Von Hippel Lindau tumor suppressor controls m6A-dependent gene expression in renal tumorigenesis.

N6-Methyladenosine (m6A) is the most abundant posttranscriptional modification, and its contribution to cancer evolution has recently been appreciated. Renal cancer is the most common adult genitourinary cancer, approximately 85% of which is accounted for by the clear cell renal cell carcinoma (ccRCC) subtype characterized by VHL loss. However, it is unclear whether VHL loss in ccRCC affects m6A patterns. In this study, we demonstrate that VHL binds and promotes METTL3/METTL14 complex formation while VHL depletion suppresses m6A modification, which is distinctive from its canonical E3 ligase role. m6A RNA immunoprecipitation sequencing (RIP-Seq) coupled with RNA-Seq allows us to identify a selection of genes whose expression may be regulated by VHL-m6A signaling. Specifically, PIK3R3 is identified to be a critical gene whose mRNA stability is regulated by VHL in a m6A-dependent but HIF-independent manner. Functionally, PIK3R3 depletion promotes renal cancer cell growth and orthotopic tumor growth while its overexpression leads to decreased tumorigenesis. Mechanistically, the VHL-m6A-regulated PIK3R3 suppresses tumor growth by restraining PI3K/AKT activity. Taken together, we propose a mechanism by which VHL regulates m6A through modulation of METTL3/METTL14 complex formation, thereby promoting PIK3R3 mRNA stability and protein levels that are critical for regulating ccRCC tumorigenesis.

MicroRNA-140-3p inhibits proliferation and promotes apoptosis in non-small cell lung cancer by targeting MDIG.

BACKGROUND: MicroRNAs (miRNAs) are associated with cancer progression. MiR-140-3p is a tumor suppressor. Nevertheless, its function in non-small cell lung cancer (NSCLC) is unclear. METHODS: MiR-140-3p expression in NSCLC clinical specimens was examined using the TCGA database and real-time PCR. NSCLC cell proliferation and apoptosis were investigated after the miRNA overexpression. Then, mineral dust-induced gene (MDIG) levels in NSCLC clinical specimens were monitored by real-time PCR and western blotting. Bioinformatics predicated the binding of miR-140-3p to MDIG, and their relationship was validated by luciferase reporter assay. The miR-140-3p/MDIG axis was further validated through rescue experiments. The involvement of STAT3 signaling in the actions of miR-140-3p/MDIG axis was investigated. RESULTS: MiR-140-3p was decreased in NSCLC tissues and negatively correlated with MDIG expression. Additionally, it was also lower in high-grade specimens than in low-grade ones. MiR-140-3p restrained cell proliferation, facilitated apoptosis, and inhibited STAT3 signaling in NSCLC. Interestingly, MDIG was a target of this miRNA. Furthermore, MDIG upregulation abolished miR-140-3p's effect on cell proliferation, apoptosis, and STAT3 pathway in NSCLC cells. CONCLUSION: MiR-140-3p restrained NSCLC development through the regulation of the STAT3 pathway by targeting MDIG. This axis may be a promising target for NSCLC treatment.

Changes in aspartate metabolism in the medial-prefrontal cortex of nicotine addicts based on J-edited magnetic resonance spectroscopy.

This study aims to explore the changes of the aspartate (Asp) level in the medial-prefrontal cortex (mPFC) of subjects with nicotine addiction (nicotine addicts [NAs]) using the J-edited 1 H MR spectroscopy (MRS), which may provide a positive imaging evidence for intervention of NA. From March to August 2022, 45 males aged 40-60 years old were recruited from Henan Province, including 21 in NA and 24 in nonsmoker groups. All subjects underwent routine magnetic resonance imaging (MRI) and J-edited MRS scans on a 3.0 T MRI scanner. The Asp level in mPFC was quantified with reference to the total creatine (Asp/Cr) and water (Aspwater-corr , with correction of the brain tissue composition) signals, respectively. Two-tailed independent samples t-test was used to analyze the differences in levels of Asp and other coquantified metabolites (including total N-acetylaspartate [tNAA], total cholinine [tCho], total creatine [tCr], and myo-Inositol [mI]) between the two groups. Finally, the correlations of the Asp level with clinical characteristic assessment scales were performed using the Spearman criteria. Compared with the control group (n = 22), NAs (n = 18) had higher levels of Asp (Asp/Cr: p = .005; Aspwater-corr : p = .004) in the mPFC, and the level of Asp was positively correlated with the daily smoking amount (Asp/Cr: p < .001; Aspwater-corr : p = .004). No significant correlation was found between the level of Asp and the years of nicotine use, Fagerstrom Nicotine Dependence (FTND), Russell Reason for Smoking Questionnaire (RRSQ), or Barratt Impulsivity Scale (BIS-11) score. The elevated Asp level was observed in mPFC of NAs in contrast to nonsmokers, and the Asp level was positively correlated with the amount of daily smoking, which suggests that nicotine addiction may result in elevated Asp metabolism in the human brain.

HILPS, a long noncoding RNA essential for global oxygen sensing in humans.

Adaptation to low levels of oxygen (hypoxia) is a universal biological feature across metazoans. However, the unique mechanisms how different species sense oxygen deprivation remain unresolved. Here, we functionally characterize a novel long noncoding RNA (lncRNA), LOC105369301, which we termed hypoxia-induced lncRNA for polo-like kinase 1 (PLK1) stabilization (HILPS). HILPS exhibits appreciable basal expression exclusively in a wide variety of human normal and cancer cells and is robustly induced by hypoxia-inducible factor 1α (HIF1α). HILPS binds to PLK1 and sequesters it from proteasomal degradation. Stabilized PLK1 directly phosphorylates HIF1α and enhances its stability, constituting a positive feed-forward circuit that reinforces oxygen sensing by HIF1α. HILPS depletion triggers catastrophic adaptation defect during hypoxia in both normal and cancer cells. These findings introduce a mechanism that underlies the HIF1α identity deeply interconnected with PLK1 integrity and identify the HILPS-PLK1-HIF1α pathway as a unique oxygen-sensing axis in the regulation of human physiological and pathogenic processes.

EIF4A3-regulated hsa_circ_0001445 can inhibit the progression of laryngeal squamous cell carcinoma via hsa-miR-432-5p-dependent up-regulation of RGMA expression.

Laryngeal squamous cell carcinoma (LSCC) is a common malignant tumor in the head and neck, the 5-year relative survival rate of patients diagnosed with laryngeal cancer was estimated to be 61% from 2012 to 2018. An increasing number of studies have shown that circular RNAs (circRNAs) play a key role in the occurrence and development of cancer and may function as cancer biomarkers and new therapeutic targets. At present, the research on the relationship between circRNAs and LSCC is still in its infancy and needs further exploration. In this study, we found a circRNA (hsa_circ_0001445) associated with LSCC based on bioinformatics analysis. Quantitative real-time polymerase chain reaction (qRT-PCR) assay indicated that the expression of hsa_circ_0001445 was down-regulated in LSCC tissues and cell lines. Notably, the expression of hsa_circ_0001445 was negatively correlated with aggressive clinicopathological features and poor prognosis. Then, functional experiments found that overexpression of hsa_circ_0001445 inhibited the proliferation, migration and invasion of LSCC cells and tumor growth in vivo. Mechanistically, RNA immunoprecipitation (RIP), biotin-labeled probe pull-down, luciferase reporter assay and western blot experiments were employed and found that EIF4A3 reduced the expression of hsa_circ_0001445, and the direct binding of hsa_circ_0001445 to hsa-miR-432-5p attenuated the inhibitory effect of hsa-miR-432-5p on RGMA. In summary, our research suggests that hsa_circ_0001445 may be used as a potential prognostic biomarker and therapeutic target for LSCC.

Intrareticular Charge Transfer Triggered Self-Electrochemiluminescence of Zirconium-Based Metal-Organic Framework Nanoparticles for Potential-Resolved Multiplex Immunoassays with Isolated Coreactants.

In this work, a potential-resolved electrochemiluminescence (ECL) multiplex immunoassay (MIA) was developed using zirconium-based metal-organic framework (MOF) nanoparticles with intense self-ECL as an anodic ECL tag and CdTe nanocrystals (NCs) as a cathodic ECL tag. ECL luminophore 5,5'-(anthracene-9,10-diyl)diisophthalic acid (H4ADIP) and coreactant hexamethylenetetramine (HMT) bound to zirconium nodes in the MOF, giving Zr-ADIP-HMT nanoparticles. Benefiting from the intrareticular charge transfer (ICT) between the oxidized ligands of H4ADIP and HMT via hydrogen bonds, the intense self-ECL from Zr-ADIP-HMT was applied to the potential-resolved ECL MIA without an exogenous anodic coreactant, which can eliminate detrimental effects of multiplex coreactants and anodic ECL emission from CdTe NCs. The ICT within Zr-ADIP-HMT nanoparticles could shorten the electron transport path and reduce the complexity of radical intermediate transport. The ECL intensity from Zr-ADIP-HMT was 18.6-fold that from the mixture of H4ADIP and HMT. In potential-resolved ECL MIA, two lung cancer biomarkers, carcinoembryonic antigen and neuron-specific enolase, were adopted as model analytes, with detection limits of 18 and 5.3 fg·mL-1, respectively. The dual-ligand Zr-ADIP-HMT nanoparticles provide a proof of concept using ICT-based self-ECL luminophores for potential-resolved ECL MIAs with isolated coreactants.

Development and validation of a tumor immune cell infiltration-related gene signature for recurrence prediction by weighted gene co-expression network analysis in prostate cancer.

Introduction: Prostate cancer (PCa) is the second most common malignancy in men. Despite multidisciplinary treatments, patients with PCa continue to experience poor prognoses and high rates of tumor recurrence. Recent studies have shown that tumor-infiltrating immune cells (TIICs) are associated with PCa tumorigenesis. Methods: The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets were used to derive multi-omics data for prostate adenocarcinoma (PRAD) samples. The CIBERSORT algorithm was used to calculate the landscape of TIICs. Weighted gene co-expression network analysis (WGCNA) was performed to determine the candidate module most significantly associated with TIICs. LASSO Cox regression was applied to screen a minimal set of genes and construct a TIIC-related prognostic gene signature for PCa. Then, 78 PCa samples with CIBERSORT output p-values of less than 0.05 were selected for analysis. WGCNA identified 13 modules, and the MEblue module with the most significant enrichment result was selected. A total of 1143 candidate genes were cross-examined between the MEblue module and active dendritic cell-related genes. Results: According to LASSO Cox regression analysis, a risk model was constructed with six genes (STX4, UBE2S, EMC6, EMD, NUCB1 and GCAT), which exhibited strong correlations with clinicopathological variables, tumor microenvironment context, antitumor therapies, and tumor mutation burden (TMB) in TCGA-PRAD. Further validation showed that the UBE2S had the highest expression level among the six genes in five different PCa cell lines. Discussion: In conclusion, our risk-score model contributes to better predicting PCa patient prognosis and understanding the underlying mechanisms of immune responses and antitumor therapies in PCa.

Glycopolymeric Photosensitizers with Cholic Acid for HepG2-Targeted Chemo-Photodynamic Synergistic Therapy.

The aggregation-caused quenching, premature drug release, and hypoxia-caused resistance of photodynamic therapy (PDT) are challenges in the design and preparation of novel porphyrin-containing photosensitizers. In this work, a series of block copolymers consisting of a hydrophilic glycopolymer block and a porphyrin-containing hydrophobic block were prepared via reversible addition-fragmentation chain transfer polymerization. The polymeric photosensitizers generate singlet oxygen and excellent PDT against HepG2, which can be strengthened by the addition of cholic acid. To combine with chemotherapy, doxorubicin (Dox) was successfully loaded into copolymers, which were observed to be more phototoxic, indicating that the therapeutic benefit of the synergistic effect of PDT and chemotherapy is better than their simple combination. The sugar-cell-specific interaction of galactose-containing photosensitizers results in a stronger mean fluorescent index (MFI) intracellular uptake in HepG2 cells in vitro compared to L929 and MCF-7 cells. These polymeric nanoplatforms present a versatile and effective avenue for developing synergistic therapy for cancer treatment.

HDAC5-mediated PRAME regulates the proliferation, migration, invasion, and EMT of laryngeal squamous cell carcinoma via the PI3K/AKT/mTOR signaling pathway.

Laryngeal squamous cell carcinoma (LSCC) is an aggressive and lethal malignant neoplasm with extremely poor prognoses. Accumulating evidence has indicated that preferentially expressed antigen in melanoma (PRAME) is correlated with several kinds of cancers. However, there is little direct evidence to substantiate the biological function of PRAME in LSCC. The purpose of the current study is to explore the oncogenic role of PRAME in LSCC. PRAME expression was analyzed in 57 pairs of LSCC tumor tissue samples through quantitative real-time PCR, and the correlation between PRAME and clinicopathological features was analyzed. The result indicated that PRAME was overexpressed in the LSCC patients and correlated with the TNM staging and lymphatic metastasis. The biological functions and molecular mechanism of PRAME in LSCC progression were investigated through in vitro and in vivo assays. Functional studies confirmed that PRAME facilitated the proliferation, invasion, migration, and epithelial-mesenchymal transition of LSCC cells, and PRAME also promoted tumor growth in vivo. HDAC5 was identified as an upstream regulator that can affect the expression of PRAME. Moreover, PRAME played the role at least partially by activating PI3K/AKT/mTOR pathways. The above findings elucidate that PRAME may be a valuable oncogene target, contributing to the diagnosis and therapy of LSCC.

Development and safety of PI3K inhibitors in cancer.

The phosphatidylinositol 3-kinase (PI3K) signalling pathway regulates cell survival, proliferation, migration, metabolism and other vital cellular life processes. In addition, activation of the PI3K signalling pathway is important for cancer development. As a result, a variety of PI3K inhibitors have been clinically developed to treat malignancies. Although several PI3K inhibitors have received approval from the Food and Drug Administration (FDA) for significant antitumour activity, frequent and severe adverse effects have greatly limited their clinical application. These toxicities are mostly on-target and immune-mediated; nevertheless, the underlying mechanisms are still unclear. Current management usually involves intervention through symptomatic treatment, with discontinuation if toxicity persists. Therefore, it is necessary to comprehensively understand these adverse events and ensure the clinical safety application of PI3K inhibitors by establishing the most effective management guidelines, appropriate intermittent dosing regimens and new combination administration. Here, the focus is on the development of PI3K inhibitors in cancer therapy, with particular emphasis on isoform-specific PI3K inhibitors. The most common adverse effects of PI3K inhibitors are also covered, as well as potential mechanisms and management approaches.

Development of "smart" drug delivery systems for chemo/PDT synergistic treatment.

Although chemotherapy and photodynamic therapy (PDT) have been developed for fighting cancer, the complex and heterogeneous nature of tumors makes it difficult for a single therapy to completely inhibit tumor growth. In order to reduce multidrug resistance of cancer cells to chemotherapeutic drugs and overcome low PDT efficiency in the hypoxic tumor microenvironment (TME), chemo/PDT synergistic treatment has received much attention in recent years. Depending on the characteristic signals of TME, various drug delivery systems can be constructed to target tumors and improve the therapeutic efficacy and the pharmacokinetic profile of anticancer drugs. This review highlights the synergistic strategies, treatment protocols, and design of chemo/PDT co-therapy in recent years to explore its scope and limitations. Taking advantage of stimuli-responsive materials and active cancer-targeting agents, cancer-targeting synergistic therapy is presented and discussed, providing ideas and suggestions for the construction of chemo/PDT co-therapy "smart" nanocarriers.

Hypermethylation-Mediated lncRNA MAGI2-AS3 Downregulation Facilitates Malignant Progression of Laryngeal Squamous Cell Carcinoma via Interacting With SPT6.

Long noncoding RNAs (lncRNAs) have an effect on the occurrence and progression of a considerable number of diseases, especially cancer. Existing research has suggested that MAGI2 antisense RNA 3 (MAGI2-AS3) takes on a critical significance in the development of hepatocellular carcinoma and lung cancer. However, the functions of MAGI2-AS3 in laryngeal squamous cell carcinoma (LSCC) remain unclear. In this study, MAGI2-AS3 expression level in LSCC tissue and cell lines was detected, and the effect of MAGI2-AS3 overexpressed on LSCC phenotypes and the possible influence mechanisms were examined. MAGI2-AS3 was downregulated in the tissues of LSCC patients versus non-tumor tissues, and it was correlated with advanced TNM (tumor, node, metastasis) stage and lymph node metastases, as indicated by the results of this study. MAGI2-AS3 inhibited the proliferation, migration, and invasion of LSCC cells in vitro and in vivo. Furthermore, the hypermethylation level of the MAGI2-AS3 promoter region was indicated by bisulfite genomic sequencing and methylation-specific polymerase chain reaction, such that MAGI2-AS3 expression was downregulated. Besides, MAGI2-AS3 promoter hypermethylation was regulated by DNA methyltransferase 1 (DNMT1), and MAGI2-AS3 expression was reversed by 5-Aza-2'-deoxycytidine (5-Aza). Moreover, the result of the RNA pull-down experiment suggested that 38 proteins were enriched in the MAGI2-AS3 group versus the control group in TU177 cells. To be specific, SPT6 (ie, a conserved protein) was enriched by fold change >10. SPT6 knockdown reduced the antitumor effect of MAGI2-AS3 in TU177 and AMC-HN-8 cells. Meanwhile, SPT6 overexpression inhibited the proliferation, metastasis, and invasion of TU177 and AMC-HN-8 cells. As revealed by the above findings, DNMT1-regulated MAGI2-AS3 promoter hypermethylation led to downregulated MAGI2-AS3 expression, such that the presence and progression of LSCC were inhibited in an SPT6 binding-dependent manner.

Deletion of mdig enhances H3K36me3 and metastatic potential of the triple negative breast cancer cells.

In this report, we provide evidence showing diminished expression of the mineral dust-induced gene (mdig), a previously identified oncogenic gene, in human triple negative breast cancer (TNBC). Using a mouse model of orthotopic xenograft of the TNBC MDA-MB-231 cells, we demonstrate that mdig promotes the growth of primary tumors but inhibits metastasis of these cells in vivo. Knockout of mdig resulted in an enhancement of H3K36me3 in the genome and upregulation of some X chromosome-linked genes for cell motility, invasion, and metastasis. Silencing MAGED2, one of the most upregulated and H3K36me3-enriched genes resulted from mdig depletion, can partially reverse the invasive migration of the mdig knockout cells. The anti-metastatic and inhibitory role of mdig on H3K36me3 was cross-validated in another cell line, A549 lung cancer cells. Together, our data suggest that mdig is antagonist against H3K36me3 that enforces expression of genes, such as MAGED2, for cell invasion and metastasis.

Parthanatos participates in glutamate-mediated HT22 cell injury and hippocampal neuronal death in kainic acid-induced status epilepticus rats.

AIMS: Epileptic seizures or status epilepticus (SE) can cause hippocampal neuronal death, which has detrimental effects. Parthanatos, a new form of programmed cell death, is characterized by hyperactivation of poly (ADP-ribose) polymerase-1 (PARP-1), excessive synthesis of poly ADP-ribose polymer, mitochondrial depolarization, and nuclear translocation of apoptosis-inducing factor, observed in various neurodegenerative disorders but rarely reported in epilepsy. We aimed to investigate whether parthanatos participates in the mechanism of seizure-induced hippocampal neuronal death. METHODS: Glutamate-mediated excitotoxicity cell model was used to study the mechanism of seizure-induced cell injury. Injection of kainic acid into the amygdala was used to establish the epileptic rat model. Corresponding biochemical tests were carried out on hippocampal tissues and HT22 cells following indicated treatments. RESULTS: In vitro, glutamate time-dependently induced HT22 cell death, accompanied by parthanatos-related biochemical events. Pretreatment with PJ34 (PARP-1 inhibitor) or small interfering RNA-mediated PARP-1 knockdown effectively protected HT22 cells against glutamate-induced toxic effects and attenuated parthanatos-related biochemical events. Application of the antioxidant N-acetylcysteine (NAC) rescued HT22 cell death and reversed parthanatos-related biochemical events. In vivo, PJ34 and NAC afforded protection against SE-induced hippocampal neuronal damage and inhibited parthanatos-related biochemical events. CONCLUSION: Parthanatos participates in glutamate-induced HT22 cell injury and hippocampal neuronal damage in rats following epileptic seizures. ROS might be the initiating factor during parthanatos.

Structural insight into ASH1L PHD finger recognizing methylated histone H3K4 and promoting cell growth in prostate cancer.

ASH1L is a member of the Trithorax-group protein and acts as a histone methyltransferase for gene transcription activation. It is known that ASH1L modulates H3K4me3 and H3K36me2/3 at its gene targets, but its specific mechanism of histone recognition is insufficiently understood. In this study, we found that the ASH1L plant homeodomain (PHD) finger interacts with mono-, di-, and trimethylated states of H3K4 peptides with comparable affinities, indicating that ASH1L PHD non-selectively binds to all three methylation states of H3K4. We solved nuclear magnetic resonance structures picturing the ASH1L PHD finger binding to the dimethylated H3K4 peptide and found that a narrow binding groove and residue composition in the methylated-lysine binding pocket restricts the necessary interaction with the dimethyl-ammonium moiety of K4. In addition, we found that the ASH1L protein is overexpressed in castrate-resistant prostate cancer (PCa) PC3 and DU145 cells in comparison to PCa LNCaP cells. The knockdown of ASH1L modulated gene expression and cellular pathways involved in apoptosis and cell cycle regulation and consequently induced cell cycle arrest, cell apoptosis, and reduced colony-forming abilities in PC3 and DU145 cells. The overexpression of the C-terminal core of ASH1L but not the PHD deletion mutant increased the overall H3K36me2 level but had no effect on the H3K4me2/3 level. Overall, our study identifies the ASH1L PHD finger as the first native reader that non-selectively recognizes the three methylation states of H3K4. Additionally, ASH1L is required for the deregulation of cell cycle and survival in PCas.

Blocking ATM Attenuates SKOV3 Cell Proliferation and Migration by Disturbing OGT/OGA Expression via hsa-miR-542-5p.

Blocking ataxia telangiectasia mutated (ATM), a crucial player in DNA repair responses, has been proposed as a promising strategy in anti-cancer therapy. Most previous studies have focused on DNA damage response-related pathways after administration of ATM inhibitors. However, ATM inhibition could potentially influence a wide range of changes in gene expression, which remain poorly defined. Here, we report that administration of the ATM inhibitor KU60019 led to impaired migration and enhanced apoptosis in the ovarian cancer cell line SKOV3, accompanied by abnormally elevated O-GlcNAc transferase and O-GlcNAcase expression levels. In addition, KU60019 treatment significantly suppressed expression of hsa-miR-542-5p in SKOV3 cells. Up-regulation of hsa-miR-542-5p expression inhibited increases in OGT and OGA level, and reversed the effects of ATM inhibition on apoptosis and migration in SKOV3 cells. Finally, we found aberrant expression of OGT and OGA to be associated with ovarian cancer patient survival. Taken together, our results suggest that ATM inhibition may promote SKOV3 cell apoptosis via suppressing hsa-miR-542-5p and elevating OGT and OGA expression, providing new insights into the application of ATM inhibitors in cancer immunotherapy.

The ETS1-LINC00278 negative feedback loop plays a role in COL4A1/COL4A2 regulation in laryngeal squamous cell carcinoma.

The present study aimed to investigate LINC00278 expression in laryngeal squamous cell carcinoma (LSCC) and its involvement in the process of proliferation, migration, and invasion, providing a rationale for mining potential diagnostic and therapeutic targets of LSCC. Univariate and multivariate Cox regression analyses were performed to identify optimal prognostic lncRNAs. MTS, colony formation, wound healing, and Transwell invasion assays were used to determine the effects of LINC00278 overexpression on the proliferation, migration, and invasion of cancer cells. The expressions of signaling pathway-related proteins and epithelial-mesenchymal transition (EMT) marker proteins were detected using western blot. The chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays were performed to demonstrate the binding of ETS proto-oncogene 1, transcription factor (ETS1), and LINC00278 promoter region. The molecular targets of LINC00278 were identified by RNA sequencing analysis and co-expression analysis. Kaplan-Meier analysis and CIBERSORT algorithm were used to analyze survival and immune cell infiltration based on LINC00278, COL4A1, and COL4A2. Multivariate Cox regression was used to establish a six-gene prognostic model. LINC00278 expression was low in LSCC tissues, and it was significantly associated with the TNM (tumors/nodes/metastases) stage (p<0.001), lymphatic metastasis (p<0.01), and pathological differentiation (p<0.01). LINC00278 overexpression significantly reduced LSCC cell proliferation, migration, and invasion in TU686, TU177, and AMC-HN-8 cell lines. E-cadherin protein expression was increased, while N-cadherin, Vimentin, Zeb1, and Snail protein expression was decreased in the LINC00278 group, compared to the pcDNA3.1 group. Additionally, in AMC-HN-8 and FaDu cell lines, the LINC00278-treated group had significantly lower p-AKT and p-mTOR protein levels than the control group. ETS1 is a direct transcriptional regulator of the LINC00278 gene based on luciferase reporter assays and ChIP experiments. Western blot analysis demonstrated that high LINC00278 expression inhibited both ETS1 expression and phosphorylation. COL4A1/COL4A2 were identified as potential downstream targets of LINC00278. Meanwhile, the LINC00278/COL4A1/COL4A2-dominated low-risk group showed higher antigen-presenting activity and a higher immune score than the high-risk group. The findings indicated that ETS1 upregulated LINC00278 expression on the Y chromosome, which in turn inhibited LSCC growth in vivo and in vitro by inhibiting the AKT/mTOR signaling pathway via downregulation of COL4A1/COL4A2.

Integrating Metabolomics and Network Pharmacology to Explore the Protective Effect of Ginsenoside Re against Radiotherapy Injury in Mice.

Ionizing radiation (IR) can cause radiation damage, mutagenesis, or carcinogenesis in the irradiated subject. It is manifested as metabolic disorders of the body and damage to the immune system, nervous system, and endocrine system, which can lead to physiological and pathological changes and endogenous metabolic disorders. Ginsenoside Re (G-Re), a single component of traditional Chinese medicine, has a certain ameliorating effect on radiation damage. However, its mechanism of action in the treatment of radiotherapy injury remains unclear. With this purpose, the hematopoietic function of mice damaged by X-ray radiation was studied, and the protective effect of G-Re on mice damaged by radiation was preliminarily evaluated. Network pharmacology and metabolomics analysis are used to further reveal the mechanism of G-Re to improve radiation damage through metabolomics research. Results of metabolomics analysis showed that 16 potential biomarkers were identified as participating in the therapeutic effect of G-Re on IR. Most of these metabolites are adjusted to recover after G-Re treatment. The pathways involved included glycerophospholipid metabolism, sphingolipid metabolism, and linoleic acid metabolism. According to network pharmacology analysis, we found 10 hub genes, which is partly consistent with the findings of metabolomics. Further comprehensive analysis focused on 4 key targets, including SRC, EGFR, AKT1, and MAPK8, and their related core metabolites and pathways. This study combines metabolomics and network pharmacology analysis to explore the key targets and mechanisms of G-Re in the treatment of IR, in order to provide new strategies for clinical treatment of radiotherapy injury.

Breast cancer populations may have an increased prevalence of thyroglobulin antibody and thyroid peroxidase antibody: a systematic review and meta-analysis.

PURPOSE: Thyroid autoimmunity might be in relation to other autoimmune endocrine disease or non-endocrine disorders and there are innate and adaptive immune cells in breast cancer. Because autoimmune factors are common characteristics of both thyroid autoimmunity and breast cancer, these two types of diseases may occur concurrently in certain patients. The chief goal of this meta-analysis is to perform a combined analysis of the raw data from all included studies, and thereby obtain a reliable conclusion concerning whether TgAb or TPOAb positivity and breast cancer are indeed correlated. METHODS: To determine whether a correlation exists between TgAb or TPOAb positivity and breast cancer, this study performed a review of the literature that began by searching for articles in Chinese or English from the Medline, Embase, Web of Science core, Wanfang, Weipu and SinoMed databases, published during the time span extending from January 1980 to December 2017. On the basis of these raw data, we calculated odds ratio (OR) values, 95% confidence interval (CI) values, and P values. RESULTS: A total of 11 studies were included in this study. By combining the raw data from the retrieved studies, we were able to perform a meta-analysis. The results of this meta-analysis support the hypothesis that patients with breast cancer have a higher TgAb or TPOAb positive rate than the non-breast disease control group (TgAb: OR = 2.71, 95% CI = 1.81-4.05, P < 0.001; TPOAb: OR = 2.86, 95% CI = 2.17-3.77, P < 0.001, respectively). Testing for publication bias indicated that no significant publication bias was present in this meta-analysis, and sensitivity analysis indicated that the results of analysis were stable and reliable. CONCLUSIONS: The results of this meta-analysis suggest strongly that, the TgAb or TPOAb positive rate among patients with breast cancer should be higher than among the non-breast disease control group.

Roles of the BRD4 short isoform in phase separation and active gene transcription.

BRD4, a major tandem-bromodomain-containing transcription regulator, has two isoforms. The long isoform (BRD4L) has an extended C terminus that binds transcription cofactors, while the short isoform (BRD4S) lacks this C-terminal extension. Unlike BRD4L, the role of BRD4S in gene transcription remains unclear. Here, we report that, in human cancer cells, BRD4S forms nuclear puncta that possess liquid-like properties and that colocalize with BRD4L, MED1 and sites of histone H3 lysine 27 acetylation. BRD4 puncta are correlated with BRD4S but not BRD4L expression levels. BRD4S knockdown reduces BRD4S condensation, and ectopic expression promotes puncta formation and target gene transcription. BRD4S nuclear condensation is mediated by its intrinsically disordered regions and binding of its bromodomains to DNA and acetylated chromatin, respectively, and BRD4S phosphorylation diminishes BRD4 condensation. Our study illuminates a previously unappreciated role of BRD4S in organizing chromatin and transcription factors through phase separation to sustain gene transcription in chromatin for cancer cell proliferation.