m6A modification mediates SLC3A2/SLC7A5 translation in 3-methylcholanthrene-induced uroepithelial transformation.

3-Methylcholanthracene (3-MC) is one of the most carcinogenic polycyclic aromatic hydrocarbons (PAHs). Long-term exposure to PAHs has been thought of as an important factor in urothelial tumorigenesis. N6-methyladenosine (m6A) exists widely in eukaryotic organisms and regulates the expression level of specific genes by regulating mRNA stability, translation efficiency, and nuclear export efficiency. Currently, the potential molecular mechanisms that regulate m6A modification for 3-MC carcinogenesis remain unclear. Here, we profiled mRNA, m6A, translation and protein level using "-omics" methodologies, including transcriptomes, m6A profile, translatomes, and proteomics in 3-MC-transformed urothelial cells and control cells. The key molecules SLC3A2/SLC7A5 were screened and identified in 3-MC-induced uroepithelial transformation. Moreover, SLC7A5/SLC3A2 promoted uroepithelial cells malignant phenotype in vitro and in vivo. Mechanically, METTL3 and ALKBH5 mediated m6A modification of SLC3A2/SLC7A5 mRNA in 3-MC-induced uroepithelial transformation by upregulating the translation of SLC3A2/SLC7A5. Furthermore, programmable m6A modification of SLC3A2/SLC7A5 mRNA affected the expression of its proteins. Taken together, our results revealed that the m6A modification-mediated SLC3A2/SLC7A5 translation promoted 3-MC-induced uroepithelial transformation, suggesting that targeting m6A modification of SLC3A2/SLC7A5 may be a potential therapeutic strategy for bladder cancer related to PAHs.

Severer air pollution, poorer cognitive function: Findings from 176,345 elders in Northwestern China.

BACKGROUND: Limited evidence exists regarding the link between air pollution exposure and cognitive function in developing countries, particularly in areas with abundant natural sources of particulate matter. OBJECTIVES: To investigate this association in a large representative sample of the elderly in northwestern China. METHODS: We performed a cross-sectional study among 176,345 participants aged 60-100 years in northwestern China in 2020. A satellite-based spatiotemporal model was applied to assess three-year annual averages of particulate matter with an aerodynamic diameter ≤ 2.5 µm (PM2.5), ≤ 10 µm (PM10), sulfur dioxide (SO2), nitrogen dioxide (NO2), carbon monoxide (CO), and ozone (O3) at residential address. Poor cognitive function was assessed using the Mini-Mental State Examination (MMSE). Generalized linear mixed models were used to assess associations. RESULTS: Compared with participants with the lowest quartiles of PM2.5, PM10, and O3 levels, those with the second, third, and highest quartiles of air pollutants consistently showed increased odds of poor cognitive function and decreased MMSE scores. The odds ratios of poor cognitive function associated with a 10 µg/m3 increment in PM2.5, PM10, and O3 were 1.26 (95 % confidence interval [CI]: 1.17, 1.36), 1.06 (95 %CI: 1.04, 1.08), and 2.76 (95 %CI: 2.11, 3.62), respectively. Subgroup analyses suggested stronger associations between air pollution exposures and poor cognitive function among participants who were younger, were non-Uyghur and were physically active. CONCLUSION: Long-term exposures to PM2.5, PM10 and O3 were associated with poor cognitive function in elders. Our results suggest that reducing air pollution may alleviate the burden of poor cognitive function in the elderly.

Exposure to ambient air pollution and metabolic dysfunction-associated fatty liver disease: Findings from over 2.7 million adults in Northwestern China.

Ambient air pollutants exposures may lead to aggravated Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD). However, there is still a scarcity of empirical studies that have rigorously estimated this association, especially in regions where air pollution is severe. To fill in the literature gap, we conducted a cross-sectional study involving 2711,207 adults living in five regions of southern Xinjiang Uyghur Autonomous Region in 2021. Using a Space-Time Extra-Trees model, we assessed the four-year (2017-2020) average concentrations of particulate matter with aerodynamic diameter ≤1 µm (PM1), particulate matter with aerodynamic diameter ≤2.5 µm (PM2.5), particulate matter with aerodynamic diameter ≤10 µm (PM10), ozone (O3), sulfur dioxide (SO2), and carbon monoxide (CO), and then assigned these values to the participants. Generalized linear mixed models were employed to examine the relationships between air pollutants and the prevalence of MAFLD, with adjustment for multiple confounding factors. The odds ratios and 95% confidence intervals of MAFLD were 2.002 (1.826-2.195), 1.133 (1.108-1.157), 1.034 (1.027-1.040), 1.077 (1.023-1.134), 2.703 (2.322-3.146) and 1.033 (1.029-1.036) per 10 µg/m3 increase in the 4-year average PM1, PM2.5, PM10, O3, SO2 and CO exposures, respectively. The robustness of the findings was confirmed by a series of sensitivities. In summary, long-term exposure to ambient air pollutants was associated with increased odds of MAFLD, particularly in males and individuals with unhealthy lifestyles.

N6-methyladenosine mediates Nrf2 protein expression involved in PM2.5-induced pulmonary fibrosis.

It has been reported that particulate matter with an aerodynamic diameter of <2.5 µm (PM2.5) could induce epithelial-mesenchymal transition (EMT)- and extracellular matrix (ECM)-related pulmonary fibrosis (PF). The transcription factor Nrf2 alleviated PM2.5-induced PF by antagonizing oxidative stress. The N6-methyladenosine (m6A) modification plays a significant role in the stress response. However, the effect of m6A modification on the mechanisms of Nrf2-mediated defense against PM2.5-induced PF remained unknown. Here, we explored the role and the underlying molecular mechanisms of m6A methylation of Nrf2 mRNA in PM2.5-induced PF. We established filtered air (FA), unfiltered air (UA), and concentrated PM2.5 air (CA) group mice model and 0, 50, and 100 µg/mL PM2.5-treated 16HBE cell models. The extent of lung fibrosis in mice and fibrosis indicators were detected by histopathological analysis, immunohistochemical staining and western blotting. The molecular mechanism of m6A-modified Nrf2 was demonstrated by m6A-methylated RNA immunoprecipitation (MeRIP), RNA immunoprecipitation (RIP), qRT-PCR and T3 ligase-based PCR. Our data showed that PM2.5 exposure for 16 weeks could induce pulmonary fibrosis and activate Nrf2 signaling pathway. m6A methyltransferase METTL3 was upregulated after PM2.5 treatment in vivo and in vitro. Moreover, METTL3 mediated m6A modification of Nrf2 mRNA and promoted Nrf2 translation in mice and 16HBE cells after PM2.5 exposure. Mechanistically, three m6A-modified sites (1317, 1376 and 935; numbered relative to the first nucleotide of 3'UTR) of Nrf2 mRNA were identified in PM2.5-treatment 16HBE cells. Furthermore, the m6A binding proteins YTHDF1/IGF2BP1 promoted Nrf2 translation by binding to m6A residues of Nrf2 mRNA. Our results revealed the mechanism of m6A mediated Nrf2 signaling pathway against oxidative stress, which affected the development of PM2.5-induced PF.

Does COVID-19 threat increase xenophobia? The roles of protection efficacy and support seeking.

BACKGROUND: In response to the COVID-19 pandemic, people in many countries have shown xenophobia toward China, where the pandemic began. Within China, xenophobia has also been observed toward the people of Wuhan, the city where the first cases were identified. The relationship between disease threat and xenophobia is well established, but the reasons for this relationship are unclear. This study investigated the mediation role of perceived protection efficacy and moderation role of support seeking in the relationship between perceived COVID-19 risk and xenophobia within China. METHODS: An online survey was administered to a nationally representative sample (N = 1103; 51.7% women; ages 18 to 88) of Chinese adults during the early stage of the COVID-19 pandemic. Participants completed questionnaires about their perceived COVID-19 risk, perceived protection efficacy in reducing risk, support seeking, and xenophobic attitudes toward people of the Wuhan area. RESULTS: Regression based analyses showed that the perceived COVID-19 risk positively predicted xenophobia. Low perceived protection efficacy partly mediated the relationship between perceived COVID-19 risk and xenophobic attitudes, and this indirect effect was moderated by support seeking. Specifically, the indirect effect was weaker among individuals who sought more social support. CONCLUSIONS: Under disease threat, xenophobia can appear within a country that otherwise seems culturally homogeneous. This study extends the extant research by identifying a possible psychological mechanism by which individuals' perception of disease threat elicits xenophobia, and by addressing the question of why this response is stronger among some people than others. Increasing the public's perceived efficacy in protecting themselves from infection, and encouraging support seeking, could reduce xenophobic attitudes.

Strategies for understanding the role of cellular heterogeneity in the pathogenesis of lung cancer: a cell model for chronic exposure to cigarette smoke extract.

BACKGROUND: Human tumors are highly heterogeneous at the cellular, molecular, genetic and functional levels. Tumor heterogeneity has tremendous impact on cancer progression and treatment responses. However, the mechanisms for tumor heterogeneity have been poorly understood due to the lack of experimental models. METHODS: This study provides a novel exploration and analysis of the impacts of cellular and molecular heterogeneity of human lung epithelial cells on their malignant transformation following chronic exposure to cigarette smoke extracts. RESULTS: The ability of cigarette smoke extract (CSE) to cause malignant transformation of the human bronchial epithelial cells (16HBE) is dependent on the sizes of the cells. Epithelial-mesenchymal transition (EMT) plays an important role in this process. Mechanistically, CSE-induced malignant transformation of 16HBE cells was closely linked to the reduced relative telomere length of the larger 16HBE cells, thereby up-regulation of the expression of stemness genes. CONCLUSIONS: These findings provide novel insights for understanding the impact of cellular heterogeneity in lung cancer development. The in vitro transformation model described in this study could be extrapolated to studying the pathogenesis of other malignancies, as well as for mechanistic studies that are not feasible in vivo.

Proteomic Analysis Reveals the Vital Role of Synaptic Plasticity in the Pathogenesis of Temporal Lobe Epilepsy.

Temporal lobe epilepsy (TLE) is a chronic neurological disorder that is often resistant to antiepileptic drugs. The pathogenesis of TLE is extremely complicated and remains elusive. Understanding the molecular mechanisms underlying TLE is crucial for its diagnosis and treatment. In the present study, a lithium-pilocarpine-induced TLE model was employed to reveal the pathological changes of hippocampus in rats. Hippocampal samples were taken for proteomic analysis at 2 weeks after the onset of spontaneous seizure (a chronic stage of epileptogenesis). Isobaric tag for relative and absolute quantization (iTRAQ) coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS) technique was applied for proteomic analysis of hippocampus. A total of 4173 proteins were identified from the hippocampi of epileptic rats and its control, of which 27 differentially expressed proteins (DEPs) were obtained with a fold change > 1.5 and P < 0.05. Bioinformatics analysis indicated 27 DEPs were mainly enriched in "regulation of synaptic plasticity and structure" and "calmodulin-dependent protein kinase activity," which implicate synaptic remodeling may play a vital role in the pathogenesis of TLE. Consequently, the synaptic plasticity-related proteins and synaptic structure were investigated to verify it. It has been demonstrated that CaMKII-α, CaMKII-ß, and GFAP were significant upregulated coincidently with proteomic analysis in the hippocampus of TLE rats. Moreover, the increased dendritic spines and hippocampal sclerosis further proved that synaptic plasticity involves in the development of TLE. The present study may help to understand the molecular mechanisms underlying epileptogenesis and provide a basis for further studies on synaptic plasticity in TLE.

Short AIP1 (ASK1-Interacting Protein-1) Isoform Localizes to the Mitochondria and Promotes Vascular Dysfunction.

OBJECTIVE: Vascular endothelial cells (ECs) normally maintain vascular homeostasis and are regulated by proinflammatory cytokines and reactive oxygen species. A human genome-wide association study identified that AIP1 (ASK1 [apoptosis signal-regulating kinase 1]-interacting protein-1; also identified as DAB2IP) gene variants confer susceptibility to cardiovascular disease, but the underlying mechanism is unknown. Approach and Results: We detected a normal AIP1 form (named AIP1A) in the healthy aorta, but a shorter form of AIP1 (named AIP1B) was found in diseased aortae that contained atherosclerotic plaques and graft arteriosclerosis. AIP1B transcription in resting ECs was suppressed through epigenetic inhibition by RIF1 (Rap1 [ras-related protein 1]-interacting factor 1)/H3K9 (histone H3 lysine 9) methyltransferase-mediated H3K9 trimethylation, and this inhibition was released by proinflammatory cytokines. AIP1A, but not AIP1B, was downregulated by proteolytic degradation through a Smurf1 (SMAD [suppressor of mothers against decapentaplegic miscellaneous] ubiquitylation regulatory factor 1)-dependent pathway in ECs under inflammation. Therefore, AIP1B was the major form present during inflammatory conditions. AIP1B, which lacks the N-terminal pleckstrin homology domain of AIP1A, localized to the mitochondria and augmented TNFα (tumor necrosis factor alpha)-induced mitochondrial reactive oxygen species generation and EC activation. AIP1B-ECTG (EC-specific AIP1B transgenic) mice exhibited augmented reactive oxygen species production, EC activation, and neointima formation in vascular remodeling models. CONCLUSIONS: Our current study suggests that a shift from anti-inflammatory AIP1A to proinflammatory AIP1B during chronic inflammation plays a key role in inflammatory vascular diseases.

Integrated analysis of mRNA-m6A-protein profiles reveals novel insights into the mechanisms for cadmium-induced urothelial transformation.

Objective: This study aimed to investigate the mechanisms underlying Cd-induced urothelial transformation, using multi-omics analyses (transcriptome, epitranscriptome, and proteome).Methods: Transcriptomics analysis was performed to estimate the expression of genes, methylated RNA immunoprecipitation sequencing analysis was used to detect m6A modification, while proteomics analysis was used to identify differentially expressed proteins. Differentially expressed genes (DEGs) were subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis.Results: A total of 9491 DEGs, 711 differentially expressed proteins, and 633 differentially m6A modified genes between Cd-transformed cells and control cells were identified. The regulation of most genes varied at different omics layers. The three omics data shared 57 genes, and these genes were enriched in response to DNA damage stimulus and cell proliferation. Interestingly, 13 genes, most of which are related to the onset or progression of cancer, were shared by the m6A and proteomics data, but not the transcriptome data. This suggested that m6A modification is crucial for post-transcriptional regulation related to Cd2+-induced malignant transformation.Conclusion: Our multi-omics analysis provided a comprehensive reference map of gene activity and revealed m6A signalling pathways crucial for Cd2+ carcinogenesis.

Analysis on the trend of AIDS incidence in Zhejiang, China based on the age-period-cohort model (2004-2018).

OBJECTIVE: To predict the trend of AIDS in specific age groups and to determine the objective population for AIDS screening, this study explored the three transmission routes and characterized each patient group using the APC model based on the whole, local, and immigrant populations in Zhejiang, China. METHODS: The data recruited in this paper was obtained from the national Comprehensive AIDS Prevention and Control Information System - Antiviral Therapy Management database and the Chinese Disease Prevention and Control Information System and the Statistical Yearbook of Zhejiang, China. An APC model was used to estimate the impact of age, period, and cohort on the incidence of AIDS, as well as to predict the AIDS incidence in specific age groups based on different sexes with different transmission routes. RESULTS: The AIDS incidence peaked in males aged 20-35 years; the incidence of males was higher than that of females due to the impact of period; obvious cohort effect was observed among the immigrants. In the whole and local populations, the incidences of males in all age groups and females in both the 35-year-old group and the whole age group were predicted to increase sharply in 5 years. In the immigrant population, the AIDS incidences in both sexes in all age groups were expected to increase significantly in 5 years. Under the influence of period, the incidence of AIDS via homosexual transmission in the whole population and the local population increased and remained stable after 2015. At the same time, the incidence of AIDS transmitted by homosexual and heterosexual routes in the immigrants also showed an increasing trend. CONCLUSIONS: The results elucidate that there are sex differences in AIDS incidence, and the incidence of AIDS through various transmission routes in all groups is predicted to exhibit an upward trend in the 5 years to come. Effective intervention strategies should be developed and implemented by the public health departments in Zhejiang to control the epidemic of AIDS.

Nuclear localization of the tyrosine kinase BMX mediates VEGFR2 expression.

Vascular endothelial growth factor receptors (VEGFRs) are major contributors to angiogenesis and lymphangiogenesis through the binding of VEGF ligands. We have previously shown that the bone marrow tyrosine kinase BMX is critical for inflammatory angiogenesis via its direct transactivation of VEGFR2. In the present study, we show that siRNA-mediated silencing of BMX led to a significant decrease in the total levels of VEGFR2 mRNA and protein, without affecting their stability, in human endothelial cells (ECs). Interestingly, BMX was detected in the nuclei of ECs, and the SH3 domain of BMX was necessary for its nuclear localization. Luciferase assays showed a significant decrease in the Vegfr2 (kdr) gene promoter activity in ECs after BMX silencing, indicating that BMX is necessary for Vegfr2 transcription. In addition, we found that wild-type BMX, but not a catalytic inactive mutant BMX-K445R, promoted Vegfr2 promoter activity and VEGF-induced EC migration and tube sprouting. Mechanistically, we show that the enhancement of Vegfr2 promoter activity by BMX was mediated by Sp1, a transcription factor critical for the Vegfr2 promoter. Loss of BMX significantly reduced Sp1 binding to the Vegfr2 promoter as assayed by chromatin immunoprecipitation assays. Wild-type BMX, but not a kinase-inactive form of BMX, associated with and potentially phosphorylated Sp1. Moreover, a nuclear-targeted BMX (NLS-BMX), but not cytoplasm-localized form (NES-BMX), bound to Sp1 and augmented VEGFR2 expression. In conclusion, we uncovered a novel function of nuclear-localized BMX in regulating VEGFR2 expression and angiogenesis, suggesting that BMX is a therapeutic target for angiogenesis-related diseases.

Programmable N6-methyladenosine modification of CDCP1 mRNA by RCas9-methyltransferase like 3 conjugates promotes bladder cancer development.

Accumulating evidence has revealed significant roles for N6-methyladenosine (m 6 A) modification in the development of various cancers. We previously demonstrated an oncogenic role of m 6 A-modified CUB domain containing protein 1 (CDCP1) in bladder cancer (BC) progression. However, the biological functions and underlying molecular mechanisms of engineered programmable m 6 A modification of CDCP1 mRNA in BC remain obscure. Here, we established a targeted m 6 A RNA methylation system by fusing the catalytic domain of methyltransferase like 3 (METTL3CD) to RCas9 as the RNA-targeting module. The constructed RCas9- METTL3 retained methylation activity and mediated efficient site-specific m 6 A installation in the presence of a cognate single guide RNA and short protospacer adjacent motif-containing ssDNA molecule . Subsequently, targeting m 6 A installation onto the 3' untranslated region of CDCP1 promoted CDCP1 mRNA translation and facilitated BC development in vitro and in vivo. Our findings demonstrate that the RCas9-METTL3 system mediates efficient sitespecific m 6 A installation on CDCP1 mRNA and promotes BC development. Thus, the RCas9-METTL3 system provides a new tool for studying m 6 A function and a potential strategy for BC epitranscriptome-modulating therapies.

ALKBH5-m6A-FOXM1 signaling axis promotes proliferation and invasion of lung adenocarcinoma cells under intermittent hypoxia.

Obstructive sleep apnea (OSA) is closely associated with cancer progression and cancer-related mortality. N6-methyladenosine (m6A) is involved in the process of intermittent hypoxia (IH) promoting tumor progression. However, it is unclear how m6A regulates the development of lung adenocarcinoma under IH. In this study, we found that ALKBH5 was elevated in lung adenocarcinoma cells and subcutaneous tumors in mice under IH, which was associated with decreased m6A levels in these cells and tissues. Next, we knocked out ALKBH5 in a human lung adenocarcinoma cell line under IH, and we found that the proliferation and invasion of these cells were significantly inhibited. Mechanistic analysis showed that under IH, knockout of ALKBH5 in lung adenocarcinoma cells upregulated the level of m6A in Forkhead box M1 (FOXM1) mRNA and decreased the translation efficiency of FOXM1 mRNA, resulting in downregulation of the FOXM1 protein. The FOXM1 protein is elevated in lung adenocarcinoma cells and subcutaneous tumor tissues of mice under IH. By knocking out FOXM1 in lung adenocarcinoma cells under IH, proliferation and invasion of these cells were inhibited, and overexpression of FOXM1 partially restored the inhibition of growth and invasion of lung adenocarcinoma cells due to ALKBH5 knockout. Collectively, our findings demonstrate that the m6A demethylase ALKBH5 affects the proliferation and invasion of lung adenocarcinoma cells under IH by downregulating m6A modification on FOXM1 mRNA and by promoting FOXM1 expression.

Comprehensive analysis of differential circular RNA expression in a mouse model of colitis-induced colon carcinoma.

Circular RNAs (circRNAs) have received increasing attention for their involvement in the pathogenesis of cancer; however, the characterization and function of circRNAs in colitis-induced colon carcinoma remains largely unknown. A colitis-induced colon carcinoma model was established in mice treated with azoxymethane-dextran sodium sulfate (AOM-DSS), and the circRNA profile was screened by next generation sequencing. Bioinformatic tools, including Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and network analysis were used to predict the functions of differentially expressed circRNAs and potentially coexpressed target genes. Among the detected candidate 3069 circRNA genes, 126 circRNAs were upregulated, and 108 circRNAs were down regulated in colon tissues from AOM/DSS mice compared to those from control mice. A total of six of these candidate circRNAs were validated by RT-PCR. GO analysis revealed that numerous target genes including most microRNAs were involved in the Ras-Raf-MAPK pathway, actin cytoskeleton, focal adhesion, and additional biological processes. Our study revealed a comprehensive expression and functional profile for differentially expressed circRNAs in AOM/DSS induced colon carcinogenesis, indicating possible involvement of these dysregulated circRNAs in the development of colitis-induced colon carcinoma. The mmu-circ-001226/mmu-circ-000287-miRNA-mRNA network may provide a potential mechanism for colitis-associated colorectal cancer.

LXR agonists promote the proliferation of neural progenitor cells through MEK-ERK pathway.

The liver X receptors (LXRs) are transcriptional regulators of lipid homeostasis and may be critical for neurodegeneration and neurogenesis in vivo. However, it remains largely unknown about the role of LXRs and its agonists in the in vitro proliferation of neural progenitor cells (NPCs). Here we revealed for the first time that LXRs were markedly expressed in mouse NPCs and were critical for the in vitro proliferation. LXR agonists GW3965 and LXR623 promoted the proliferation of wildtype NPCs, but not NPCs from LXR double-knockout mice. Mechanistically, phosphorylation of MEK1/2 and ERK1/2 in NPCs was enhanced upon LXR agonist treatment, while abrogation of MEK/ERK phosphorylation by the inhibitors PD98059 and U0126 impaired the proliferation of wildtype NPCs in the presence or absence of LXR agonists. Collectively, our findings suggest that LXR agonists GW3965 and LXR623 can stimulate the NPC proliferation in LXR- and MEK/ERK-dependent manner.

Mechanistic Role of Thioredoxin 2 in Heart Failure.

Thioredoxin 2 (Trx2) is a pivotal mitochondrial protein that regulates redox signaling. The mitochondrial Trx2 is expressed ubiquitously, but it is found at the highest levels in metabolically active tissues like the heart. Global gene knockout of Trx2 results in embryonic lethality, likely due to the increased cellular oxidative stress. Moreover, mice with cardiac-specific Trx2 deletion develop spontaneous dilated cardiomyopathy (DCM), correlating with increased apoptosis stress kinase-1 (ASK1) signaling and increased cardiomyocyte apoptosis. Cardiomyocyte apoptosis is a common mechanism in the pathogenesis of heart failure. Our results show that Trx2 is essential for maintaining cardiac function. In this chapter, we summarize the key mechanistic role of Trx2 in preserving cardiac function by suppressing mitochondrial reactive oxygen species (ROS) generation and by inhibiting ASK1-dependent apoptosis in heart failure. Trx2 and ASK1 represent promising targets to develop therapeutic strategies for the treatment of DCM and heart failure.

Long non-coding RNA DBCCR1-003 regulate the expression of DBCCR1 via DNMT1 in bladder cancer.

BACKGROUND: Many long non coding RNAs have been identified as key modulators in cancer development. A lncRNA, DBCCR1-003, derived from the locus of tumor suppressor gene DBCCR1 (deleted in bladder cancer chromosome region 1), has unknown function. In the present study, we explored function and molecular mechanism of DBCCR1-003 in bladder cancer (BC) development. METHODS: We evaluated the expression levels of DBCCR1-003 in tissues and cells with western blot and quantitative real-time polymerase chain reaction. Multiple approaches including chromatin immunoprecipitation assay and RNA immunoprecipitation were used to confirm the direct binding of DBCCR1-003 to DNMT1. The recombinant vector overexpressing DBCCR1-003 was constructed. Cell proliferation assay, colony formation assay and flow cytometric analysis were employed to measure the role of DBCCR1-003 in regulation of cell proliferation, cycle and apoptosis. RESULTS: Firstly we detected the expression of DBCCR1-003, DBCCR1, DNMT1 (DNA methyltransferase 1) and DNA methylation in the promoter of DBCCR1. We found low expression of DBCCR1-003, same as DBCCR1, while high expression of DNMT1 and hypermethylation of DBCCR1 gene promoter in BC tissues and T24 cells line. Further studies revealed that treatment of DNMT inhibitor, 5-aza-2-deoxycytidine(DAC), or overexpression of DBCCR1-003 led to increased DBCCR1 expression by reversion of promoter hypermethylation and DNMT1 binding to DBCCR1 promoter in T24 cells. Importantly, RNA immunoprecipitation (RIP) showed that DBCCR1-003 physically associates with DNMT1. The binding of them was increased with the inhibition of DBCCR1 promoter methylation, indicating that DBCCR1-003 may bind to DNMT1 and prevent DNMT1-mediated the methylation of DBCCR1. Furthermore, overexpression of DBCCR1-003 resulted in significant inhibition of T24 cells growth through the inducing G0/G1 arrest and apoptosis. CONCLUSIONS: Taken together, these findings demonstrated that a novel tumor suppressor DBCCR1-003 regulates the expression of DBCCR1 via binding to DNMT1 and preventing DNMT1-mediated the methylation of DBCCR1 in BC. LncRNA DBCCR1-003 may serve as a novel biomarker and therapeutic target for BC in future cancer clinic.

Common variants in QPCT gene confer risk of schizophrenia in the Han Chinese population.

Schizophrenia (SCZ) is a common and severe mental disorder, its etiology has not been elucidated completely. In one previous genome-wide association study (GWAS) of SCZ in the Caucasian population, the QPCT has been reported as susceptible gene for SCZ. The QPCT gene encodes Glutaminyl cyclase (QC), an enzyme which is involved in the post translational modification by converting N-terminal glutamate of protein to pyroglutamate, which is resistant to protease degradation, more hydrophobic, and prone to aggregation and neurotoxic. To further investigate the role of this gene in the pathogenesis of schizophrenia in the Han Chinese population, we conducted this study in 1,248 (Mean age ± S.D, 36.44 years ± 9.0) SCZ cases, 1,248 (Mean age ± S.D, 30.62 years ± 11.35) healthy control samples for a case control study. We genotyped six SNPs in this study, including one positive SNP of the previous study, using the Sequenom MassARRAY platform. We found that rs2373000 was significantly associated with SCZ before correction [rs2373000: P allele = 0.016, χ(2) = 5.784, OR [95%CI] = 0.861 [0.762-0.972], P genotype = 0.018, χ(2) = 0.069]. After permutation correction for multiple testing, rs2373000 [rs2373000: P Allele corrected = 0.063, P genotype corrected = 0.069] showed marginal association with SCZ. Additionally, one pathogenic haplotype (TGT) containing rs2373000 was also significantly associated with SCZ. Our results are consistent with the findings of previous study and the genetic risk of QPCT gene for SCZ also exists in the Han Chinese population.

ß-Arrestin2 Contributes to Cell Viability and Proliferation via the Down-Regulation of FOXO1 in Castration-Resistant Prostate Cancer.

ß-Arrestin2 has been identified to act as a corepressor of androgen receptor (AR) signaling by binding to AR and serving as a scaffold to affect the activity and expression of AR in androgen-dependent prostate cancer cells; however, little is known regarding its role in castration-resistant prostate cancer (CRPC) progression. Here, our data demonstrated that ß-arrestin2 contributes to the cell viability and proliferation of CRPC via the downregulation of FOXO1 activity and expression. Mechanistically, in addition to its requirement for FOXO1 phosphorylation induced by IGF-1, ß-arrestin2 could inhibit FOXO1 activity in an Akt-independent manner and delay FOXO1 dephosphorylation through the inhibition of PP2A phosphatase activity and the attenuation of the interaction between FOXO1 and PP2A. Furthermore, ß-arrestin2 could downregulate FOXO1 expression via ubiquitylation and proteasomal degradation. Together, our results identified a novel role for ß-arrestin2 in the modulation of the CRPC progress through FOXO1. Thus, the characterization of ß-arrestin2 may represent an alternative therapeutic target for CRPC treatment.