Long non-coding RNA HOTTIP promotes renal cell carcinoma progression through the regulation of the miR-506 pathway.

HOXA transcript at the distal tip (HOTTIP), a lncRNA, induces cell proliferation and cancer progression. However, the expression and function of HOTTIP in renal cell carcinoma (RCC) were rarely reported. The role of the HOTTIP in RCC was explored in this study. HOTTIP expresses higher in RCC tissues than in normal tissues and indicates poor prognosis based on the TCGA database. The over- and low-expression HOTTIP cell line was established in this research to assess the oncogenic function of HOTTIP in RCC progression. Mechanistic analyses revealed that HOTTIP functioned as a competing endogenous RNA (ceRNA) for miR-506. RIP experiment and luciferase assay were performed to explore the mechanisms of the sponge between HOTTIP and miR-506. HOTTIP down-regulation attenuated cell proliferation, migration, and invasion, which could be rescued by miR-506 down-regulation. On the whole, this study revealed that the HOTTIP/miR-506 axis has a dominant impact on RCC progression and potentially provides a novel strategy for RCC diagnosis and therapy.

Cav3.2 channel regulates cerebral ischemia/reperfusion injury: a promising target for intervention.

JOURNAL/nrgr/04.03/01300535-202419110-00028/figure1/v/2024-03-08T184507Z/r/image-tiff Calcium influx into neurons triggers neuronal death during cerebral ischemia/reperfusion injury. Various calcium channels are involved in cerebral ischemia/reperfusion injury. Cav3.2 channel is a main subtype of T-type calcium channels. T-type calcium channel blockers, such as pimozide and mibefradil, have been shown to prevent cerebral ischemia/reperfusion injury-induced brain injury. However, the role of Cav3.2 channels in cerebral ischemia/reperfusion injury remains unclear. Here, in vitro and in vivo models of cerebral ischemia/reperfusion injury were established using middle cerebral artery occlusion in mice and high glucose hypoxia/reoxygenation exposure in primary hippocampal neurons. The results showed that Cav3.2 expression was significantly upregulated in injured hippocampal tissue and primary hippocampal neurons. We further established a Cav3.2 gene-knockout mouse model of cerebral ischemia/reperfusion injury. Cav3.2 knockout markedly reduced infarct volume and brain water content, and alleviated neurological dysfunction after cerebral ischemia/reperfusion injury. Additionally, Cav3.2 knockout attenuated cerebral ischemia/reperfusion injury-induced oxidative stress, inflammatory response, and neuronal apoptosis. In the hippocampus of Cav3.2-knockout mice, calcineurin overexpression offset the beneficial effect of Cav3.2 knockout after cerebral ischemia/reperfusion injury. These findings suggest that the neuroprotective function of Cav3.2 knockout is mediated by calcineurin/nuclear factor of activated T cells 3 signaling. Findings from this study suggest that Cav3.2 could be a promising target for treatment of cerebral ischemia/reperfusion injury.

A Novel 7-Methylguanosine (m7G)-Related Gene Signature for Overall Survival Prediction in Patient with Clear Cell Renal Cell Carcinoma.

Clear cell renal cell carcinoma (ccRCC) is the most common pathology type of renal cancer that has an abysmal prognosis. Although a crucial role for 7-methylguanosine modification in cancer cell development has been reported, its role in ccRCC remains uncertain. This study was conducted to determine the efficacy of predictive biomarkers based on m7G-related genes in ccRCC. Firstly, we extracted clinical data and gene expression profiles of ccRCC patients from publicly accessible databases. It identified that 22 of the m7G-related 34 genes were related to overall survival, and 5 of the 22 genes were significantly expressed differently in tumor tissues. Based on Lasso regression analysis, five optimal genes (CYFIP2, EIF4A1, NUDT1, NUDT10, and NUDT4) were chosen to build a new predictive risk model in the TCGA cohort. Validation was carried out with the E-MTAB-1980 cohort. Then, a prognostic nomogram was erected, including the m7G-related gene risk score, age, histological grade, and stage status. Further studies and analysis showed that immune cell infiltration might be associated with the m7G-related risk genes. In addition, the relationship between gene expression and drug response was evaluated by the Pearson correlation test. Therefore, the risk signature with five selected m7G-related genes may be a promising prognostic biomarker and contribute to standardized prognostic assessment for ccRCC.

Cell-cell communications shape tumor microenvironment and predict clinical outcomes in clear cell renal carcinoma.

BACKGROUND: Cell-cell communications of various cell populations within tumor microenvironment play an essential role in primary tumor growth, metastasis evolution, and immune escape. Nevertheless, comprehensive investigation of cell-cell communications in the ccRCC (Clear cell renal carcinoma) microenvironment and how this interplay affects prognosis still remains limited. METHODS: Intercellular communications were characterized by single-cell data. Firstly, we employed "CellChat" package to characterize intercellular communications across all types of cells in microenvironment in VHL mutated and non-mutated samples from 8 patients, respectively. And pseudotime trajectory analyses were performed with monocle analyses. Finally clinical prognosis and immunotherapy efficacy with different landscapes of intercellular interplay are evaluated by TCGA-KIRC and immunotherapy cohort. RESULTS: Firstly, the VHL phenotype may be related to the intercellular communication landscape. And trajectory analysis reveals the potential relationship of cell-cell communication molecules with T cells and Myeloid cells differentiation. Furthermore, those molecules also correlate with the infiltration of T cells and Myeloid cells. A tumor cluster with highly expressed ligands was defined by quantitative analysis and transcription factor enrichment analysis, which was identified to be pivotal for intercellular communications in tumor microenvironment. Finally, bulk data indicates bulk that different clusters with different intercellular communications have significant predictive value for prognosis and distinguished immunotherapy efficiency. CONCLUSIONS: The intercellular communication landscapes of VHL wild and VHL mutant ccRCC vary. Intercellular communications within the tumor microenvironment also influence T cell and myeloid cell development and infiltration, as well as predict clinical prognosis and immunotherapy efficacy in ccRCC.

Association between multiple sclerosis and prostate cancer risk: A systematic review and meta­analysis.

Prostate cancer (PCa) risk in patients with multiple sclerosis (MS) remains to be elucidated. The present study conducted a meta-analysis to assess the relationship between MS and PCa. PubMed, EMBASE, Web of Science, and Cochrane Library databases were searched to identify studies on the PCa risk in patients with MS up to September 2022. A random effects meta-analyses model was performed to estimate the relative risk (RR) and the 95% confidence intervals (CI). All eight studies involving 210,943 patients with MS were identified and included in the meta-analysis. The present study revealed that there was no significant association between MS and the risk of PCa (RR=0.78, 95% CI: 0.56-1.08, P<0.0001). Subgroup analyses verified this conclusion when stratified by regions. However, after adjusting for potential confounders, the findings suggested conflicting results. The current evidence shows that compared with the population control, patients with MS have no relationship with PCa risk and further large samples and long-term trials are needed to verify these results.

A novel classification based on non-apoptosis cell death predicts clinical outcomes and immunotherapy response of clear renal cell carcinoma.

BACKGROUND: Non-apoptosis cell death could be a secondary consequence of the immune response, which profoundly influences tumor microenvironment (TME), escaping from chemotherapy/immunotherapy-induced apoptosis resistance effects. Whereas, systemic analysis of non-apoptosis regulated cell death associated with TME and clinical outcomes remains unveiled. METHODS: Our kidney clear carcinoma (KIRC) samples from The Cancer Genome Atlas (TCGA) were stratified into three clusters based on the activity of autophagic cell death, ferroptosis, pyroptosis and necroptosis. Clinical prognosis, TME landscape, biological functions and somatic mutation frequency were compared among the clusters. Additionally, to identify a gene signature highly correlated with clinical prognosis, a risk score model was constructed, and the clinical prognosis, immune infiltration, somatic mutation and biological pathways of risk score subgroups were investigated. RESULTS: Our non-apoptosis cell death clusters are robustly predictive of immunotherapy responses. Patients in Cluster B are the most sensitive to immune checkpoint blockades-depended immunotherapy. Our risk score model was also verified as a promising biomarker for clinical prognosis and immunotherapy efficiency. Where, the High-risk score group was more sensitive to immunotherapy. CONCLUSIONS: The novel non-apoptosis cell death-based classification and risk score model could predict the outcome of immunotherapy, and highly associate with immune infiltration. These findings may provide a novel strategy to aid in identificatin of biomarkers and selecting personalized therapeutic strategies.

Positive surgical margins may not affect the survival of patients with renal cell carcinoma after partial nephrectomy: A meta-analysis based on 39 studies.

Background: So far, whether positive surgical margin(PSM) has adverse effects on the prognosis of patients is still controversial, so we designed this study to systematically evaluate the effect of PSM on the prognosis of patients with renal cell carcinoma (RCC) after partial nephrectomy (PN). Methods: On the basis of three electronic databases (PubMed, Embase and the Cochrane Library) up to May 2022, all case-control studies (CCSs) comparing the effects of PSM and negative surgical margin (NSM) after PN on the oncological results of RCC patients were included. Two evaluators independently conducted a systematic literature search and extracted the data we needed. The methodological quality of all studies was evaluated by the modified Newcastle-Ottawa scale. The odds ratio (OR) was used to describe the results for dichotomous variables, and the meta-analysis was conducted using Cochrane Review Manager 5.2 and Stata 14.2. Results: A total of 39 studies involving 21461 patients were included in our meta-analysis. The pooled results showed that the rates of tumor recurrence (OR 3.93, 95% CI 2.95-5.24; p < 0.00001) and metastasis (OR 4.63, 95% CI 3.11-6.88; p < 0.00001) in the PSM group were significantly higher than those in the NSM group. However, there were no significant differences in the rates of all-cause death (OR 1.35, 95% CI 0.92-1.99; p = 0.13) or cancer-specific death (OR 0.99, 95% CI 0.51-1.94; p = 0.99) between the two groups. In addition, subgroup analyses were carried out according to different average follow-ups, which revealed similar results. Conclusion: Insignificant differences in survival between the PSM and NSM groups were observed, although significant differences in recurrence and metastasis in the PSM group were reported. Our study supported that close monitoring might be another effective choice for patients with PSM after PN. Considering the possible limitations, we recommended cautious interpretation of our results.

Peroxiredoxin-5 Knockdown Accelerates Pressure Overload-Induced Cardiac Hypertrophy in Mice.

A recent study showed that peroxiredoxins (Prxs) play an important role in the development of pathological cardiac hypertrophy. However, the involvement of Prx5 in cardiac hypertrophy remains unclear. Therefore, this study is aimed at investigating the role and mechanisms of Prx5 in pathological cardiac hypertrophy and dysfunction. Transverse aortic constriction (TAC) surgery was performed to establish a pressure overload-induced cardiac hypertrophy model. In this study, we found that Prx5 expression was upregulated in hypertrophic hearts and cardiomyocytes. In addition, Prx5 knockdown accelerated pressure overload-induced cardiac hypertrophy and dysfunction in mice by activating oxidative stress and cardiomyocyte apoptosis. Importantly, heart deterioration caused by Prx5 knockdown was related to mitogen-activated protein kinase (MAPK) pathway activation. These findings suggest that Prx5 could be a novel target for treating cardiac hypertrophy and heart failure.

Analgesic Effects of Different κ-Receptor Agonists Used in Daytime Laparoscopic Cholecystectomy.

BACKGROUND: Comparing the effect of two different κ-receptor agonists, nalbuphine and oxycodone, and regular morphine in patients for prophylactic analgesia of acute pain after daytime laparoscopic cholecystectomy. METHODS: One hundred and twenty-four patients undergoing laparoscopic cholecystectomy were randomly allocated to receive nalbuphine (group N), oxycodone (group O), and morphine (group M). The three groups were all given intravenous injection (iv.) of 0.15 mg/kg injection before incision and 0.05 mg/kg injection at the end of pneumoperitoneum. The Visual Analogue Scale (VAS) scores (incision, visceral, and shoulder) and Ramsay sedation scores at 1, 2, 4, 8, 12, 16, 20, and 24 hours after surgery, the time of extubation, the incidence of postoperative adverse events, the satisfaction of pain treatment, and the duration of stay after surgery were all recorded. RESULTS: Compared with group M, the VAS scores of visceral pain at rest decreased in group N and group O at 1-8 h after surgery (P < 0.05). The VAS scores of visceral pain at movement in group N decreased longer than those in group O (P < 0.05). Compared with that of group M, the postoperative time in Ramsay sedation score of group O increased longer than that of group N (P < 0.05). Compared with group N, patients had worse sleep quality in group O, longer length of stay in group M, and lower satisfaction in both groups. CONCLUSION: Compared with morphine, prophylactic use of the κ-receptor agonists, nalbuphine and oxycodone, during laparoscopic cholecystectomy can reduce postoperative visceral pain. Furthermore, the nalbuphine group had fewer adverse reactions, better analgesia, and better satisfaction.

CuGeO3 Nanoparticles: An Efficient Photothermal Theragnosis Agent for CT Imaging-Guided Photothermal Therapy of Cancers.

The photothermal agents have been widely developed due to the minimally invasive treatment for targeted tumor photothermal therapy, which is considered to have great potential for antitumor bioapplications. The development of multifunctional photothermal agents is extremely challenging. This work presents a novel photothermal theragnosis agent, i.e., CuGeO3 nanoparticles (CGO NPs), showing intense absorption in the near-infrared (NIR) window and excellent ability of CT imaging. Due to the strong NIR absorption, CGO NPs exhibit excellent photothermal effect with a photothermal conversion efficiency of 59.4%. Moreover, because of the high X-ray attenuation coefficient of germanium, the CGO NPs have a great potential of CT imaging diagnosis in clinical application. Additionally, the CGO NPs show negligible cytotoxicity in vitro and in vivo, indicating that it can be served as an outstanding contrast and anticancer agent in a biosafe way. Our work opens the way for the development of bimetallic copper-based oxides used in photothermal diagnostic agents for cancer treatment.

A prognostic long non-coding RNA-associated competing endogenous RNA network in head and neck squamous cell carcinoma.

BACKGROUND: This study aimed to develop multi-RNA-based models using a competing endogenous RNA (ceRNA) regulatory network to provide survival risk prediction in head and neck squamous cell carcinoma (HNSCC). METHODS: All long non-coding RNA (lncRNA), microRNA (miRNA), and mRNA expression data and clinicopathological features related to HNSCC were derived from The Cancer Genome Atlas. Differentially expressed RNAs were calculated using R. Prognostic factors were identified using univariate Cox regression analysis. Functional analysis was performed using GO, KEGG pathways, and PPI network. Based on the results, we derived a risk signature and compared high- and low-risk subgroups using LASSO regression analysis. Survival analysis and the relationship between risk signature and clinicopathological features were performed using log-rank tests and Cox regression analysis. A ceRNA regulatory network was constructed, and prognostic lncRNAs and miRNA expression levels were validated in vitro and in vivo. RESULTS: A list of 207 lncRNAs, 18 miRNAs and 362 mRNAs related to overall survival was established. Five lncRNAs (HOTTIP, LINC00460, RMST, SFTA1P, and TM4SF19-AS1), one miRNA (hsa-miR-206), and one mRNA (STC2) were used to construct the ceRNA network. Three prognostic models contained 13 lncRNAs, eight miRNAs, and 17 mRNAs, which correlated with the patient status, disease-free survival (DFS), stage, grade, T stage, N stage, TP53 mutation status, angiolymphatic invasion, HPV status, and extracapsular spread. KEGG pathway analysis revealed significant enrichment of "Transcriptional misregulation in cancer" and "Neuroactive ligand-receptor interaction." In addition, HOTTIP, LINC00460, miR-206 and STC2 were validated in GTEx data, GEO microarrays and six HNSCC cell lines. CONCLUSIONS: Our findings clarify the interaction of ceRNA regulatory networks and crucial clinicopathological features. These results show that prognostic biomarkers can be identified by constructing multi-RNA-based prognostic models, which can be used for survival risk prediction in patients with HNSCC.

Peroxiredoxin-1 Overexpression Attenuates Doxorubicin-Induced Cardiotoxicity by Inhibiting Oxidative Stress and Cardiomyocyte Apoptosis.

Background. Previous research has shown that peroxiredoxin 1 (Prdx1) is an important modulator of physiological and pathophysiological cardiovascular events. This study is aimed at investigating the role and underlying mechanism of Prdx1 in doxorubicin- (DOX-) induced cardiotoxicity. Cardiac-specific expression of Prdx1 was induced in mice, and the mice received a single dose of DOX (15 mg/kg) to generate cardiotoxicity. First, our study demonstrated that Prdx1 expression was upregulated in the heart and in cardiomyocytes after DOX treatment. Second, we provided direct evidence that Prdx1 overexpression ameliorated DOX-induced cardiotoxicity by attenuating oxidative stress and cardiomyocyte apoptosis. Mechanistically, we found that DOX treatment increased the phosphorylation level of apoptosis signal-regulating kinase-1 (ASK1) and the downstream protein p38 in the heart and in cardiomyocytes, and these effects were decreased by Prdx1 overexpression. In contrast, inhibiting Prdx1 promoted DOX-induced cardiac injury via the ASK1/p38 pathway. These results suggest that Prdx1 may be an effective therapeutic option to prevent DOX-induced cardiotoxicity.

Dexmedetomidine pretreatment attenuates myocardial ischemia reperfusion induced acute kidney injury and endoplasmic reticulum stress in human and rat.

BACKGROUND: Patients undergoing cardiopulmonary bypass (CPB) often develop acute kidney injury (AKI) caused by myocardial ischemia reperfusion (MI/R), and this renal injury can be resolved notably by dexmedetomidine. Endoplasmic reticulum (ER) stress was reported to get involved in organ injury including AKI. OBJECTIVES: The current study aimed to address the correlation between MI/R induced AKI with ER stress and to assess the effects of dexmedetomidine pretreatment on AKI protection. METHOD: Patients selected for heart valve replacement surgery were randomly assigned to NS group (pre-anesthesia with 0.9% NaCl) and DEX group (pre-anesthesia with dexmedetomidine). Rat MI/R model was induced by occluding coronary artery for 30 min followed by 48-hour reperfusion. Rats were randomized into Sham (0.9% NaCl), I/R (MI/R + 0.9% NaCl) and I/R + DEX (MI/R + dexmedetomidine). Organ function and ER stress condition were evaluated by blood chemistry, pathology, and molecular test. RESULTS: Clinical data indicated dexmedetomidine pretreatment attenuated AKI and oxidative stress as well as postischemic myocardial injury in patients. Accordingly animal results suggested dexmedetomidine reduced cellular injury and improved postischemic myocardial and renal function. Dexmedetomidine also reduced myocardial and renal cells apoptosis and down-regulated ER stress. CONCLUSIONS: These results suggested that dexmedetomidine pretreatment attenuates MI/R injury-induced AKI by relieving the ER stress.

Neuroprotective effects of 1-O-hexyl-2,3,5-trimethylhydroquinone on ischaemia/reperfusion-induced neuronal injury by activating the Nrf2/HO-1 pathway.

1-O-Hexyl-2,3,5-trimethylhydroquinone (HTHQ), a lipophilic phenolic agent, has an antioxidant activity and reactive oxygen species (ROS) scavenging property. However, the role of HTHQ on cerebral ischaemic/reperfusion (I/R) injury and the underlying mechanisms remain poorly understood. In the present study, we demonstrated that HTHQ treatment ameliorated cerebral I/R injury in vivo, as demonstrated by the decreased infarct volume ration, neurological deficits, oxidative stress and neuronal apoptosis. HTHQ treatment increased the levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream antioxidant protein, haeme oxygenase-1 (HO-1). In addition, HTHQ treatment decreases oxidative stress and neuronal apoptosis of PC12 cells following hypoxia and reperfusion (H/R) in vitro. Moreover, we provided evidence that PC12 cells were more vulnerable to H/R-induced oxidative stress after si-Nrf2 transfection, and the HTHQ-mediated protection was lost in PC12 cells transfected with siNrf2. In conclusion, these results suggested that HTHQ possesses neuroprotective effects against oxidative stress and apoptosis after cerebral I/R injury via activation of the Nrf2/HO-1 pathway.

Peroxiredoxin-1 ameliorates pressure overload-induced cardiac hypertrophy and fibrosis.

BACKGROUND: Previous studies have demonstrated that Peroxiredoxin 1 (Prdx1) is a modulator of physiological and pathophysiological cardiovascular events. However, the roles of Prdx1 in cardiac hypertrophy and heart failure (HF) have barely been explored. Thus, this study aimed to investigate whether Prdx1 participates in cardiac hypertrophy and to elucidate the possible associated mechanisms. METHODS: Mice were subjected to transverse aortic constriction (TAC) for four weeks to induce pathological cardiac hypertrophy. Cardiomyocyte-specific Prdx1 overexpression in mice was achieved using an adeno-associated virus system. Morphological examination; echocardiography; and hemodynamic, biochemical and histological analyses were used to evaluate the roles of Prdx1 in pressure overload-induced cardiac hypertrophy and HF. RESULTS: First, the results showed that Prdx1 expression was noticeably upregulated in hypertrophic mouse hearts and cardiomyocytes with phenylephrine (PE)-induced hypertrophy in vitro. Prdx1 overexpression exerted protective effects against cardiac hypertrophy and fibrosis and ameliorated cardiac dysfunction in mice subjected to pressure overload. In addition, Prdx1 overexpression decreased pressure overload-induced cardiac inflammation and oxidative stress. Further studies demonstrated that Prdx1 overexpression increased the levels of nuclear factor-erythroid 2-related factor 2 (Nrf2) and its downstream antioxidant protein, heme oxygenase-1 (HO-1), in mice. Moreover, Nrf2 knockdown offset the antihypertrophic and anti-oxidative stress effects of Prdx1 overexpression. CONCLUSIONS: Prdx1 protects against pressure overload-induced cardiac hypertrophy and HF by activating Nrf2/HO-1 signaling. These data indicate that targeting Prdx1 may be an attractive pharmacotherapeutic strategy for the treatment of cardiac hypertrophy and HF.

Dexmedetomidine with sufentanil in intravenous patient-controlled analgesia for relief from postoperative pain, inflammation and delirium after esophageal cancer surgery.

BACKGROUND AND AIMS: Postoperative pain can cause serious adverse reactions that severely affect postoperative outcome. The present study evaluated the effect of dexmedetomidine (DEX) added to sufentanil in intravenous patient-controlled analgesia (PCA) on the relief of pain and inflammatory responses during postoperative recovery of patients undergoing a combined thoracoscopic-laparoscopic esophagectomy (TLE). METHODS: Sixty patients undergoing TLE were randomly allocated to receive 1 µg/ml of sufentanil alone (Group S) or 1 µg/ml of sufentanil plus 2.5 µg/ml of DEX (Group D) for postoperative intravenous (IV) PCA. Postoperative pain relief, cumulative PCA requirements, inflammatory marker levels, delirium and recovery were assessed. RESULTS: A joint DEX and sufentanil regimen significantly reduced the area under the curve of numerical rating scores for pain at rest (NRSR) and coughing (NRSC) at 1-48 h postoperatively (P = 0.000) that were associated with lower PCA-delivered cumulative sufentanil consumption and less PCA frequency until 48 h postoperatively (P < 0.05 and P < 0.0001, respectively). The simultaneous administration of DEX and sufentanil significantly reduced plasma IL-6 and TNF-α concentrations and increased IL-10 level (P < 0.0001, P = 0.0003 and P = 0.0345, respectively), accompanied by better postoperative delirium categories and health statuses of patients (P = 0.024 and P < 0.05, respectively). There was no hypotension, bradycardia, respiratory depression or oversedation in Group D. CONCLUSION: Patients receiving DEX in addition to IV PCA sufentanil for TLE exhibited better postoperative analgesia, fewer inflammatory responses and lower postoperative delirium categories and better health statuses.

Nomogram for predicting overall survival of patients with bladder cancer: A population-based study.

OBJECTIVE: The aim of this study was to develop and validate a reliable nomogram to estimate overall survival in bladder cancer. METHOD: Patients diagnosed with bladder cancer identified in the Surveillance, Epidemiology, and End Results database were randomly divided into training and validation cohorts. The powerful prognostic variables were examined using Cox regression analyses. A nomogram was developed on the prognostic factors. RESULTS: The results suggested that age, sex, race, grade, histologic type, primary site, pathological stage, surgical treatment, and number of primary tumors, were the powerful prognostic factors. All these factors were integrated to construct the nomogram. The nomogram for predicting overall survival showed better discrimination power than the tumor-node-metastasis (TNM) stage system 8th edition. CONCLUSION: The nomogram has the potential to provide an individualized prediction of overall survival in patients with bladder cancer.

Effect of m6A RNA Methylation Regulators on Malignant Progression and Prognosis in Renal Clear Cell Carcinoma.

Objectives: This study aims to explore the roles of 13 m6A RNA methylation regulators in clear cell renal cell carcinoma (ccRCC), and identify a risk signature and prognostic values of m6A RNA methylation regulators in ccRCC. Materials and Methods: RNA sequence data of ccRCC was obtained from The Cancer Genome Atlas (TCGA) database. Differentially expressed of 13 m6A RNA methylation regulators in ccRCC stratified by different clinicopathological characteristics were unveiled using "limma" package in R version 3.6.0. Cox regression and LASSO analyses were conducted to identify the powerful independent prognostic factors in ccRCC associated with overall survival (OS). Protein-protein interaction (PPI) network and correlation analyses of the 13 m6A RNA methylation regulators were performed using "STRING" and R package, respectively. Principal component analysis (PCA) was also done using R. In addition, gene ontology (GO), GSEA and Kyoto Encyclopedia of Genes and Genomes pathways were used to functionally annotate the differentially expressed genes in different subgroups. Results: Most of the 13 m6A RNA methylation regulators are differentially expressed in ccRCC tissue samples stratified by different clinicopathological characteristics in 537 patients. Next, a risk signature for predicting prognosis of ccRCC patients, was established based on two powerful independent prognostic m6A RNA methylation regulators (METTL14 and METTL3). Then, two subgroups (cluster1 and 2) were identified by consensus clustering to the two powerful independent factors and the cluster1 had a poorer prognosis than cluster2. Furthermore, the genes in cluster1 were significantly enriched in cancer-related pathways, biological process, and hallmarks, including "cell adhesion molecules (CAMs)," "leukocyte migration," "Wnt/ß-catenin signaling," and so on. Conclusion: M6A RNA methylation regulators play important roles in the initiation and progression of ccRCC and provide a novel sight to understand m6A RNA modification in ccRCC.

Identification and analysis of long non-coding RNA related miRNA sponge regulatory network in bladder urothelial carcinoma.

BACKGROUND: The aim of this study was to investigate the regulatory network of lncRNAs as competing endogenous RNAs (ceRNA) in bladder urothelial carcinoma (BUC) based on gene expression data derived from The Cancer Genome Atlas (TCGA). MATERIALS AND METHODS: RNA sequence profiles and clinical information from 414 BUC tissues and 19 non-tumor adjacent tissues were downloaded from TCGA. Differentially expressed RNAs derived from BUC and non-tumor adjacent samples were identified using the R package "edgeR". Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was performed using the "clusterProfiler" package. Gene ontology and protein-protein interaction (PPI) networks were analyzed for the differentially expressed mRNAs using the "STRING" database. The network for the dysregulated lncRNA associated ceRNAs was then constructed for BUC using miRcode, miRTarBase, miRDB, and TargetScan. Cox regression analysis was performed to identify independent prognostic RNAs associated with BUC overall survival (OS). Survival analysis for the independent prognostic RNAs within the ceRNA network was calculated using Kaplan-Meier curves. RESULTS: Based on our analysis, a total of 666, 1819 and 157 differentially expressed lncRNAs, mRNAs and miRNAs were identified respectively. The ceRNA network was then constructed and contained 59 lncRNAs, 23 DEmiRNAs, and 52 DEmRNAs. In total, 5 lncRNAs (HCG22, ADAMTS9-AS1, ADAMTS9-AS2, AC078778.1, and AC112721.1), 2 miRNAs (hsa-mir-145 and hsa-mir-141) and 6 mRNAs (ZEB1, TMEM100, MAP1B, DUSP2, JUN, and AIFM3) were found to be related to OS. Two lncRNAs (ADAMTS9-AS1 and ADAMTS9-AS2) and 4 mRNA (DUSP2, JUN, MAP1B, and TMEM100) were validated using GEPIA. Thirty key hub genes were identified using the ranking method of degree. KEGG analysis demonstrated that the majority of the DEmRNAs were involved in pathways associated with cancer. CONCLUSION: Our findings provide an understanding of the important role of lncRNA-related ceRNAs in BUC. Additional experimental and clinical validations are required to support our findings.

Construction and comprehensive analysis of dysregulated long non-coding RNA-associated competing endogenous RNA network in clear cell renal cell carcinoma.

OBJECTIVE: This study aimed to assess the long noncoding RNA (lncRNA)-microRNA (miRNA)-messenger RNA (mRNA) regulatory network in clear cell renal cell carcinoma (ccRCC) by gene expression analyses. MATERIALS AND METHODS: LncRNA, miRNA, and mRNA expression profiles in ccRCC were obtained from The Cancer Genome Atlas. Differentially expressed lncRNAs, mRNAs (cut-off: |log 2 [fold change, FC])| > 2.0 and adjusted P < 0.01) and miRNAs (|log 2FC| > 1.5 and adjusted P < 0.01) were unveiled using R. Cox regression analysis was performed to identify prognostic factors of ccRCC related to overall survival (OS). A protein-protein interaction (PPI) network was constructed for differentially expressed mRNAs (DEmRNAs) by Search Tool for the Retrieval of Interacting Genes (STRING). Key hub genes were screened from top 300 DEmRNAs. LncRNA-miRNA and miRNA-mRNA regulatory network were constructed and combined into the competing endogenous RNA regulatory network. Gene ontology biological terms were screened by STRING; Kyoto Encyclopedia of Genes and Genomes pathways were identified using the "clusterProfiler" package in R. RESULTS: A total of 2331, 1517, and 83 DEmRNAs, lncRNAs, and miRNAs were identified, respectively. Eleven lncRNAs (AC016773.1, HOTTIP, LINC00460, NALCN-AS1, PVT1, TRIM36-IT1, WT1-AS, COL18A1-AS1, LINC00443, LINC00472, and TCL6), three miRNAs (hsa-mir-21, hsa-mir-144, and hsa-mir-155), and three mRNAs (COL4A4, NOD2, and GOLGA8B) were associated with OS. Specifically, four lncRNAs (PVT1, LINC00472, TCL6, and WT1-AS1) and one mRNA (Collagen Type IV Alpha 4 Chain) were verified as independent prognostic factors by Gene Expression Profiling Interactive Analysis. Eleven key hub genes were obtained by PPI analysis. "Cell adhesion molecules (CAMs)," "chemical carcinogenesis," and "cytokine-cytokine receptor interaction" were significantly enriched in the network. CONCLUSION: The findings clarify the pathogenesis of ccRCC and might provide potential therapeutic targets.