B-cell Translocation Gene Research Articles

Molecular Biomarker Exploration of Rituximab plus CHOP Therapy in Real-World Diffuse Large B-Cell Lymphoma Patients.

Presently, several classification methods are based on diffuse large B-cell lymphoma (DLBCL), but its clinical application has not yet been testified in Asian populations. Twenty-five DLBCL patients were subjected to second-generation gene sequencing (NGS), and retrospective analysis of clinical features of the patients was to explore genotyping and survival prognosis biomarkers. The prevalent mutant genes in DLBCL patients cover myeloid differentiation factor 88 (MyD88) (40%), TP53 (32%), B-cell translocation gene 2 (BTG2) (28%), PIM1 (28%), and CREB-binding protein (CREBBP) (24%) in this study. The classical International Prognostic Index (IPI) scores were associated with progression-free survival (PFS) (HR: 7.52, 95% CI 1.51 - 37.6, p = 0.00393) via univariate analysis. Furthermore, patients with ETS-variant gene 6 (ETV6) (HR: 5.1, 95% CI 0.927 - 28.1, p = 0.0371), platelet-derived growth factor receptor A (PDGFRA) (HR: 4.29, 95% CI 0.824 - 22.3, p = 0.0594), platelet-derived growth factor receptor B (PDGFRB) (HR: 10.8, 95% CI 0.979 - 119, p = 0.0149) was distinctively correlated with poor PFS except for the IPI score. Nevertheless, the mutation of PDGFRA/B gene was not distinct in further multivariate analysis (PFS: HR: 2.72, 95% CI 0.52 - 14.23, p = 0.2369). Additionally, better survival prognosis was in DLBCL patients who did not progress within 12 months (POD12). Ultimately, caspase recruitment domain 11 (CARD11) gene mutations were enriched in patients with primary intranodal tumors, but the prognostic relevance was not discovered. ETV6 and platelet-derived growth factor receptor (PDGFR)A/B gene mutations are supposed to be potential biomarkers for the prognosis of DLBCL patients via the statistical analysis of this small sample, and POD12 is also expected to be an effective endpoint for efficacy assessment.

The Role of Noncoding RNA Antisense Transcript of the B-Cell Translocation Gene 3 Regulation of BTG3 in Pancreatic Ductal Adenocarcinoma Tumor Progression

Antisense transcript of the B-cell translocation gene 3 (ASBEL) is a highly conserved antisense non-coding RNA (ncRNA) and participates in a variety of biological processes. However, the ASBEL expression status in pancreatic ductal adenocarcinoma (PDAC) and its correlation with BTG3 expression and tumor cell progression were not completely clear. We conducted cell experiments and animal experiments to confirm that ASBEL plays a crucial role in the tumorigenesis of PDAC by targeting BTG3. ASBEL regulation in PDAC tumorigenesis was evaluated using Western blotting, quantitative polymerase chain reaction, Cell Counting Kit-8 assay, flow cytometry, and cell transfection. We also evaluated the expression of ASBEL and BTG3 in tumor tissues and cells using Western blotting and quantitative real-time polymerase chain reaction. Finally, we explored the role of ASBEL in tumor development by silencing or overexpressing ASBEL gene in AsPC-1 or CFPAC-1 cells, respectively, and evaluated the antitumor activity in vivo using an ASBEL antagonist. Our study revealed the expression of ASBEL in all pancreatic cell lines. The expression level of ASBEL in tumor tissues was found to be higher than that of paracarcinomatous tissues. ASBEL suppresses expression of BTG3, enhances proliferation and suppresses apoptosis, and promotes migration and invasion in pancreatic cancer cell. Antagonist regulates the expression of ASBEL in AsPC-1, and suppresses tumor growth in xenograft mouse model. Our results indicate that ASBEL may play a tumor-promoting factor in PDAC by targeting BTG3 and could be as an important biomarker for PDAC treatment. (Curr Ther Res Clin Exp. 2023; 84:XXX-XXX).

BTG2 suppresses renal cell carcinoma progression through N6-methyladenosine.

The biological functions of N6-methyladenosine (m6A) modification of mRNA have recently received a great deal of attention. In previous studies, m6A methylation modification has been shown to regulate mRNA fate and to be crucial for the progression and development of tumors. BTG2 (B-cell translocation gene 2) is a member of BTG/TOB anti-proliferative protein family. BTG2 could inhibit cell proliferation and migration and regulate the cell cycle progression. In this study, we confirm that BTG2 is frequently down-regulated in renal cell carcinoma (RCC) tissues and its low expression is associated with unfavorable prognosis and decreased m6A level. Moreover, we found that m6A methylation modifies the 5'UTR of BTG2 to promote its mRNA stability by binding to IGF2BP2. It has been shown that CRISPR/dCas13b-METLL3 can specifically increase BTG2 m6A modification to significantly increase its m6A and expression levels. Then m6A hypermethylation in BTG2 mRNA could dramatically inhibit RCC cells proliferation and migration, and induce cells apoptosis. Taken together, our data show that BTG2 functions as a tumor suppressor and is frequently silenced via m6A modification in RCC.

Long Non-Coding RNA CASC2 Functions as A Tumor Suppressor in Colorectal Cancer via Modulating The miR-18a-5p/BTG3 Pathway.

Reportedly, long non-coding RNA (lncRNA) cancer susceptibility candidate 2 (CASC2) is involved in regulating colorectal cancer (CRC) progression. However, the function and detailed downstream mechanism of CASC2 in CRC progression are not fully elucidated. The aim of the study was to investigate the potential function and molecular mechanism of CASC2 in CRC progression. In this experimental study, quantitative real-time polymerase chain reaction (qRT-PCR) was adopted to probe CASC2, microRNA-18a-5p (miR-18a-5p) and B cell translocation gene 3 (BTG3) mRNA expression in CRC tissues and cell lines. After CASC2 was overexpressed in Colo-678 and HCT116 cell lines, methylthiazol tetrazolium (MTT) and 5-bromo-2'-deoxyuridine (BrdU) assays were employed to examine the proliferation of CRC cells. Transwell migration and invasion assays were executed to evaluate the metastatic potential of CRC cells. The targeting relationships among CASC2, miR-18a-5p and BTG3 were validated by dual luciferase reporter gene assay. Western blot assay was applied to examine the regulatory effects of CASC2 and miR-18a-5p on BTG3 protein expression. CASC2 was decreased in CRC tissues and cell lines, and its low expression in CRC tissues was associated with larger tumor size and lymph node metastasis. CASC2 overexpression restrained proliferative, migrative and invasive capabilities of CRC cells. CASC2 could function as a molecular sponge for miR-18a-5p and repress the expression of miR-18a-5p. Furthermore, the inhibitory effects of CASC2 on the malignant phenotypes of CRC cells was counteracted by miR-18a-5p mimics. Additionally, CASC2 could positively regulate BTG3 expression via suppressing miR-18a-5p. CASC2 inhibits CRC development by suppressing miR-18a-5p and raising BTG3 expression.

LncRNA CARMN inhibits cervical cancer cell growth via the miR-92a-3p/BTG2/Wnt/β-catenin axis.

Long noncoding RNA (lncRNA) cardiac mesoderm enhancer-associated noncoding RNA (CARMN) is a newly discovered tumor-suppressor lncRNA in cancers. However, its role in cervical cancer (CC) remains elusive. This study was conducted to analyze the molecular mechanism of CARMN in CC cell growth and provide a novel theoretical basis for CC treatment. RT-qPCR and clinical analysis revealed that CARMN and B-cell translocation gene 2 (BTG2) were downregulated, whereas miR-92a-3p was upregulated in CC tissues and cells and their expressions were correlated with clinicopathological characteristics and prognosis. MTT assay, flow cytometry, and Transwell assays revealed that CARMN overexpression reduced proliferation, migration, and invasion and increased apoptosis rate in CC cells. Mechanically, CARMN repressed miR-92a-3p to promote BTG2 transcription. Functional rescue assays revealed that miR-92a-3p overexpression or BTG2 downregulation reversed the inhibitory role of CARMN overexpression in CC cell growth. Western blot analysis elicited that Wnt3a and β-catenin were elevated in CC cells and CARMN blocked the Wnt/β-catenin signaling pathway via the miR-92a-3p/BTG2 axis. Overall, our findings demonstrated that CARMN repressed miR-92a-3p to upregulate BTG2 transcription and then blocked the Wnt/β-catenin signaling pathway, thereby suppressing CC cell growth.

The roles of BTG1 mRNA expression in cancers: A bioinformatics analysis.

BTG1 (B-cell translocation gene 1) may inhibit proliferation and cell cycle progression, induce differentiation, apoptosis, and anti-inflammatory activity. The goal of this study was to clarify the clinicopathological and prognostic significances of BTG1 mRNA expression and related signal pathways in cancers. Using the Oncomine, TCGA (the cancer genome atlas), xiantao, UALCAN (The University of ALabama at Birmingham Cancer data analysis Portal), and Kaplan-Meier plotter databases, we undertook a bioinformatics study of BTG1 mRNA expression in cancers. BTG1 expression was lower in gastric, lung, breast and ovarian cancer than normal tissue due to its promoter methylation, which was the opposite to BTG1 expression. BTG1 expression was positively correlated with dedifferentiation and histological grading of gastric cancer (p < 0.05), with squamous subtype and young age of lung cancer (p < 0.05), with infrequent lymph node metastasis, low TNM staging, young age, white race, infiltrative lobular subtype, Her2 negativity, favorable molecular subtyping, and no postmenopause status of breast cancer (p < 0.05), and with elder age, venous invasion, lymphatic invasion, and clinicopathological staging of ovarian cancer (p < 0.05). BTG1 expression was negatively correlated with favorable prognosis of gastric, lung or ovarian cancer patients, but the converse was true for breast cancer (p < 0.05). KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis showed that the top signal pathways included cytokine-cytokine receptor interaction, cell adhesion molecules, chemokine, immune cell receptor and NF (nuclear factor)-κB signal pathways in gastric and breast cancer. The top hub genes mainly contained CD (cluster of differentiation) antigens in gastric cancer, FGF (fibroblast growth factor)-FGFR (FGF receptor) in lung cancer, NADH (nicotinamide adenine dinucleotide): ubiquinone oxidoreductase in breast cancer, and ribosomal proteins in ovarian cancer. BTG1 expression might be employed as a potential marker to indicate carcinogenesis and subsequent progression, even prognosis.

Novel Therapeutic Mechanism of Adipose-Derived Mesenchymal Stem Cells in Osteoarthritis via Upregulation of BTG2.

Background Osteoarthritis (OA) is a debilitating and degenerative joint disease, which is characterized by progressive destruction of articular cartilage. Mesenchymal stem cells (MSCs) have been implicated in the treatment of OA. However, the function of adipose-derived MSCs (AD-MSCs) in OA and its underlying mechanism remain obscure. Aim We aimed to explore the function of AD-MSCs in OA and investigate its potential regulatory mechanism. Methods A guinea pig model of OA was constructed. AD-MSCs injected into the articular cavity of OA guinea pigs were viewed by in vivo bioluminescence imaging. The effect of AD-MSCs on the gonarthritis of OA guinea pigs was evaluated through both macroscopic and microscopic detections. The detailed molecular mechanism was predicted by GEO databases and bioinformatics tools and then verified via mechanism experiments, including ChIP assay, DNA pulldown assay, and luciferase reporter assay. Results AD-MSCs had a significant positive therapeutic effect on the gonarthritis of the OA model, and the overall effects of it was better than that of sodium hyaluronate (SH). B-cell translocation gene 2 (BTG2) was significantly downregulated in the articular cartilage of the OA guinea pigs. Furthermore, BTG2 was positively regulated by Krüppel-like factor 4 (KLF4) in AD-MSCs at the transcriptional level. AD-MSCs performed an effect on KLF4 expression at the transcriptional levels. Conclusion AD-MSCs suppresses OA progression through KLF4-induced transcriptional activation of BTG2. Our findings revealed an AD-MSCs-dominated therapeutic method for OA.

Proper regulation of β-adrenergic signal requires Btg2 gene for lipolysis and thermogenesis in response to starvation or cold acclimation in female mice

Mammals maintain constant body temperature in cold environment by activating thermogenesis via adrenergic/protein kinase A (PKA) signaling. B-cell translocation gene 2 (BTG2/Tis21), induced by PKA signaling, regulates glucose and lipid metabolism in liver, yet its role in lipolysis and in thermogenesis is not explored. Here, Btg2-knockout (KO) mice failed to maintain body temperature under starvation, or in cold acclimation. And norepinephrine-induced thermogenic response was turned off earlier in the KO mice. Gender specifically, gonadal white adipose tissues (gWAT) of female-KO were very active in lipolysis in fed state, however, the fat degradation was diminished upon fasting or cold acclimation. Also, insulin sensitivity was increased in female-KO, but not in male-KO mice, along with the low bone mineral density and small brown adipose tissues (BAT). In the mechanistic aspect, expressions of UCP1 and lipases (LPL, ATGL, HSL) in gWAT of female-KO mice were significantly reduced in response to adrenergic signals. Here, we present some data that Btg2 gene is essential for properly respond to β-adrenergic signals, and plays as a negative regulator of insulin signaling in female mice.

B-Cell Translocation Gene 2 Upregulation Is Associated with Favorable Prognosis in Lung Adenocarcinoma and Prolonged Patient Survival.

The tumor suppressor protein B-cell translocation gene 2 (BTG2) is downexpressed in lung adenocarcinoma (LUAD); however, its role in LUAD survival remains unknown. This investigation is aimed at exploring the activity of BTG2 in LUAD. We analyzed BTG2 expression in LUAD datasets of the TCGA database and examined that BTG2 was markedly downregulated in comparison with adjacent normal tissues. The prognostic analysis suggested that higher expression of BTG2 protein correlates with prolonged survival in patients. Vectors expressing BTG2 were stably transduced into lung adenocarcinoma A549 cells. The overexpression of BTG2 in A549 cells causes cellular G1 phase arrest but did not affect cell proliferation, accompanied by increased activation of NF-κB. Our data indicate that BTG2 overexpression may trigger an autoregulatory prosurvival NF-κB pathway, which is resistant to environmental intervention owing to an increased level of BTG2.

Emerging role of anti-proliferative protein BTG1 and BTG2

The B cell translocation gene 1 (BTG1) and BTG2 play a key role in a wide range of cellular activities including proliferation, apoptosis, and cell growth via modulating a variety of central biological steps such as transcription, post-transcriptional, and translation. BTG1 and BTG2 have been identified by genomic profiling of B-cell leukemia and diverse lymphoma types where both genes are commonly mutated, implying that they serve as tumor suppressors. Furthermore, a low expression level of BTG1 or BTG2 in solid tumors is frequently associated with malignant progression and poor treatment outcomes. As physiological aspects, BTG1 and BTG2 have been discovered to play a critical function in regulating quiescence in hematopoietic lineage such as Hematopoietic stem cells (HSCs) and naïve and memory T cells, highlighting their novel role in maintaining the quiescent state. Taken together, emerging evidence from the recent studies suggests that BTG1 and BTG2 play a central antiproliferative role in various tissues and cells, indicating their potential as targets for innovative therapeutics.

Methylation Mediated Downregulation of TOB1-AS1 and TOB1 Correlates with Malignant Progression and Poor Prognosis of Esophageal Squamous Cell Carcinoma.

TOB1, a member of the transducer of erbB-2 /B-cell translocation gene family, was detected to be down-regulated in ESCC by RNA sequencing. TOB1-AS1, a head-to-head antisense lncRNA with TOB1, was down-regulated in several cancers. However, the roles of them in esophageal squamous cell carcinoma (ESCC) remained unclarified. To investigate the roles and functions of TOB1-AS1 and TOB1 in ESCC tumorigenesis. The expression levels, methylation status, biological function and mechanisms of TOB1-AS1 and TOB1 in ESCC were, respectively, detected. Frequent down-regulation of TOB1-AS1 and TOB1 was verified in esophageal cancer cells and ESCC tissues, and there was a positive correlation between them in ESCC tissues. The CpG sites hypermethylation within proximal promoter of TOB1-AS1 and TOB1 could lead to transcriptional inhibition of both genes. Furthermore, expression and proximal promoter methylation status of TOB1-AS1 or TOB1 may be associated with ESCC patients' prognosis. TOB1-AS1 and TOB1 may function as tumor suppressors by inhibiting growth, migration, and invasion of esophageal cancer cells. Up-regulation of TOB1-AS1 increased expression level of TOB1, and TOB1-AS1 could work as a ceRNA to modulate ATF3 expression via competitively binding with miR-103a-2-5p. Meanwhile, ATF3, as a transcription factor, could regulate transcription of TOB1; down-regulation of TOB1-AS1 in ESCC led to decreased expression of ATF3 through ceRNA mechanism, and further influenced the transcription of TOB1. TOB1-AS1 and TOB1 may act as tumor suppressors and may serve as potential targets for antitumor therapy in ESCC.

RNA binding protein PUM2 promotes hepatocellular carcinoma proliferation and apoptosis via binding to the 3'UTR of BTG3.

Pumilio homolog 2 (PUM2) is an RNA-binding protein that functions as an oncogene in various types of cancer. However, its role in hepatocellular carcinoma (HCC) has remained to be fully elucidated. In the present study, the role of PUM2 was investigated in HCC and its regulation was assessed by examining its binding to the 3′-untranslated region (UTR) of B-cell translocation gene 3 (BTG3). The expression levels of PUM2 were determined in datasets from the UALCAN and Cancer Cell Line Encyclopedia databases. Furthermore, Gene Expression Profiling Interactive Analysis was used to analyze overall survival in patients with HCC. Reverse transcription-quantitative PCR (RT-qPCR) and western blot analyses were then performed to detect the expression levels of PUM2 and BTG3 in HCC cells. Cell proliferation was assessed using Cell Counting Kit-8 and colony-formation assays. The induction of cell apoptosis was evaluated using TUNEL and western blotting assays. StarBase and RNA-Protein Interaction Prediction were used to determine the possible direct interaction between PUM2 and BTG3. The interaction between PUM2 and BTG3 was then verified by luciferase reporter and RNA-binding protein immunoprecipitation assays. The results indicated that PUM2 expression was upregulated in HCC tissues and cells and that it was associated with the prognosis of patients with HCC. PUM2 silencing inhibited the proliferation and promoted the apoptosis of Huh-7 cells. In addition, PUM2 was confirmed to directly bind to the 3′UTR of BTG3. Downregulation of BTG3 reversed the effects of PUM2 silencing on cell proliferation and apoptosis in Huh-7 cells. Collectively, the results suggested that PUM2 regulated HCC cell proliferation and apoptosis via interacting with BTG3, which may provide a novel therapeutic strategy for the treatment of human HCC.

NADPH Oxidase 2 Has a Crucial Role in Cell Cycle Progression of Esophageal Squamous Cell Carcinoma.

NADPH oxidases (NOXs) are transmembrane proteins that generate reactive oxygen species. Recent studies have reported that NOXs are involved in tumor progression in various cancers. However, the expression and role of NOX2 in esophageal squamous cell carcinoma (ESCC) remain unclear. This study aimed to clarify the pathophysiologic role of NOX2 in patients with ESCC and cell lines. Two human ESCC cell lines (TE5 and KYSE170) were used for NOX2 transfection experiments, and the effects on cell proliferation, cell cycle, cell motility, and cell survival were analyzed. An mRNA microarray analysis was also performed to assess gene expression profiles. Additionally, NOX2 immunohistochemistry was performed on 130 primary ESCC tumor samples to assess the prognostic value of NOX2 in patients with ESCC. NOX2 depletion significantly inhibited cell proliferation with the G0/G1 arrest and resulted in apoptosis in two cell lines. Microarray analysis revealed a strong relationship between NOX2 gene expression and the signaling pathway of cell cycle regulation by the B-cell translocation gene 2 (BTG2) family, including BTG2, CCNE2, E2F1, and CDK2 genes. Immunohistochemical staining revealed that high NOX2 protein expression was significantly associated with deeper tumor invasion and selected as one of the independent prognostic factors associated with the 5-year OS rate in patients with ESCC. NOX2 expression in ESCC cells affects tumorigenesis, especially cell cycle progression via the BTG2-related signaling pathway, as well as the prognosis of patients with ESCC. NOX2 may be a novel biomarker and therapeutic target for ESCC.

Impact of AKT1 polymorphism on DNA damage, BTG2 expression, and risk of colorectal cancer development.

BackgroundAKT, also called protein kinase B, is a serine-threonine kinase that functions as a mediator of PI3K-Akt-mTOR signaling pathway and plays an important role in an array of cellular processes. Many single nucleotide polymorphisms (SNP) in AKT gene have been observed to be associated with various types of cancers. In the current research the association of a functional SNP rs1130233 in AKT, depicting G to A transition, was studied with AKT activation, DNA damage, an early response B-cell translocation gene 2 (Btg2) expression and risk of colorectal cancer (CRC) development.Patients and methodsA total 197 population-based controls and 200 CRC patients were genotyped for SNP rs1130233. AKT expression, activation and BTG2 expression were determined in GG, AG and AA genotype carriers. DNA damage was determined through comet assay.ResultsThe heterozygous AG genotype (55.67%) was more prevalent in the local population compared to homozygous wild type GG (37.78%) and homozygous AA genotypes (6.55%). Moreover, AG and AA alleles were observed to be significant contributors (P = 0.01, OR = 1.80, CI = 1.18 to 2.74, and P = 0.001, OR = 5.00, CI = 1.90 to 13.18, respectively) in increasing the risk of CRC. The immunoblot analysis revealed that G to A transition decreased the expression and activation of AKT. Moreover, AG and AA genotypes of AKT1 rs1130233 showed a significant increase in DNA damage and Btg2 expression.ConclusionsThe data concludes that G to A substitution is a risk factor for CRC development involving a decrease in AKT expression and activation and increase in DNA damage.

Adipose mesenchymal stem cell–derived exosomal microRNAs ameliorate polycystic ovary syndrome by protecting against metabolic disturbances

Polycystic ovary syndrome (PCOS) is the most common endocrine and metabolic disorder in women of childbearing age. Adipose mesenchymal stem cells (AMSCs) secrete cytokines involved in the regulation of metabolism and immunity. However, it remains unclear whether exosomes secreted by AMSCs (AMSC-EXOs) can rescue the polycystic phenotype and metabolic dysfunction in PCOS ovaries. Here, we show that AMSC-EXOs can protect against metabolic disturbances, ameliorate ovarian polycystic, and improve fertility in a rat model of PCOS. AMSC-EXOs inhibited the expression of B-cell translocation gene 2 by transferring miR-21-5p to the livers of rats with PCOS, thus activating the IRS1/AKT pathway and increasing hepatic metabolism. The role of AMSC-EXOs in transferring miRNAs to the liver to improve metabolic dysfunction in PCOS and reproduction by rescuing a non-coding RNA pathway was also discovered. This study provides a theoretical basis for the use of rat adipose stem cells and their secreted exosomes to treat PCOS.

Integrated Analysis of miRNAs and Gene Expression Profiles Reveals Potential Biomarkers for Osteoarthritis.

Purpose: Currently, the early diagnosis and treatment of osteoarthritis (OA) remain a challenge. In the present study, we attempted to explore potential biomarkers for the diagnosis and treatment of OA. Methods: The differentially expressed genes (DEGs) were identified based on three mRNA datasets of synovial tissues for OA patients and normal controls downloaded from the Gene Expression Omnibus (GEO) database. Furthermore, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were used for evaluating gene function related categories. Then, miRNA sequencing was performed for differentially expressed miRNAs’ identification. Finally, weighted gene co-expression network analysis (WGCNA) was performed for genes detected by the three mRNA datasets and a competing endogenous RNA (ceRNA) network with DEGs and differentially expressed microRNAs (miRNAs) was constructed for central genes identification. In addition, the relationship between central gene expression and immune infiltration was analyzed, and the candidate agents for OA were predicted based on the Connectivity Map database. Quantitative RT-PCR (qRT-PCR), Western blotting analysis, and immunofluorescent staining were performed to validate the expression levels of differentially expressed miRNAs and differentially expressed target genes in normal and OA tissues and chondrocytes. MiRNA–mRNA network was also validated in chondrocytes in vitro. Results: A total of 259 DEGs and 26 differentially expressed miRNAs were identified, among which 94 miRNA–mRNA interactions were predicted. The brown module in WGCNA was most closely correlated with the clinical traits of OA. After overlapping the brown module genes with miRNA–mRNA pairs, 27 miRNA–mRNA pairs were obtained. A ceRNA network was constructed with 5505 lncRNA–miRNA–mRNA interactions. B-cell translocation gene 2(BTG2), Abelson-related gene (ABL2), and vascular endothelial growth factor A (VEGFA) were identified to be the central genes with good predictive performance, which were significantly correlated with immune cell infiltration in OA, reflected by declined activated dendritic cells (aDCs), and elevated contents of B cells, macrophages, neutrophils, and T helper cells. Anisomycin, MG-132, thapsigargin, and lycorine were predicted to be the potential candidate agents for OA intervention. In vitro, the expression levels of differentially expressed miRNAs and biomarkers identified in the present study were consistent with the results obtained in normal or OA knee cartilage tissues and chondrocytes. Furthermore, BTG2 was identified to be negatively regulated by miR-125a-5p. Conclusion: BTG2, ABL2, and VEGFA can be regarded as potential predictive and treatment biomarkers for OA, which might guide the clinical therapy of OA.

ASIC1a promotes hepatic stellate cell activation through the exosomal miR-301a-3p/BTG1 pathway

Activation of hepatic stellate cells (HSCs) is a key cause of liver fibrosis. However, the mechanisms leading to the activation of HSCs are not fully understood. In the pathological process, acid-sensing ion channel 1a (ASIC1a) is widely involved in the development of inflammatory diseases, suggesting that ASIC1a may play an important role in liver fibrosis. We found that in an acidic environment, ASIC1a leads to HSC-T6 cell activation. Meanwhile, exosomes produced by activated HSC-T6 cells (HSC-EXOs) can be reabsorbed by quiescent HSC-T6 cells to promote their activation. Exosomes mainly carry miRNAs involved in intercellular information exchange. We performed exosome miRNA whole transcriptome sequencing. The results indicated that the acidic environment could alter the miRNA expression profile in the exosomes of HSC-T6 cells. Further studies revealed that ASIC1a promotes the activation of HSCs by regulating miR-301a-3p targeting B-cell translocation gene 1 (BTG1). In conclusion, our study found that ASIC1a may affect HSC activation through the exosomal miR-301a-3p/BTG1 axis, and inhibiting ASIC1a may be a promising treatment strategy for liver fibrosis.

Conformational transitions in BTG1 antiproliferative protein and their modulation by disease mutants

B cell translocation gene 1 (BTG1) protein belongs to the BTG/transducer of ERBB2 (TOB) family of antiproliferative proteins whose members regulate various key cellular processes such as cell cycle progression, apoptosis, and differentiation. Somatic missense mutations in BTG1 are found in ∼70% of a particularly malignant and disseminated subtype of diffuse large B cell lymphoma (DLBCL). Antiproliferative activity of BTG1 has been linked to its ability to associate with transcriptional cofactors and various enzymes. However, molecular mechanisms underlying these functional interactions and how the disease-linked mutations in BTG1 affect these mechanisms are currently unknown. To start filling these knowledge gaps, here, using atomistic molecular dynamics (MD) simulations, we explored structural, dynamic, and kinetic characteristics of BTG1 protein, and studied how various DLBCL mutations affect these characteristics. We focused on the protein region formed by α2 and α4 helices, as this interface has been reported not only to serve as a binding hotspot for several cellular partners but also to harbor sites for the majority of known DLBCL mutations. Markov state modeling analysis of extensive MD simulations revealed that the α2-α4 interface in the wild-type (WT) BTG1 undergoes conformational transitions between closed and open metastable states. Importantly, we show that some of the mutations in this region that are observed in DLBCL, such as Q36H, F40C, Q45P, E50K (in α2), and A83T and A84E (in α4), either overstabilize one of these two metastable states or give rise to new conformations in which these helices are distorted (i.e., kinked or unfolded). Based on these results, we conclude that the rapid interconversion between the closed and open conformations of the α2-α4 interface is an essential component of the BTG1 functional dynamics that can prime the protein for functional associations with its binding partners. Disruption of the native dynamic equilibrium by DLBCL mutants leads to the ensemble of conformations in BTG1 that are unlikely structurally and/or kinetically to enable productive functional interactions with the binding proteins.

Elevated BTG2 improves the radiosensitivity of non-small cell lung cancer (NSCLC) through apoptosis.

BackgroundTo identify radio‐responsive genes and explore the biological function of encoded proteins in non‐small cell lung cancer (NSCLC).MethodsRadio‐responsive genes in irradiated H460 cells were screened from microarray data deposited in the Gene Expression Omnibus (GEO) database. A quantitative real time polymerase chain reaction assay was used to detect the expression of candidate radio‐responsive genes in irradiated cells. CCK‐8 assay, EDU assay, clone formation assay, immunofluorescence and flow cytometry were conducted to evaluate the biological function of B cell translocation gene 2 (BTG2) in NSCLC.ResultsBioinformatic analysis using GES20549 showed that BTG2 was a radio‐responsive gene in irradiated H460 cells. The mRNA expression level of BTG2 was lower in H460 cells compared with that in BEAS‐2B normal lung epithelial cells. BTG2 expression was elevated upon IR exposure, in a dose‐dependent but not a time‐dependent manner. CCK‐8 and EDU assays revealed that BTG2 overexpression inhibited the growth rate of irradiated cells. Clone formation showed that elevated BTG2 promoted DNA damage of irradiated H460 cells. The number of γ‐H2AX foci induced by DNA damage was also markedly increased upon BTG2 overexpression. Flow cytometry showed that BTG2 increased IR‐induced cell apoptosis.ConclusionsBTG2 may be a novel radio‐responsive factor and a promising therapeutic target for radiotherapy of NSCLC.

Exogenous insulin promotes the expression of B-cell translocation gene 1 and 2 in chicken pectoralis

B-cell translocation genes (BTG) have been proved to play important roles in carbohydrate metabolism through modifying insulin homeostasis and glucose metabolism. This study, therefore, was conducted to investigate the effects of exogenous insulin on the expression of BTG1 and BTG2 in chickens. Twenty-four-day-old broilers and layers were fasted for 16 h and randomly assigned to insulin treatment group (subcutaneously injected with 5 IU/kg body weight) or control group (received an equivalent volume of phosphate-buffered saline). Blood glucose concentration was measured, and it showed that the blood glucose concentrations in the layers were significantly (P < 0.05) higher than that in the broilers under fasting state. Response to exogenous insulin, the blood glucose concentrations were greatly reduced in both breeds. Of note, the blood glucose concentration restored to 62% of the basal state at 240 min (P < 0.05) after insulin stimulation in layers, whereas it was still in low level until 240 min in broilers (under fast state). Tissue profiling revealed that both BTG1 and BTG2 were abundantly expressed in the skeletal muscles of broilers. A negative correlation was observed between blood glucose and BTG1 (ρ = −0.289, P = 0.031) /BTG2 (ρ = −0.500, P < 0.001) in pectoralis, and BTG1 (ρ = −0.462, P < 0.001) in pancreas. As blood glucose decreased due to exogenous insulin administration (under fast state), the expression of both BTG1 and BTG2 notably upregulated in birds’ pectoralis at 120 min and/or 240 min, meanwhile pancreas BTG1 was also upregulated. Re-feeding at 120 min elevated the blood glucose and reduced the expression of BTG genes in pectoralis generally. In addition, the change of BTG1 and BTG2 expression showed distinct difference between layers and broilers at 120 min and 240 min after insulin stimulation in pectoralis, pancreas and heart tissue; even after re-feeding at 120 min, BTG2 expression at 240 min after insulin injection was downregulated in the pectoralis of layers, while it was upregulated in that broilers. Collectively, these results indicated that response to exogenous insulin, chicken blood glucose exhibited breed-specific dynamic change, and meanwhile the expressions of both BTG1 and BTG2 genes in chickens were significantly altered by exogenous insulin in a breed- and tissue-specific manner. BTG1 and BTG2 genes may negatively regulate bird's blood glucose by promoting the glucose uptake corporately in pectoralis, and through regulating the insulin secretion in pancreas (especially BTG1).