Integration of proteomics and transcriptomics to construct a prognostic signature of renal clear cell carcinoma.

Background: Protein information is often replaced by RNA data in studies to understand cancer-related biological processes or molecular functions, and proteins of prognostic significance in Kidney clear cell carcinoma (KIRC) remain to be mined. Methods: The cancer genome atlas program (TCGA) data was utilized to screen for proteins that are prognostically significant in KIRC. Machine learning algorithms were employed to develop protein prognostic models. Additionally, immune infiltration abundance, somatic mutation differences, and immunotherapeutic responses were analyzed in various protein risk subgroups. Ultimately, the validation of protein-coding genes was confirmed by utilizing an online database and implementing quantitative real-time PCR (qRT-PCR). Results: The patients were divided into two risk categories based on prognostic proteins, and notable disparities in both overall survival (OS) and progression free interval (PFI) were observed between the two groups. The OS was more unfavorable in the high-risk group, and there was a noteworthy disparity in the level of immune infiltration observed between the two groups. In addition, the nomogram showed high accuracy in predicting survival in KIRC patients. Conclusion: In this research, we elucidated the core proteins associated with prognosis in terms of survival prediction, immunotherapeutic response, somatic mutation, and immune microenvironment. Additionally, we have developed a reliable prognostic model with excellent predictive capabilities.

Long noncoding RNA PCA3 regulates prostate cancer through sponging miR-218-5p and modulating high mobility group box 1.

OBJECTIVE: The purpose of this study was to investigate the mechanism of long noncoding RNA (lncRNA) prostate cancer antigen 3 (PCA3) in prostate cancer (PCa) via regulating the miR-218-5p/high mobility group box 1 (HMGB1) axis. METHODS: The Cancer Genome Atlas database was used to divide differentially expressed lncRNAs, microRNAs, and messenger RNA (mRNAs). The mRNA expressions of lncRNA PCA3, miR-218-5p, and HMGB1 were determined by reverse transcription polymerase chain reaction. Cell propagation was evaluated using the Cell Counting Kit-8 assay and the apoptotic rate was examined by flow cytometry. Cell migration and invasion were observed through the wound healing assay and transwell assay. Target relationships among PCA3, miR-218-5p, and HMGB1 were validated via dual-luciferase reporter gene assay. A nude mouse model in vivo was designed to evaluate the effect of PCA3 on prostate tumor growth. RESULTS: PCA3 and HMGB1 were high-expressed in PCa, whereas miR-218-5p was low-expressed. PCA3 knockdown or miR-218-5p overexpression suppressed PCa cell proliferation, migration, and invasion, but promoted apoptosis. Besides, targeted relationships and interactions on the expression between miR-218-5p and PCA3 or HMGB1 were elucidated. PCA3 weakened cell viability and mobility whereas induced apoptosis through binding with miR-218-5p. Meanwhile, miR-218-5p also inhibited PCa tumorigenesis via downregulation of HMGB1. Knockdown of PCA3 impeded tumor growth by downregulating its downstream gene HMGB1. CONCLUSIONS: lncRNA PCA3 facilitated PCa progression through sponging miR-218-5p and regulating HMGB1.

Aquaporin1-3 expression in normal and hydronephrotic kidneys in the human fetus.

BACKGROUND: Decreased expression of the renal aquaporin (AQP) protein family is associated with hydronephrosis in adult humans and animals. However, the expression of AQPs, especially subtypes AQP1-3, which play a core role in the urinary concentration function, in hydronephrotic human fetuses is not clear. The aim of this study is to investigate the expression of the AQP1-3 in normal and hydronephrotic human fetal kidneys. METHODS: Twenty-one normal and six hydronephrotic kidney (HK) samples were harvested from abortive fetuses. Meanwhile, seven normal adult human kidney samples were collected as positive controls. Quantitative real-time PCR, western blotting, and immunohistochemistry were used to analyze the expression of AQP1-3. RESULTS: Both the protein and messenger mRNA expression levels of AQP1-3 increased with gestational age in the normal fetuses, but the levels were significantly lower than those in the adult tissues and significantly higher than those in the hydronephrotic fetuses at the same gestational age. CONCLUSIONS: The increased expression of AQP1-3 with gestational age in the fetal kidney may indicate maturation of the urinary concentrating ability. The lower expression of AQP1-3 in HKs may reflect a maturation obstacle with regard to urinary concentration in human hydronephrotic fetuses.

Predicting bladder cancer survival with high accuracy: insights from MAPK pathway-related genes.

The mitogen-activated protein kinase (MAPK) pathway plays a critical role in tumor development and immunotherapy. Nevertheless, additional research is necessary to comprehend the relationship between the MAPK pathway and the prognosis of bladder cancer (BLCA), as well as its influence on the tumor immune microenvironment. To create prognostic models, we screened ten genes associated with the MAPK pathway using COX and least absolute shrinkage and selection operator (LASSO) regression analysis. These models were validated in the Genomic Data Commons (GEO) cohort and further examined for immune infiltration, somatic mutation, and drug sensitivity characteristics. Finally, the findings were validated using The Human Protein Atlas (HPA) database and through Quantitative Real-time PCR (qRT-PCR). Patients were classified into high-risk and low-risk groups based on the prognosis-related genes of the MAPK pathway. The high-risk group had poorer overall survival than the low-risk group and showed increased immune infiltration compared to the low-risk group. Additionally, the nomograms built using the risk scores and clinical factors exhibited high accuracy in predicting the survival of BLCA patients. The prognostic profiling of MAPK pathway-associated genes represents a potent clinical prediction tool, serving as the foundation for precise clinical treatment of BLCA.

A novel role of TCAIM: suppressing renal carcinoma growth and enhancing its sensitivity to sunitinib.

Renal carcinoma is a common malignancy for which the underlying molecular mechanisms warrant further investigation. T cell activation inhibitor mitochondrial (TCAIM), a mitochondrial protein, was found to be expressed to a low extent in renal carcinoma specimens. However, its role in carcinomas remains unclear. In the present study, the role of TCAIM in renal carcinoma was explored through loss-of-function and gain-of-function experiments. Here, we showed that TCAIM delayed the growth of renal carcinoma cells both in vitro and in vivo by modulating their cell cycle progress. Additionally, TCAIM also enhanced their sensitivity to sunitinib by aggravating apoptosis. Furthermore, TCAIM also decreased the adhesion and migration of renal carcinoma cells. Moreover, the transcription of TCAIM was regulated by vitamin D receptor, which acts as a transcriptional factor. To identify the pathways regulated by TCAIM, 425 unique proteins bound to TCAIM were pulled down through co-immunoprecipitation and analyzed by mass spectrometry followed by Gene Ontology analysis and Kyoto Encyclopedia of Genes and Genomes analysis. In summary, the present study reveals a tumor-suppressor role of TCAIM in renal carcinoma cells, as well as its upstream regulation and downstream potential mechanisms. Our study provides theoretical bases and novel insights with respect to the development of new therapeutic strategies for the treatment of renal carcinoma.

Melamine-related urinary stones in 195 infants and young children: clinical features within 2 years of follow-up.

OBJECTIVE: To summarize the clinical features and follow-up, the effects of melamine-tainted milk powder (MMP) consumption on kidney and body growth in children who suffered from melamine-related urinary stones (MUS) 2 years earlier were checked. MEASUREMENTS: Body height and weight, kidney and bladder morphology monitored by ultrasound, urinalysis and renal function were recorded. Plain abdominal radiography was performed for differential diagnosis. The first follow-up was carried out at 15 months and the second 2 years later for patients who showed any abnormality at the first follow-up. Two hundred age- and gender-matched cohorts were included. RESULTS: All cases received conservative treatment in hospital. Fifteen months of follow-up was successfully carried out in 167 cases. 91 children had residual MUS at the time of discharge, 58 MUS disappeared completely, 25 dissolved partially, 1 increased in size, and 7 did not change. At 2 years of follow-up, the residual stones all disappeared except for 1 case; the patient who showed a delayed development with regard to height caught up at 24 months of follow-up. CONCLUSIONS: Conservative treatment shows a high effectiveness in cases with residual MUS. Consumption of MMP with timely treatment did not demonstrate an evident impact on kidney and bladder although body height is slightly affected in a few cases.

[Bioinformatic analysis of immune-related lncRNA based on TCGA database in patients with prostate cancer].

Objective To investigate the clinical significance of immune-related long non-coding RNAs (lncRNAs) and their potential role in guiding the treatment of prostate cancer. Methods lncRNAs of prostate cancer were obtained from TCGA database. The immune-related gene sets were downloaded from Molecular Signatures Database. Gene-lncRNA co-expression was confirmed by Pearson correlation analysis, and univariate Cox regression and selected operator regression (Lasso) were performed to identify important and immune-related lncRNAs. "gglot package" and "survival package" of R software were used to evaluate the correlation between the lncRNAs and clinical characteristics and the prognostic value of the lncRNAs. lnc2RNA database was used to analyze the difference of lncRNAs between normal prostate tissue and prostate cancer tissue. Starbase and David database were used to determine the predict function of lncRNAs in prostate cancer. Results AL162586.1, AC138028.4, SLC25A25-AS1, AC002553.1, AC004816.1, LINC00641 and AC027796.4 were key immune-related lncRNAs, and their expression was positively associated with N stage; the expression levels of AL162586.1 and SLC25A25-AS1 increased with higher T stage. The expression levels of SLC25A25-AS1 and LINC00641 were significantly different in tumor tissues from that of normal tissues. The GO enrichment showed that SLC25A25-AS1 was mainly distributed in membrane, had negative regulation of mRNA splicing via spliceosome and by a nucleotide binding. KEGG pathway enrichment showed that targeted genes were mainly involved in spliceosome pathway. Conclusion lncRNA has become a new research direction in prostate cancer and SLC25A25-AS1 may affect the prognosis of patients through splicing pathway.

Quercetin inhibits kidney fibrosis and the epithelial to mesenchymal transition of the renal tubular system involving suppression of the Sonic Hedgehog signaling pathway.

Quercetin is the most ubiquitous flavonoid in fruits, herbs, vegetables and products made from them. It shows the potential to inhibit the progression of kidney fibrosis and the epithelial to mesenchymal transition (EMT) of the renal tubular system, but the molecular mechanism behind this is still not known. In our study, we explored the effect of quercetin treatment on extracellular matrix (ECM) deposition and stimulation of the EMT in vitro and in vivo and tried to deduce the mechanisms regulating these effects. In rats having unilateral ureter obstruction (UUO), quercetin treatment significantly prevented renal function decline. Quercetin reduced the TGF-ß1 expression and inhibited the epithelial cell to mesenchymal cell phenotypic switch, as well as ECM deposition in rats with UUO. In cultured epithelial cells of the renal tubular region (NRK-52E), quercetin markedly ameliorated the EMT and ECM synthesis induced by TGF-ß1. Activation of the Hedgehog pathway was closely related to EMT induction. Quercetin effectively suppressed the hyperactive Hedgehog pathway in NRK-52E cells treated with TGF-ß1 and in kidney obstructed rats, which reduced the EMT, ECM deposition and cellular proliferation. Moreover, we examined certain transcriptional factors (slug, snail, ZEB-1 and twist) that govern the E-cadherin expression at the level of transcription. The results unveiled that the four transcriptional factors were highly repressed in NRK-52E cells treated with TGF-ß1 and also in obstructed kidneys by quercetin-mediated inhibition. Therefore, these outcomes indicate that quercetin could alleviate fibrosis and the EMT in vitro and in vivo by inhibiting the activation of Hedgehog signaling and could act as a therapeutic agent for patients having several kinds of renal fibrotic diseases.

Study on neuropathological mechanisms of primary monosymptomatic nocturnal enuresis in children using cerebral resting-state functional magnetic resonance imaging.

Primary monosymptomatic nocturnal enuresis (PMNE) is a heterogeneous disorder, which remains a difficult condition to manage due to lack of knowledge on the underlying pathophysiological mechanisms. Here we investigated the underlying neuropathological mechanisms of PMNE with functional MRI (fMRI), combining the amplitude of low frequency fluctuation (ALFF), regional homogeneity (ReHo), and seed-based functional connectivity (seed-based FC) analyses. Compared to the control group, PMNE group showed decreased ALFF value in the left medial orbital superior frontal gyrus (Frontal_Med_Orb_L), and increased ReHo value in the left superior occipital gyrus (Occipital_Sup_L). With left thalamus as the seed, PMNE group showed significantly decreased functional connectivity to the left medial superior frontal gyrus (Frontal_Sup_Medial_L). We conclude that these abnormal brain activities are probably important neuropathological mechanisms of PMNE in children. Furthermore, this study facilitated the understanding of underlying pathogenesis of PMNE and may provide an objective basis for the effective treatment.

Analysis of cyclin E co-expression genes reveals nuclear transcription factor Y subunit alpha is an oncogene in gastric cancer.

OBJECTIVE: To explore genes potentially co-expressed with cyclin E in gastric cancer and discover possible targets for gastric cancer treatment. METHODS: The Cancer Genome Atlas (TCGA) stomach adenocarcinoma sequencing data were used to predict genes co-expressed with cyclin E. Co-expression genes predicted by cBioPortal online analysis with Pearson correlation coefficient ≥0.4 were analyzed by gene ontology (GO) enrichment annotation using the PANTHER online platform (Ver. 7). Interactions between proteins encoded by these genes were analyzed using the STRING online platform (Ver. 10.5) and Cytoscape software (Ver. 3.5.1). Genes displaying a high degree of connection were analyzed by transcription factor enrichment prediction using FunRich software (Ver. 3). The significant transcription factor and cyclin E expression levels and their impact on gastric cancer progression were analyzed by Western blotting and Kaplan-Meier survival curve analysis. RESULTS: After filtering the co-expression gene prediction results, 78 predicted genes that included 73 protein coding genes and 5 non-coding genes with Pearson correlation coefficient ≥0.4 were selected. The expressions of the genes were considered to be correlated with cyclin E expression. Among the 78 genes co-expressed with cyclin E, 19 genes at the central of the regulatory network associated with cyclin E were discovered. Nuclear transcription factor Y subunit alpha (NF-YA) was identified as a significant transcription factor associated with cyclin E co-expressing genes. Analysis of specimen donors' clinical records revealed that high expression of NF-YA tended to be associated with increased cyclin E expression. The expression of both was associated with progression of gastric cancer. Western blotting results showed that compared with normal tissues, NF-YA and cyclin E were highly expressed in tumor tissues (P < 0.001). Survival curve analysis clearly demonstrated relatively poor overall survival of gastric cancer patients with high cyclin E or high NF-YA expression level, compared to patients with low cyclin E or NF-YA expression (P < 0.05). CONCLUSIONS: NF-YA may promote gastric cancer progression by increasing the transcription of cyclin E and other cell cycle regulatory genes. NF-YA might be a potential therapeutically useful prognostic factor for gastric cancer.

PAFR selectively mediates radioresistance and irradiation-induced autophagy suppression in prostate cancer cells.

Platelet-activating factor receptor (PAFR) promotes tumorigenesis, angiogenesis and metastasis. Here, we defined the PAFR as a yielding new inhibiting target to selectively enhance the sensitivity of prostate cancer (PCa) cells to radiation. The selective responding to PAFR inhibiter may be caused by the differential expression pattern of PAFR in PCa cells. In this study, we also determined PAFR as a molecular basis by which the radiation induces autophagy suppression independent of activating mTOR pathway. PAFR can bind to the autophagy-indispensable protein Beclin 1, leading to the disability in its serine phosphorylation. The PAFR antagonist Ginkgolide B (GB) can sensitize radiotherapy by disrupting the formation of PAFR/Beclin 1 complex in PC3 and LNCaP cells, which have elevated PAFR expression after radiation exposure. Most importantly, GB efficiently radiosensitized PC3 and LNCaP tumor xenografts in vivo, and significantly reduced tumor burden. Overall, our results elucidated a significant role of GB in selectively improving the outcomes of PCa receiving radiation therapy.