SELENBP1 overexpression in the prefrontal cortex underlies negative symptoms of schizophrenia.

The selenium-binding protein 1 (SELENBP1) has been reported to be up-regulated in the prefrontal cortex (PFC) of schizophrenia patients in postmortem reports. However, no causative link between SELENBP1 and schizophrenia has yet been established. Here, we provide evidence linking the upregulation of SELENBP1 in the PFC of mice with the negative symptoms of schizophrenia. We verified the levels of SELENBP1 transcripts in postmortem PFC brain tissues from patients with schizophrenia and matched healthy controls. We also generated transgenic mice expressing human SELENBP1 (hSELENBP1 Tg) and examined their neuropathological features, intrinsic firing properties of PFC 2/3-layer pyramidal neurons, and frontal cortex (FC) electroencephalographic (EEG) responses to auditory stimuli. Schizophrenia-like behaviors in hSELENBP1 Tg mice and mice expressing Selenbp1 in the FC were assessed. SELENBP1 transcript levels were higher in the brains of patients with schizophrenia than in those of matched healthy controls. The hSELENBP1 Tg mice displayed negative endophenotype behaviors, including heterotopias- and ectopias-like anatomical deformities in upper-layer cortical neurons and social withdrawal, deficits in nesting, and anhedonia-like behavior. Additionally, hSELENBP1 Tg mice exhibited reduced excitabilities of PFC 2/3-layer pyramidal neurons and abnormalities in EEG biomarkers observed in schizophrenia. Furthermore, mice overexpressing Selenbp1 in FC showed deficits in sociability. These results suggest that upregulation of SELENBP1 in the PFC causes asociality, a negative symptom of schizophrenia.

PRDM1 promotes the ferroptosis and immune escape of thyroid cancer by regulating USP15-mediated SELENBP1 deubiquitination.

BACKGROUND: The deubiquitinating enzyme Ubiquitin-specific peptidase 15 (USP15) is upregulated in various cancers and promotes tumor progression by increasing the expression of several oncogenes. This project is designed to explore the role and mechanism of USP15 in thyroid cancer (TC) progression. METHODS: Selenium-binding protein 1 (SELENBP1), USP15, CCL2/5, CXCL10/11, IL-4, and TGF-ß1 mRNA levels were detected using real-time quantitative polymerase chain reaction (RT-qPCR). SELENBP1, USP15, GPX4, IL-10, Arg-1, Granzyme B, TNF-α, and PR domain zinc finger protein 1 (PRDM1) protein levels were examined by western blot assay. Fe+ level, malondialdehyde (MDA), and lipid-ROS levels were determined using special kits. The proportion of CD11b+CD206+ positive cells was detected using a flow cytometry assay. The role of SELENBP1 on TC cell growth was examined using a xenograft tumor model in vivo. After GeneMANIA prediction, the interaction between USP15 and SELENBP1 was verified using Co-immunoprecipitation (CoIP) assay. The binding between PRDM1 and USP15 promoter was predicted by JASPAR and validated using Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays. RESULTS: SELENBP1 was increased in TC subjects and cell lines, and its knockdown repressed TC cell proliferation, migration, invasion, immune escape, and induced ferroptosis in vitro, as well as blocked tumor growth in vivo. In mechanism, USP15 interacted with SELENBP1 and maintained its stabilization by removing ubiquitin. Meanwhile, the upregulation of USP15 was induced by the transcription factor PRDM1. CONCLUSION: USP15 transcriptionally mediated by PRDM1 might boost TC cell malignant behaviors through deubiquitinating SELENBP1, providing a promising therapeutic target for TC treatment.

Tumor microenvironment-related gene selenium-binding protein 1 (SELENBP1) is associated with immunotherapy efficacy and survival in colorectal cancer.

BACKGROUND: Selenium-binding protein 1 (SELENBP1), a member of the selenium-containing protein family, plays an important role in malignant tumorigenesis and progression. However, it is currently lacking research about relationship between SELENBP1 and immunotherapy in colorectal cancer (CRC). METHODS: We first analyzed the expression levels of SELENBP1 based on the Cancer Genome Atlas (TCGA), Oncomine andUALCAN. Chisq.test, Fisher.test, Wilcoxon-Mann-Whitney test and logistic regression were used to analyze the relationship of clinical characteristics with SELENBP1 expression. Then Gene ontology/ Kyoto encyclopedia of genes and genomes (GO/KEGG), Gene set enrichment analysis (GSEA) enrichment analysis to clarify bio-processes and signaling pathways. The cBioPortal was used to perform analysis of mutation sites, types, etc. of SELENBP1. In addition, the correlation of SELENBP1 gene with tumor immune infiltration and prognosis was analyzed using ssGSEA, ESTIMATE, tumor immune dysfunction and rejection (TIDE) algorithm and Kaplan-Meier (KM) Plotter database. Quantitative real-time PCR (qRT-PCR) and western blotting (WB) were used to validate the expression of SELENBP1 in CRC samples and matched normal tissues. Immunohistochemistry (IHC) was further performed to detect the expression of SELENBP1 in CRC samples and matched normal tissues. RESULTS: We found that SELENBP1 expression was lower in CRC compared to normal colorectal tissue and was associated with poor prognosis. The aggressiveness of CRC increased with decreased SELENBP1 expression. Enrichment analysis showed that the SELENBP1 gene was significantly enriched in several pathways, such as programmed death 1 (PD-1) signaling, signaling by interleukins, TCR signaling, collagen degradation, costimulation by the CD28 family. Decreased expression of SELENBP1 was associated with DNA methylation and mutation. Immune infiltration analysis identified that SELENBP1 expression was closely related to various immune cells and immune chemokines/receptors. With increasing SELENBP1 expression, immune and stromal components in the tumor microenvironment were significantly decreased. SELENBP1 expression in CRC patients affects patient prognosis by influencing tumor immune infiltration. Beside this, SELENBP1 expression is closely related to the sensitivity of chemotherapy and immunotherapy. CONCLUSIONS: Survival analysis as well as enrichment and immunoassay results suggest that SELENBP1 can be considered as a promising prognostic biomarker for CRC. SELENBP1 expression is closely associated with immune infiltration and immunotherapy. Collectively, our study provided useful information on the oncogenic role of SELENBP1, contributing to further exploring the underlying mechanisms.

Serum SELENBP1 and VCL Are Effective Biomarkers for Clinical and Forensic Diagnosis of Coronary Artery Spasm.

Coronary artery spasm (CAS) plays an important role in the pathogenesis of many ischemic heart entities; however, there are no established diagnostic biomarkers for CAS in clinical and forensic settings. This present study aimed to identify such serum biomarkers by establishing a rabbit CAS provocation model and integrating quantitative serum proteomics, parallel reaction monitoring/mass spectrometry-based targeted proteomics, and partial least-squares discriminant analysis (PLS-DA). Our results suggested that SELENBP1 and VCL were potential candidate biomarkers for CAS. In independent clinical samples, SELENBP1 and VCL were validated to be significantly lower in serum but not blood cells from CAS patients, with the reasons for this possibly due to the decreased secretion from cardiomyocytes. The areas under the curve of the receiver operating characteristics (ROC) analysis were 0.9384 for SELENBP1 and 0.9180 for VCL when diagnosing CAS. The CAS risk decreased by 32.3% and 53.6% for every 10 unit increases in the serum SELENBP1 and VCL, respectively. In forensic samples, serum SELENBP1 alone diagnosed CAS-induced deaths at a sensitivity of 100.0% and specificity of 72.73%, and its combination with VCL yielded a diagnostic specificity of 100.0%, which was superior to the traditional biomarkers of cTnI and CK-MB. Therefore, serum SELENBP1 and VCL could be effective biomarkers for both the clinical and forensic diagnosis of CAS.

Selenium-binding protein 1 alters energy metabolism in prostate cancer cells.

OBJECTIVE: The broad goal of the research described in this study was to investigate the contributions of selenium-binding protein 1 (SBP1) loss in prostate cancer development and outcome. METHODS: SBP1 levels were altered in prostate cancer cell lines and the consequences on oxygen consumption, expression of proteins associated with energy metabolism, and cellular transformation and migration were investigated. The effects of exposing cells to the SBP1 reaction products, H2 O2 and H2 S were also assessed. In silico analyses identified potential HNF4α binding sites within the SBP1 promoter region and this was investigated using an inhibitor specific for that transcription factor. RESULTS: Using in silico analyses, it was determined that the promoter region of SBP1 contains putative binding sites for the HNF4α transcription factor. The potential for HNF4α to regulate SBP1 expression was supported by data indicating that HNF4α inhibition resulted in a dose-response increase in the levels of SBP1 messenger RNA and protein, identifying HNF4α as a novel negative regulator of SBP1 expression in prostate cancer cells. The consequences of altering the levels of SBP1 were investigated by ectopically expressing SBP1 in PC-3 prostate cancer cells, where SBP1 expression attenuated anchorage-independent cellular growth and migration in culture, both properties associated with transformation. SBP1 overexpression reduced oxygen consumption in these cells and increased the activation of AMP-activated protein kinase (AMPK), a major regulator of energy homeostasis. In addition, the reaction products of SBP1, H2 O2 , and H2 S also activated AMPK. CONCLUSIONS: Based on the obtained data, it is hypothesized that SBP1 negatively regulates oxidative phosphorylation (OXPHOS) in the healthy prostate cells by the production of H2 O2 and H2 S and consequential activation of AMPK. The reduction of SBP1 levels in prostate cancer can occur due to increased binding of HNF4α, acting as a transcriptional inhibitor to the SBP1 promoter. Consequently, there is a reduction in H2 O2 and H2 S-mediated signaling, inhibition of AMPK, and stimulation of OXPHOS and building blocks of biomolecules needed for tumor growth and progression. Other effects of SBP1 loss in tumor cells remain to be discovered.

Selenium-binding protein 1 transcriptionally activates p21 expression via p53-independent mechanism and its frequent reduction associates with poor prognosis in bladder cancer.

BACKGROUND: Recent studies have shown that selenium-binding protein 1 (SELENBP1) is significantly down-regulated in a variety of solid tumors. Nevertheless, the clinical relevance of SELENBP1 in human bladder cancer has not been described in any detail, and the molecular mechanism underlying its inhibitory role in cancer cell growth is largely unknown. METHODS: SELENBP1 expression levels in tumor tissues and adjacent normal tissues were evaluated using immunoblotting assay. The association of SELENBP1 expression, clinicopathological features, and clinical outcome was determined using publicly available dataset from The Cancer Genome Atlas bladder cancer (TCGA-BLCA) cohort. DNA methylation in SELENBP1 gene was assessed using online MEXPRESS tool. We generated stable SELENBP1-overexpression and their corresponding control cell lines to determine its potential effect on cell cycle and transcriptional activity of p21 by using flow cytometry and luciferase reporter assay, respectively. The dominant-negative mutant constructs, TAM67 and STAT1 Y701F, were employed to define the roles of c-Jun and STAT1 in the regulation of p21 protein. RESULTS: Here, we report that the reduction of SELENBP1 is a frequent event and significantly correlates with tumor progression as well as unfavorable prognosis in human bladder cancer. By utilizing TCGA-BLCA cohort, DNA hypermethylation, especially in gene body, is shown to be likely to account for the reduction of SELENBP1 expression. However, an apparent paradox is observed in its 3'-UTR region, in which DNA methylation is positively related to SELENBP1 expression. More importantly, we verify the growth inhibitory role for SELENBP1 in human bladder cancer, and further report a novel function for SELENBP1 in transcriptionally modulating p21 expression through a p53-independent mechanism. Instead, ectopic expression of SELENBP1 pronouncedly attenuates the phosphorylation of c-Jun and STAT1, both of which are indispensable for SELENBP1-mediated transcriptional induction of p21, thereby resulting in the G0/G1 phase cell cycle arrest in bladder cancer cell. CONCLUSIONS: Taken together, our findings provide clinical and molecular insights into improved understanding of the tumor suppressive role for SELENBP1 in human bladder cancer, suggesting that SELENBP1 could potentially be utilized as a prognostic biomarker as well as a therapeutic target in future cancer therapy.

Selenium-Binding Protein 1 in Human Health and Disease.

Selenium-binding protein 1 (SBP1) is a highly conserved protein that covalently binds selenium. SBP1 may play important roles in several fundamental physiological functions, including protein degradation, intra-Golgi transport, cell differentiation, cellular motility, redox modulation, and the metabolism of sulfur-containing molecules. SBP1 expression is often reduced in many cancer types compared to the corresponding normal tissues and low levels of SBP1 are frequently associated with poor clinical outcome. In this review, the transcriptional regulation of SBP1, the different physiological roles reported for SBP1, as well as the implications of SBP1 function in cancer and other diseases are presented.

Peripheral Lymphocytes in Primary Liver Cancers: Elevated NK and CD8+ T Cells and Dysregulated Selenium Metabolism.

Peripheral blood lymphocytes (PBLs), which play a pivotal role in orchestrating the immune system, garner minimal attention in hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). The impact of primary liver cancers on PBLs remains unexplored. In this study, flow cytometry facilitated the quantification of cell populations, while transcriptome of PBLs was executed utilizing 10× single-cell sequencing technology. Additionally, pertinent cases were curated from the GEO database. Subsequent bioinformatics and statistical analyses were conducted utilizing R (4.2.1) software. Elevated counts of NK cells and CD8+ T cells were observed in both ICC and HCC when compared to benign liver disease (BLD). In the multivariate Cox model, NK cells and CD8+ T cells emerged as independent risk factors for recurrence-free survival. Single-cell sequencing of PBLs uncovered the downregulation of TGFß signaling in tumor-derived CD8+ T cells. Pathway enrichment analysis, based on differential expression profiling, highlighted aberrations in selenium metabolism. Proteomic analysis of preoperative and postoperative peripheral blood samples from patients undergoing tumor resection revealed a significant upregulation of SELENBP1 and a significant downregulation of SEPP1. Primary liver cancer has a definite impact on PBLs, manifested by alterations in cellular quantities and selenoprotein metabolism.

SELENBP1 Inhibits the Warburg Effect and Tumor Growth by Reducing the HIF1α Expression in Colorectal Cancer.

INTRODUCTION: Colorectal cancer (CRC) is experiencing a significant increase in both incidence and mortality rates globally. The expression of Selenium-binding protein 1 (SELENBP1) has been reported to be notably downregulated in various malignancies, yet its biological functions and cellular mechanisms in CRC remain incompletely understood. METHOD: In our investigation, we observed the downregulation of SELENBP1 in CRC tissues through quantitative real-time PCR and western blotting and identified a positive correlation between higher SELENBP1 expression and improved survival prognosis using Kaplan-Meier survival analysis. Through loss-of-function and gain-of-function studies, we demonstrated the tumor-suppressive roles of SELENBP1 in CRC, supported by results from both in vitro and in vivo experiments. Furthermore, we uncovered the pivotal functions of SELENBP1 in suppressing aerobic glycolysis in CRC cells by regulating glucose uptake, lactate generation, and extracellular acidification rate. RESULT: At a mechanistic level, we found that SELENBP1 inhibits the expression of the key glycolytic modulator hypoxia-inducible factor 1 subunit alpha (HIF1α), and the inhibition of glycolysis by SELENBP1 can be reversed by ectopic expression of HIF1α. Therefore, our study highlights the potential of SELENBP1 as a promising target for CRC therapy, given its significant impact on tumor suppression and reprogrammed glucose metabolism. CONCLUSION: These findings contribute to a deeper understanding of the molecular mechanisms underlying CRC progression and may pave the way for the development of targeted therapies for this challenging disease.

Methanethiol: A Scent Mark of Dysregulated Sulfur Metabolism in Cancer.

In order to cope with increased demands for energy and metabolites as well as to enhance stress resilience, tumor cells develop various metabolic adaptations, representing a hallmark of cancer. In this regard, the dysregulation of sulfur metabolism that may result in elevated levels of volatile sulfur compounds (VSCs) in body fluids, breath, and/or excretions of cancer patients has recently gained attention. Besides hydrogen sulfide (H2S), methanethiol is the predominant cancer-associated VSC and has been proposed as a promising biomarker for non-invasive cancer diagnosis. Gut bacteria are the major exogenous source of exposure to this foul-smelling toxic gas, with methanethiol-producing strains such as Fusobacterium nucleatum highly abundant in the gut microbiome of colorectal carcinoma (CRC) patients. Physiologically, methanethiol becomes rapidly degraded through the methanethiol oxidase (MTO) activity of selenium-binding protein 1 (SELENBP1). However, SELENBP1, which is considered a tumor suppressor, is often downregulated in tumor tissues, and this has been epidemiologically linked to poor clinical outcomes. In addition to impaired removal, an increase in methanethiol levels may derive from non-enzymatic reactions, such as a Maillard reaction between glucose and methionine, two metabolites enriched in cancer cells. High methionine concentrations in cancer cells may also result in enzymatic methanethiol production in mitochondria. Moreover, enzymatic endogenous methanethiol production may occur through methyltransferase-like protein 7B (METTL7B), which is present at elevated levels in some cancers, including CRC and hepatocellular carcinoma (HCC). In conclusion, methanethiol contributes to the scent of cancer as part of the cancer-associated signature combination of volatile organic compounds (VOCs) that are increasingly being exploited for non-invasive early cancer diagnosis.

Single-cell RNA landscape of cell heterogeneity and immune microenvironment in ligation-induced vascular remodeling in rat.

BACKGROUND AND AIMS: Vascular remodeling is a common pathological basis for cardiovascular diseases. Although both immune and non-immune cells have been suggested to contribute to this process, the complex cellular heterogeneity and intercellular interactions remain largely uncharacterized. METHODS AND RESULTS: In this study, we simulated early and late vascular remodeling by ligating the rat carotid artery for 1 week and 4 weeks, respectively. Using single-cell RNA-sequencing, we characterized gene expression signatures and driver signals of major cell types involved in vascular remodeling. Focused analysis revealed a novel sub-population of Selenbp1hi smooth muscle cells (SMCs) associated with vascular remodeling. Results of intercellular communication analyses predicted several ligand-receptor pairs between immune cells with SMCs and endothelial cells (ECs), implicating SMCs apoptosis and repair, ECs aging and inflammatory responses. CONCLUSIONS: We present a comprehensive single-cell atlas of vascular cells in early and late stages of ligated rat carotid artery, providing valuable insights into the understanding of the initiation and progression of vascular remodeling.

Selenium-binding protein 1 inhibits malignant progression and induces apoptosis via distinct mechanisms in non-small cell lung cancer.

BACKGROUND: Selenium is an essential trace element in the human body. In epidemiological and clinical studies, Se supplementation significantly reduced the incidence of lung cancer in individuals with low baseline Se levels. The significant action of selenium is based on the selenium-containing protein as a mediator. Of note, the previous studies reported that the expression of selenium-binding protein 1 (SELENBP1) was obviously decreased in many human cancer tissues including non-small cell lung cancer (NSCLC). However, its roles in the origin and development of NSCLC are still unclear. METHODS: The expression of SELENBP1 was measured by qRT-PCR, Western blotting and IHC in our collected clinical NSCLC tissues and cell lines. Next, the CCK-8, colony formation, wound-haeling, Millicell, Transwell, FCM assay, and in vivo xenograft model were performed to explore the function of SELENBP1 in NSCLC. The molecular mechanisms of SELENBP1 were investigated by Western blotting or IF assay. RESULTS: We further identified that the expression of SELENBP1 was significantly decreased in NSCLC tissues in TCGA database and 45 out of 59 collected clinical NSCLC tissues compared with adjacent nontumor tissues, as well as in four NSCLC cell lines compared with normal lung cells. Particularly, we unexpectedly discovered that SELENBP1 was obviously expressed in alveolar type 2 (AT-II) cells for the first time. Then, a series of in vitro experiments uncovered that overexpression of SELENBP1 inhibited the proliferation, migration, and invasion of NSCLC cells, and induced cell apoptosis. Moreover, overexpression of SELENBP1 also inhibited growth and induced apoptosis of NSCLC cells in vivo. Mechanistically, we demonstrated that overexpression of SELENBP1 inhibited the malignant characteristics of NSCLC cells in part via inactivating the PI3K/AKT/mTOR signal pathway. Meanwhile, we found that overexpression of SELENBP1 inducing the apoptosis of NSCLC cells was associated with the activation of caspase-3 signaling pathway under nonhigh level of oxidative stress, but overexpression of SELENBP1 facilitating the cell apoptosis might be related to its combining with GPX1 and colocalizing in the nucleus under high level of oxidative stress. CONCLUSIONS: Our findings highlighted that SELENBP1 was an important tumor suppressor during the origin and development of NSCLC. It may help to discover novel biomarkers or drug therapy targets for NSCLC.

The role of SELENBP1 and its epigenetic regulation in carcinogenic progression.

The initiation and progression of cancer is modulated through diverse genetic and epigenetic modifications. The epigenetic machinery regulates gene expression through intertwined DNA methylation, histone modifications, and miRNAs without affecting their genome sequences. SELENBP1 belongs to selenium-binding proteins and functions as a tumor suppressor. Its expression is significantly downregulated and correlates with carcinogenic progression and poor survival in various cancers. The role of SELENBP1 in carcinogenesis has not been fully elucidated, and its epigenetic regulation remains poorly understood. In this review, we summarize recent findings on the function and regulatory mechanisms of SELENBP1 during carcinogenic progression, with an emphasis on epigenetic mechanisms. We also discuss the potential cancer treatment targeting epigenetic modification of SELENBP1, either alone or in combination with selenium-containing compounds or dietary selenium.

Altered Capacity for H2S Production during the Spontaneous Differentiation of Caco-2 Cells to Colonocytes Due to Reciprocal Regulation of CBS and SELENBP1.

Hydrogen sulfide (H2S) has been proposed to promote tumor growth. Elevated H2S levels have been detected in human colorectal cancer (CRC) biopsies, resulting from the selective upregulation of cystathionine ß-synthase (CBS). In contrast, the recently identified novel H2S-generating enzyme, selenium-binding protein 1 (SELENBP1), is largely suppressed in tumors. Here, we provide the first comparative analysis of the four human H2S-producing enzymes and the key H2S-catabolizing enzyme, sulfide:quinone oxidoreductase (SQOR), in Caco-2 human colorectal adenocarcinoma cells. The gene expression pattern of proliferating Caco-2 cells parallels that of CRC, while confluent cells undergo spontaneous differentiation to a colonocyte-like phenotype. SELENBP1 and SQOR were strongly upregulated during spontaneous differentiation, whereas CBS was downregulated. Cystathionine γ-lyase and 3-mercaptopyruvate sulfurtransferase remained unaffected. Terminally differentiated cells showed an enhanced capacity to produce H2S from methanethiol and homocysteine. Differentiation induced by exposure to butyrate also resulted in the upregulation of SELENBP1, accompanied by increased SELENBP1 promoter activity. In contrast to spontaneous differentiation, however, butyrate did not cause downregulation of CBS. In summary, SELENBP1 and CBS are reciprocally regulated during the spontaneous differentiation of Caco-2 cells, thus paralleling their opposing regulation in CRC. Butyrate exposure, while imitating some aspects of spontaneous differentiation, does not elicit the same expression patterns of genes encoding H2S-modulating enzymes.

Downregulation of SELENBP1 enhances oral squamous cell carcinoma chemoresistance through KEAP1-NRF2 signaling.

PURPOSE: Limited value is achieved in systemic chemotherapy for oral squamous cell carcinoma (OSCC), due to cancer cell resistance against cytotoxic agents. Tumor suppressor activities of selenium-binding protein 1 (SELENBP1) have been shown in multiple human cancers except for OSCC. The aim of this study is to clarify the biological functions and potential mechanism of SELENBP1 in OSCC. METHODS: SELENBP1 expression and its clinical significance in OSCC were analyzed from The Cancer Genome Atlas (TCGA) database. Quantitative polymerase chain reaction (qPCR) or western blot was applied to determine SELENBP1, NRF2 and KEAP1 mRNA or protein levels. Sulforhodamine B assay (SRB) was performed to examine the cytotoxic effects of 5-fluorouracil (5-FU) and cisplatin on OSCC cells. Luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay were conducted to investigate the role of SELENBP1 in KEAP1 transcription. RESULTS: SELENBP1 downregulation is positively correlated with a poor prognosis for OSCC patients. SELENBP1 knockdown enhances resistance of OSCC cells to 5-FU and cisplatin, while SENENBP1 overexpression displays the opposite effects. Mechanistically, SELENBP1 reduces NRF2 protein levels by promoting its polyubiquitination and degradation. SELENBP1 induces KEAP1 transcription by binding to KEAP1 promoter. Downregulation of SELENBP1 is induced by miR-4786-3p binding to the 3' untranslated region (UTR) of SELENBP1. CONCLUSION: SENENBP1 is identified as a novel protective biomarker for OSCC patients. Targeting at the miR-4786-3p-SELENBP1-KEAP1-NRF2 signaling axis may enhance the efficacy of chemotherapy for OSCC.

Nonnegative matrix factorization-based bioinformatics analysis reveals that TPX2 and SELENBP1 are two predictors of the inner sub-consensuses of lung adenocarcinoma.

BACKGROUND: Lung adenocarcinoma (LUAD) is a heterogeneous disease. However the inner sub-groups of LUAD have not been fully studied. Markers predicted the sub-groups and prognosis of LUAD are badly needed. AIMS: To identify biomarkers associated with the sub-groups and prognosis of LUAD. MATERIALS AND METHODS: Using nonnegative matrix factorization (NMF) clustering, LUAD patients from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) datasets and LUAD cell lines from Genomics of Drug Sensitivity in Cancer (GDSC) dataset were divided into different sub-consensuses based on the gene expression profiling. The overall survival of LUAD patients in each sub-consensus was determined by Kaplan-Meier survival analysis. The common genes which were differentially expressed in each sub-consensus of LUAD patients and LUAD cell lines were identified using TBtools. The predictive accuracy of TPX2 and SELENBP1 for theinner sub-consensuses of LUAD was determined by Receiver operator characteristic (ROC) analysis. The Kaplan-Meier survival analysis was also used to test the prognostic significance of TPX2 and SELENBP1 in LUAD patients. RESULTS: Using nonnegative matrix factorization clustering, LUAD patients in The Cancer Genome Atlas (TCGA), GSE30219, GSE42127, GSE50081, GSE68465, and GSE72094 datasets were divided into three sub-consensuses. Sub-consensus3 LUAD patients were with low overall survival and were with high TP53 mutations. Similarly, LUAD cell lines were also divided into three sub-consensuses by NMF method, and sub-consensus2 cell lines were resistant to EGFR inhibitors. Identification of the common genes which were differentially expressed in different sub-consensuses of LUAD patients and LUAD cell lines revealed that TPX2 was highly expressed in sub-consensus3 LUAD patients and sub-consensus2 LUAD cell lines. On the contrary, SELENBP1 was highly expressed in sub-consensus1 LUAD patients and sub-consensus1 LUAD cell lines. The expression levels of TPX2 and SELENBP1 could distinguish sub-consensus3 LUAD patients or sub-consensus2 LUAD cell lines from other sub-consensuses of LUAD patients or cell lines. Moreover, compared with normal lung tissues, TPX2 was highly expressed, while, SELENBP1 was lowly expressed in LUAD tissues. Furthermore, the higher expression levels of TPX2 were associated with the lower relapse-free survival and the lower overall survival of LUAD patients. While, the higher expression levels of SELENBP1 were associated with the higher relapse-free survival and higher overall survival. At last, we showed that TP53 mutant LUAD patients were with higher TPX2 and lower SELENBP1 expressions. DISCUSSION: Both iCluster and NMF method are proved to be robust LUAD classification systems. However, the LUAD patients in different iclusters had no significant clinical overall survival, while, sub-consensus3 LUAD patients from NMF classification were with lower overall survival than other sub-consensuses. CONCLUSIONS: By integrated analysis of 1765 LUAD patients and 64 LUAD cell lines, we showed that NMF was a robust inner sub-consensuses classification method of LUAD. TPX2 and SELENBP1 were differentially expressed in different LUAD sub- consensuses, and predicted the inner sub-consensuses of LUAD with high accuracy. TPX2 was an unfavorable prognostic biomarker of LUAD which was up-regulated in LUAD tissues and associated with the low overall survival of LUAD. SELENBP1 was a favorable prognostic biomarker of LUAD which was down-regulated in LUAD tissues and associated with the prolonged overall survival of LUAD.

Cell-Type Specific Analysis of Selenium-Related Genes in Brain.

Selenoproteins are a unique class of proteins that play key roles in redox signaling in the brain. This unique organ is comprised of a wide variety of cell types that includes excitatory neurons, inhibitory neurons, astrocytes, microglia, and oligodendrocytes. Whereas selenoproteins are known to be required for neural development and function, the cell-type specific expression of selenoproteins and selenium-related machinery has yet to be systematically investigated. Due to advances in sequencing technology and investment from the National Institutes of Health (NIH)-sponsored BRAIN initiative, RNA sequencing (RNAseq) data from thousands of cortical neurons can now be freely accessed and searched using the online RNAseq data navigator at the Allen Brain Atlas. Hence, we utilized this newly developed tool to perform a comprehensive analysis of the cell-type specific expression of selenium-related genes in brain. Select proteins of interest were further verified by means of multi-label immunofluorescent labeling of mouse brain sections. Of potential significance to neural selenium homeostasis, we report co-expression of selenoprotein P (SELENOP) and selenium binding protein 1 (SELENBP1) within astrocytes. These findings raise the intriguing possibility that SELENBP1 may negatively regulate astrocytic SELENOP synthesis and thereby limit downstream Se supply to neurons.

Brain, blood, cerebrospinal fluid, and serum biomarkers in schizophrenia.

Over the last decade, finding a reliable biomarker for the early detection of schizophrenia (Scz) has been a topic of interest. The main goal of the current review is to provide a comprehensive view of the brain, blood, cerebrospinal fluid (CSF), and serum biomarkers of Scz disease. Imaging studies have demonstrated that the volumes of the corpus callosum, thalamus, hippocampal formation, subiculum, parahippocampal gyrus, superior temporal gyrus, prefrontal and orbitofrontal cortices, and amygdala-hippocampal complex were reduced in patients diagnosed with Scz. It has been revealed that the levels of interleukin 1ß (IL-1ß), IL-6, IL-8, and TNF-α were increased in patients with Scz. Decreased mRNA levels of brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B (TrkB), neurotrophin-3 (NT-3), nerve growth factor (NGF), and vascular endothelial growth factor (VEGF) genes have also been reported in Scz patients. Genes with known strong relationships with this disease include BDNF, catechol-O-methyltransferase (COMT), regulator of G-protein signaling 4 (RGS4), dystrobrevin-binding protein 1 (DTNBP1), neuregulin 1 (NRG1), Reelin (RELN), Selenium-binding protein 1 (SELENBP1), glutamic acid decarboxylase 67 (GAD 67), and disrupted in schizophrenia 1 (DISC1). The levels of dopamine, tyrosine hydroxylase (TH), serotonin or 5-hydroxytryptamine (5-HT) receptor 1A and B (5-HTR1A and 5-HTR1B), and 5-HT1B were significantly increased in Scz patients, while the levels of gamma-aminobutyric acid (GABA), 5-HT transporter (5-HTT), and 5-HT receptor 2A (5-HTR2A) were decreased. The increased levels of SELENBP1 and Glycogen synthase kinase 3 subunit α (GSK3α) genes in contrast with reduced levels of B-cell translocation gene 1 (BTG1), human leukocyte antigen DRB1 (HLA-DRB1), heterogeneous nuclear ribonucleoprotein A3 (HNRPA3), and serine/arginine-rich splicing factor 1 (SFRS1) genes have also been reported. This review covers various dysregulation of neurotransmitters and also highlights the strengths and weaknesses of studies attempting to identify candidate biomarkers.

Downregulation of plasma SELENBP1 protein in patients with recent-onset schizophrenia.

Upregulation of selenium binding protein 1 (SELENBP1) mRNA expression has been reported in schizophrenia, primarily in the dorsolateral prefrontal cortex. However, peripheral blood studies are limited and results are inconsistent. In this study, we examined SELENBP1 mRNA expression in whole blood and protein expression in plasma from patients with recent-onset schizophrenia (n = 30), treatment-resistant schizophrenia (n = 71) and healthy controls (n = 57). We also examined the effects of SELENBP1 genetic variation on gene and protein expression. We found lower SELENBP1 plasma protein levels in patients with recent-onset schizophrenia (p = 0.042) but not in treatment-resistant schizophrenia (p = 0.81). Measurement of peripheral mRNA levels showed no difference between treatment-resistant schizophrenia and healthy controls (p = 0.234) but clozapine plasma levels (p = 0.036) and duration of illness (p = 0.028) were positively correlated with mRNA levels. Genetic variation was not associated with mRNA or protein expression. Our data represent the first peripheral proteomic study of SELENBP1 in schizophrenia and suggest that plasma SELENBP1 protein is downregulated in patients with recent-onset schizophrenia.

Selenium-binding protein 1 is down-regulated in malignant melanoma.

Selenium-binding protein 1 (SELENBP1) expression is reduced in various epithelial cancer entities compared to corresponding normal tissue and has already been described as a tumor suppressor involved in the regulation of cell proliferation, senescence, migration and apoptosis. We identified SELENBP1 to be down-regulated in cutaneous melanoma, a malignant cancer of pigment-producing melanocytes in the skin, which leads to the assumption that SELENBP1 also functions as tumor suppressor in the skin, as shown by others e.g. for prostate or lung carcinoma. However, in vitro analyses indicate that SELENBP1 re-expression in human melanoma cell lines has no impact on cell proliferation, migration or tube formation of the tumor cells themselves when compared to control-transfected cells. Interestingly, supernatant taken from melanoma cell lines transfected with a SELENBP1 re-expression plasmid led to suppression of vessel formation of HMEC cells. Furthermore, SELENBP1 re-expression alters the sensitivity of melanoma cells for Vemurafenib treatment. The data also hint to a functional interaction of SELENBP1 with GPX1 (Glutathione peroxidase 1). Low SELENBP1 mRNA levels correlate inversely with GPX1 expression in melanoma. The re-expression of SELENBP1 combined with down-regulation of GPX1 expression led to reduction of the proliferation of melanoma cells. In summary, SELENBP1 influences the tumor microenvironment and SELENBP1 action is functionally influenced by GPX1.