.9%) had a self-reported history of kidney stones. Data were obtained from the National Health and Nutrition Examination Survey 2013-2016. Physical activity was calculated using metabolic equivalent, weekly frequency, and duration. Logistic regression and restricted cubic spline (RCS) curves were used to explore the association between physical activity, EO, and kidney stones. Dose-response curves from the RCS showed a nonlinear positive association between EO and kidney stones. Multivariate logistic regression analysis revealed an adjusted odds ratio (aOR) of 1.548 (95% confidence interval 1.123-2.135, P = 0.008) for the risk of kidney stones among participants in the highest quartile (Q4) group compared with those in the lowest quartile (Q1) group. Furthermore, compared to the Q1 group, the aOR for risk of kidney stones in the Q4 group was 1.326 in participants without physical activity, a decreased risk (aOR 1.239) in participants with low physical activity, and an increased risk (aOR 1.981) in those with high physical activity. This study suggests that EO is a risk factor for kidney stones and that suitable physical activity may moderate this relationship to some extent; however, excessive physical activity can exacerbate this relationship.

Identification of prognostic factors for predicting survival of patients with malignant adrenal tumors: A population-based study.

Background: This study aimed to identify the prognostic factors for overall survival (OS) and cancer-specific survival (CSS) in patients with malignant adrenal tumors and establish a predictive nomogram for patient survival. Methods: The clinical characteristics of patients diagnosed with malignant adrenal tumors between 1988 and 2015 were retrieved from the Surveillance, Epidemiology and End Results (SEER) database. As the external validation set, we included 110 real-world patients from our medical centers. Univariate and multivariate Cox regressions were implemented to determine the prognostic factors of patients. The results from Cox regression were applied to establish the nomogram. Results: A total of 2,206 eligible patients were included in our study. Patients were randomly assigned to the training set (1,544; 70%) and the validation set (662; 30%). It was determined that gender, age, marital status, histological type, tumor size, SEER stage, surgery, and chemotherapy were prognostic factors that affected patient survival. The OS prediction nomogram contained all the risk factors, while gender was excluded in the CSS prediction nomogram. The receiver operating characteristic (ROC) curve and decision curve analysis (DCA) indicated that the nomogram had a better predictive performance than SEER stage. Moreover, the clinical impact curve (CIC) showed that the nomograms functioned as effective predictive models in clinical application. The C-index of nomogram for OS and CSS prediction was 0.773 (95% confidence interval [CI]: 0.761-0.785) and 0.689 (95% CI: 0.675-0.703) in the training set. The calibration curves exhibited significant agreement between the nomogram and actual observation. Additionally, the results from the external validation set also presented that established nomograms functioned well in predicting the survival of patients with malignant adrenal tumors. Conclusions: The following clinical variables were identified as prognostic factors: age, marital status, histological type, tumor size, SEER stage, surgery, and chemotherapy. The nomogram for patients with malignant adrenal tumors contained the accurate predictive performance of OS and CSS, contributing to optimizing individualized clinical treatments.

Development and validation of a prognostic nomogram for adult patients with renal sarcoma: A retrospective study based on the SEER database.

Background: Renal sarcoma (RS) is rarely seen in clinical practice. The purpose of this study was to develop a prognostic nomogram model, which could predict the probability of overall survival (OS) and cancer-specific survival (CSS) in adult patients with RS. Methods: Patients diagnosed with RS were recruited from the SEER database between 2004 and 2015, and randomized to two cohorts: the training cohort and the validation cohort. Uni- and multivariate Cox regression analyses in the training cohort were used to screen independent prognostic factors for OS and CSS. Prognostic nomograms for OS and CSS were created separately for adult RS patients based on independent risk factors. The area under the receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA) were used to validate the nomograms. Results: A total of 232 eligible patients were recruited, including 162 in the training cohort and 70 in the validation cohort. Sex, histological type, SEER stage, and surgery were independent prognostic factors for OS, while histological type, SEER stage, surgery, chemotherapy were independent prognostic factors for CSS. Based on the above independent prognostic factors, prognostic nomograms for OS and CSS were created respectively. In the training cohort, the AUCs of the nomograms for OS and CSS were 0.742 and 0.733, respectively. In the validation cohort, the AUCs of the nomograms for OS and CSS were 0.837 and 0.758, respectively. The calibration curves of the nomograms showed high consistencies between the predicted and actual survival rates. Finally, the DCA demonstrated that the nomograms in the wide high-risk threshold had a higher net benefit than the SEER stage. Conclusion: A prognostic nomogram for renal sarcoma was created and validated for reliability and usefulness in our study, which assisted urologists in accurately assessing the prognosis of adult RS patients.

Prognostic value of glucose to lymphocyte ratio for patients with renal cell carcinoma undergoing laparoscopic nephrectomy: A multi-institutional, propensity score matching cohort study.

Background: We evaluated the prognostic value of preoperative blood glucose to lymphocyte ratio (GLR) in renal cell carcinoma (RCC) patients who underwent laparoscopic nephrectomy through a multi-institutional clinical study. Methods: A total of 420 patients with RCC from three medical centers from 2014 to 2019 were included in this study. The effect of GLR on overall survival (OS) and cancer-specific survival (CSS) in RCC patients was assessed by Kaplan-Meier survival curves, univariate and multivariate Cox regression analysis. Moreover, a 1:1 propensity score matching (PSM) analysis of different GLR groups was utilized to further confirm the prognostic ability of GLR. Results: The optimal cut-off value for GLR was 6.8. Patients were divided into high GLR and low GLR groups according to the optimal cut-off value. GLR was significant association with diabetes, cardiovascular disease and AJCC stage. High GLR predicted adverse OS ( P = 0.002) and CSS ( P < 0.01) in RCC patients. Multivariate Cox regression analysis revealed that high GLR was an independent prognostic factor for OS [hazard ratio (HR): 2.389, 95% confidence interval (CI), 1.136-5.027, P = 0.008] and CSS (HR: 3.474, 95% CI, 1.555-7.761, P = 0.002). After PSM analysis of the patients in the high GLR and low GLR groups, high GLR still predicted poor OS ( P = 0.021) and CSS ( P = 0.037). Conclusions: High GLR is associated with adverse prognosis in RCC patients, and GLR can serve as an independent prognostic marker for OS and CSS in RCC patients receiving laparoscopic nephrectomy.

Erratum: Depletion of CDC5L inhibits bladder cancer tumorigenesis: Erratum.

[This corrects the article DOI: 10.7150/jca.32850.].

ASNS can predict the poor prognosis of clear cell renal cell carcinoma.

Purpose: Clear cell renal cell carcinoma (ccRCC) is one of the most common malignancies of the urinary system. This study was conducted to discover a new target that can predict the prognosis and promote the treatment of ccRCC. Methods: The raw data were downloaded from the TCGA database, and the predictive value of ASNS for various clinicopathological features was verified in the following analysis. Then, we analyzed the potential involvement of ASNS in tumor immunity and obtained the possible pathways involving ASNS through GO/KEGG enrichment analysis and GSEA. We also further verified our findings in pathological specimens of ccRCC patients. Results: ASNS expression was significantly increased in ccRCC, which was associated with advanced clinicopathological characteristics. It was an independent prognostic factor for overall survival in 535 patients with ccRCC. Immune cell infiltration analysis revealed that ASNS expression was related to T lymphocyte infiltration of tumors and poor prognosis. Moreover, we performed relevant functional enrichment analyses of ASNS. Conclusions: ASNS might play a significant role in the development and immune cell infiltration of ccRCC and serve as a valuable clinical prognostic biomarker.

Combination of preoperative plasma fibrinogen and neutrophil-to-lymphocyte ratio to predict the prognosis for patients undergoing laparoscopic nephrectomy for renal cell carcinoma.

This study was conducted to investigate the prognostic significance of a combination of fibrinogen and neutrophil-to-lymphocyte ratio (NLR) named the F-NLR score as a novel indicator and further create nomograms for predicting the prognosis of patients with renal cell carcinoma (RCC) treated with laparoscopic nephrectomy. A total of 425 patients with RCC who underwent laparoscopic nephrectomy were included in this study. Then, we divided the patients based on the cut-off values of their F-NLR score into three categories: F-NLR 2 (both high fibrinogen and NLR), F-NLR 0 (both low fibrinogen and NLR), and F-NLR 1 (remaining patients). Cox regression analysis was performed to investigate the predictive performance of the F-NLR score on overall survival (OS) and cancer-specific survival (CSS). Predictive nomograms of F-NLR were established and internally validated. Time-dependent receiver operating characteristic (ROC) curve analysis was performed to assess the predictive accuracy of the nomogram, NLR, and fibrinogen as prognostic markers. The F-NLR 0, 1, and 2 groups included 226 (53.2%), 147 (34.6%), and 52 (12.2%) patients, respectively. Cox regression analysis showed that a high F-NLR score was significantly associated with poor prognosis and acted as an independent prognostic factor for OS and CSS (all P < 0.05). Predictive nomograms with F-NLR for OS (C-index: 0.773) and CSS (C-index: 0.838) were well developed. Time-dependent ROC results showed that nomograms containing F-NLR had better predictive performance than NLR and fibrinogen. F-NLR score was a novel effective prognostic biomarker for patients with RCC undergoing laparoscopic nephrectomy.

Transfection with Plasmid-Encoding lncRNA-SLERCC nanoparticle-mediated delivery suppressed tumor progression in renal cell carcinoma.

BACKGROUND: The accumulating evidence confirms that long non-coding RNAs (lncRNAs) play a critical regulatory role in the progression of renal cell carcinoma (RCC). But, the application of lncRNAs in gene therapy remains scarce. Here, we investigated the efficacy of a delivery system by introducing the plasmid-encoding tumor suppressor lncRNA-SLERCC (SLERCC) in RCC cells. METHODS: We performed lncRNAs expression profiling in paired cancer and normal tissues through microarray and validated in our clinical data and TCGA dataset. The Plasmid-SLERCC@PDA@MUC12 nanoparticles (PSPM-NPs) were tested in vivo and in vitro, including cellular uptake, entry, CCK-8 assay, tumor growth inhibition, histological assessment, and safety evaluations. Furthermore, experiments with nude mice xenografts model were performed to evaluate the therapeutic effect of PSPM-NPs nanotherapeutic system specific to the SLERCC. RESULTS: We found that the expression of SLERCC was downregulated in RCC tissues, and exogenous upregulation of SLERCC could suppress metastasis of RCC cells. Furthermore, high expression DNMT3A was recruited at the SLERCC promoter, which induced aberrant hypermethylation, eventually leading to downregulation of SLERCC expression in RCC. Mechanistically, SLERCC could directly bind to UPF1 and exert tumor-suppressive effects through the Wnt/ß-catenin signaling pathway, thereby inhibiting progression and metastasis in RCC. Subsequently, the PSPM-NPs nanotherapeutic system can effectively inhibit the growth of RCC metastases in vivo. CONCLUSIONS: Our findings suggested that SLERCC is a promising therapeutic target and that plasmid-encapsulated nanomaterials targeting transmembrane metastasis markers may open a new avenue for the treatment in RCC.

LTBP2 inhibits prostate cancer progression and metastasis via the PI3K/AKT signaling pathway.

Biochemical recurrence (BCR) is a cause of concern in advanced prostate cancer (PCa). Thus, novel diagnostic biomarkers are required to improve clinical care. However, research on PCa immunotherapy is also scarce. Hence, the present study aimed to explore promising BCR-related diagnostic biomarkers, and their expression pattern, prognostic value, immune response effects, biological functions, and possible molecular mechanisms were evaluated. GEO datasets (GSE46602, GSE70768, and GSE116918) were downloaded and merged as the training cohort, and differential expression analysis was performed. Lasso regression and SVM-RFE algorithm, as well as PPI analysis and MCODE algorithm, were then applied to filter BCR-related biomarker genes. The CIBERSORT and estimation of stromal and immune cells in malignant tumor tissues using expression data (ESTIMATE) methods were used to calculate the fractions of tumor-infiltrating immune cells. GO/DO enrichment analyses were used to identify the biological functions. The expression of latent transforming growth factor ß-binding protein 2 (LTBP2) was determined by RT-qPCR and western blotting. The role of LTBP2 in PCa was determined by CCK-8, Transwell, and the potential mechanism was investigated by KEGG and GSEA and confirmed by western blotting. In total, 44 BCR-related differentially expressed genes (DEGs) in the training cohort were screened. LTBP2 was found to be a diagnostic biomarker of BCR in PCa and was associated with CD4+ T-cell infiltration and response to anti-PD-1/PD-L1 immunotherapy. Subsequently, using the ESTIMATE algorithm, it was identified that LTBP2 was associated with the tumor microenvironment and could be a predictor of the clinical benefit of immune checkpoint blockade. Finally, the expression and biological function of LTBP2 were evaluated via cellular experiments. The results showed that LTBP2 was downregulated in PCa cells and inhibited PCa proliferation and metastasis via the PI3K/AKT signaling pathway in vitro. In conclusion, LTBP2 was a promising diagnostic biomarker of BCR of PCa and had an important role in CD4+ T-cell recruitment. Moreover, it was associated with immunotherapy in patients with PCa who developed BCR, and it inhibited PCa proliferation and metastasis via the PI3K/AKT signaling pathway in vitro.