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Background: Pilon fractures are challenging to treat and carry a risk of delayed healing. MicroRNA (miRNA) is closely associated with various diseases due to its ability to regulate gene expression. Consequently, this study aimed to examine the connection between miR-1271-5p expression levels and pilon fracture healing processes, while also exploring the underlying mechanisms. The objective of this research was to provide valuable insights for the future clinical treatment of pilon fractures. Materials: Venous blood samples were obtained for RNA extraction from patients with normal healing (n = 107) or delayed healing (n = 45) of pilon fractures. The expression levels of miR-1271-5p were measured using qRT-PCR. MiR-1271-5p and ZBTB7A biological functions in MC3T3-E1 cells were examined using the Cell Counting Kit-8 (CCK-8), flow cytometry, and qRT-PCR. Finally, an investigation into the underlying mechanisms was carried out using a dual luciferase reporter assay. Results: This study found that, compared to those who healed normally, patients who experienced delayed healing of pilon fractures had significantly higher expression of miR-1271-5p. This suggests that miR-1271-5p may be an indicator for delayed healing in pilon fractures. Moreover, the upregulation of miR-1271-5p may result in a reduction of ZBTB7A expression, which is thought to mediate the effects of miR-1271-5p on MC3T3-E1 cell activities. Conclusions: MiR-1271-5p was involved in the healing processes of pilon fractures via targeting ZBTB7A. MiR-1271-5p was a possible target for the therapy of pilon fractures. [ABSTRACT FROM AUTHOR]

Background: Endometrial cancer (EC) is the sixth most frequent cancer in women worldwide and has higher fatality rates. The pathophysiology of EC is complex, and there are currently no reliable methods for diagnosing and treating the condition. Long non-coding RNA (lncRNA), according to mounting evidence, is vital to the pathophysiology of EC. HOTAIR is regarded as a significant prognostic indicator of EC. ZBTB7A decreased EC proliferation and migration, according to recent studies, however the underlying mechanism still needs to be clarified. Methods: The research utilized RT-qPCR to measure HOTAIR expression in clinical EC tissues and various EC cell lines. Kaplan-Meier survival analysis was employed to correlate HOTAIR levels with patient prognosis. Additionally, the study examined the interaction between ZBTB7A and HOTAIR using bioinformatics tools and ChIP assays. The experimental approach also involved manipulating the expression levels of HOTAIR and ZBTB7A in EC cell lines and assessing the impact on various cellular processes and gene expression. Results: The study found significantly higher levels of HOTAIR in EC tissues compared to adjacent normal tissues, with high HOTAIR expression correlating with poorer survival rates and advanced cancer characteristics. EC cell lines like HEC-1 A and KLE showed higher HOTAIR levels compared to normal cells. Knockdown of HOTAIR in these cell lines reduced proliferation, angiogenesis, and migration. ZBTB7A was found to be inversely correlated with HOTAIR, and its overexpression led to a decrease in HOTAIR levels and a reduction in malignant cell behaviors. The study also uncovered that HOTAIR interacts with ELAVL1 to regulate SOX17, which in turn activates the Wnt/β-catenin pathway, promoting malignant behaviors in EC cells. Conclusion: HOTAIR is a critical regulator in EC, contributing to tumor growth and poor prognosis. Its interaction with ZBTB7A and regulation of SOX17 via the Wnt/β-catenin pathway underlines its potential as a therapeutic target.Highlights: The expressions of HOTAIR are positively related to SOX17, and both are significantly overexpressed in endometrial carcinoma. The transcription factor ZBTB7A inactivates the transcription of HOTAIR by binding to the promoter region of HOTAIR. The study uncovers a novel mechanism where HOTAIR recruits ELAVL1 to regulate SOX17, subsequently activating the Wnt/β-catenin pathway. [ABSTRACT FROM AUTHOR]

Background: As new treatment options for patients with higher-risk myelodysplastic syndromes are emerging, identification of prognostic markers for hypomethylating agent (HMA) treatment and understanding mechanisms of their delayed and short-term responses are essential. Early fetal hemoglobin (HbF) induction has been suggested as a prognostic indicator for decitabine-treated patients. Although epigenetic mechanisms are assumed, responding patients' epigenomes have not been thoroughly examined. We aimed to clarify HbF kinetics and prognostic value for azacytidine treated patients, as well as the epigenetic landscape that might influence HbF re-expression and its clinical relevance. Results: Serial HbF measurements by high-performance liquid chromatography (n = 20) showed induction of HbF only among responders (p = 0.030). Moreover, HbF increase immediately after the first azacytidine cycle demonstrated prognostic value for progression-free survival (PFS) (p = 0.032, HR = 0.19, CI 0.24–1.63). Changes in methylation patterns were revealed with methylated DNA genome-wide sequencing analysis (n = 7) for FOG-1, RCOR-1, ZBTB7A and genes of the NuRD-complex components. Targeted pyrosequencing methodology (n = 28) revealed a strong inverse correlation between the degree of γ-globin gene (HBG2) promoter methylation and baseline HbF levels (p = 0.003, rs = − 0.663). A potential epigenetic mechanism of HbF re-expression in azacytidine responders was enlightened by targeted methylation analysis, through hypomethylation of site -53 of HBG2 promoter (p = 0.039, rs = − 0.504), which corresponds to MBD2-NuRD binding site, and to hypermethylation of the CpG326 island of ZBTB7A (p = 0.05, rs = 0.482), a known HbF repressor. These changes were associated to blast cell clearance (pHBG2 = 0.011, rs = 0.480/pZBTB7A = 0.026, rs = 0.427) and showed prognostic value for PFS (pZBTB7A = 0.037, HR = 1.14, CI 0.34–3.8). Conclusions: Early HbF induction is featured as an accessible prognostic indicator for HMA treatment and the proposed potential epigenetic mechanism of HbF re-expression in azacytidine responders includes hypomethylation of the γ-globin gene promoter region and hypermethylation of the CpG326 island of ZBTB7A. The association of these methylation patterns with blast clearance and their prognostic value for PFS paves the way to discuss in-depth azacytidine epigenetic mechanism of action. [ABSTRACT FROM AUTHOR]

BACKGROUND: miRNAs play an important role in the pathogenesis of osteoporosis, which therefore can be important therapeutic targets. Among them, targeting the miR-100-5p regulatory axis to promote osteoblast differentiation is a potential therapeutic target for osteoporosis. OBJECTIVE: To explore the targeted regulatory roles of has-miR-100-5p and has-miR-101-3p in postmenopausal osteoporosis. METHODS: Differentially expressed genes between high and low bone mineral density in the GSE56814 and GSE56815 datasets were identified and subjected to enrichment analyses. Target genes of has-miR-100-5p and has-miR-101-3p among the differentially expressed genes were predicted. Peripheral blood samples from 40 patients with postmenopausal osteoporosis and 40 healthy controls were selected and qRT-PCR experiments were performed to detect the differential expression of has-miR-100-5p and has-miR-101-3p as well as target genes. Dual luciferase reporter assay was used to measure the targeting effect of miRNAs to the 3'UTR of target genes. RESULTS AND CONCLUSION: A total of 81 common differentially expressed genes were identified between high and low bone mineral density, mainly significantly enriched in immunity, nuclear factor-κB compound, and tumor necrosis factor signaling pathway. Has-miR-100-5p and has-miR-101-3p were targeted to regulate zinc finger and BTB domain containing 7A (ZBTB7A) based on miRTargetbase database and miRTarget database predictions. Has-miR-100- 5p was up-regulated (P < 0.001) and has-miR-101-3p and ZBTB7A were down-regulated (P < 0.001) in postmenopausal osteoporosis patients compared with the healthy controls. The fluorescence activity of 293T cells was down-regulated after co-transfection of has-miR-100-5p with wild-type ZBTB7A-3’UTR. To conclude, has-miR-100-5p targeting ZBTB7A may be a potential target for postmenopausal osteoporosis. [ABSTRACT FROM AUTHOR]

Aims: The isocitrate dehydrogenase (IDH) phenotype is associated with reprogrammed energy metabolism in glioblastoma (GBM) cells. Small nucleolar RNAs (snoRNAs) are known to exert an important regulatory role in the energy metabolism of tumor cells. The purpose of this study was to investigate the role of C/D box snoRNA U3 and transcription factor zinc finger and BTB domain‐containing 7A (ZBTB7A) in the regulation of aerobic glycolysis and the proliferative capacity of IDH1 wild‐type (IDH1WT) GBM cells. Methods: Quantitative reverse transcription PCR and western blot assays were utilized to detect snoRNA U3 and ZBTB7A expression. U3 promoter methylation status was analyzed via bisulfite sequencing and methylation‐specific PCR. Seahorse XF glycolysis stress assays, lactate production and glucose consumption measurement assays, and cell viability assays were utilized to detect glycolysis and proliferation of IDH1WT GBM cells. Results: We found that hypomethylation of the CpG island in the promoter region of U3 led to the upregulation of U3 expression in IDH1WT GBM cells, and the knockdown of U3 suppressed aerobic glycolysis and the proliferation ability of IDH1WT GBM cells. We found that small nucleolar‐derived RNA (sdRNA) U3‐miR, a small fragment produced by U3, was able to bind to the ZBTB4 3′UTR region and reduce ZBTB7A mRNA stability, thereby downregulating ZBTB7A protein expression. Furthermore, ZBTB7A transcriptionally inhibited the expression of hexokinase 2 (HK2) and lactate dehydrogenase A (LDHA), which are key enzymes of aerobic glycolysis, by directly binding to the HK2 and LDHA promoter regions, thereby forming the U3/ZBTB7A/HK2 LDHA pathway that regulates aerobic glycolysis and proliferation of IDH1WT GBM cells. Conclusion: U3 enhances aerobic glycolysis and proliferation in IDH1WT GBM cells via the U3/ZBTB7A/HK2 LDHA axis. [ABSTRACT FROM AUTHOR]

ZBTB7A, a transcription factor containing a tandem array of four Cys2‐His2 zinc fingers (ZFs), is vital for multiple physiological events through directional binding to different genomic loci. Our previously determined crystal structure of ZBTB7A in complex with a GCCCCTTCCCC sequence revealed that all four ZFs (ZF1–4) are involved in binding to γ‐globin −200 gene element to repress fetal haemoglobin expression. Recently, it has been reported that ZBTB7A drives primed‐to‐naïve transition (PNT) of pluripotent stem cells through binding to a 12‐bp consensus sequence ([AAGGACCCAGAT], referred to as PNT‐associated sequence). Here, we report a crystal structure of ZBTB7A ZF1–3 in complex with the PNT‐associated sequence. The structure shows that ZF1 and ZF2 primarily contribute to recognizing the GACCC core sequence mimicking the half part (GCCCC) of γ‐globin −200 gene element via specific hydrogen bonding and van der Waals contacts. The mutations of key residues in ZF1–2 remarkably reduce their binding affinities for the PNT‐associated sequence in vitro and cannot restore epiblast stem cells to the naïve pluripotent state in vivo. Collectively, our studies demonstrate that ZBTB7A mainly employs its ZF1–2 to recognize the PNT‐associated sequence but recognizes γ‐globin −200 gene element via ZF1–4, providing insights into the molecular mechanism for the diversity of ZBTB7A's genomic localization. [ABSTRACT FROM AUTHOR]

Astrocytes are the primary support cells of the central nervous system (CNS) that help maintain the energetic requirements and homeostatic environment of neurons. CNS injury causes astrocytes to take on reactive phenotypes with an altered overall function that can range from supportive to harmful for recovering neurons. The characterization of reactive astrocyte populations is a rapidly developing field, and the underlying factors and signaling pathways governing which type of reactive phenotype that astrocytes take on are poorly understood. Our previous studies suggest that transglutaminase 2 (TG2) has an important role in determining the astrocytic response to injury. Selectively deleting TG2 from astrocytes improves functional outcomes after CNS injury and causes widespread changes in gene regulation, which is associated with its nuclear localization. To begin to understand how TG2 impacts astrocytic function, we used a neuron-astrocyte co-culture paradigm to compare the effects of TG2−/− and wild-type (WT) mouse astrocytes on neurite outgrowth and synapse formation. Neurons were grown on a control substrate or an injury-simulating matrix comprised of inhibitory chondroitin sulfate proteoglycans (CSPGs). Compared to WT astrocytes, TG2−/− astrocytes supported neurite outgrowth to a significantly greater extent only on the CSPG matrix, while synapse formation assays showed mixed results depending on the pre- and post-synaptic markers analyzed. We hypothesize that TG2 regulates the supportive functions of astrocytes in injury conditions by modulating gene expression through interactions with transcription factors and transcription complexes. Based on the results of a previous yeast two-hybrid screen for TG2 interactors, we further investigated the interaction of TG2 with Zbtb7a, a ubiquitously expressed transcription factor. Co-immunoprecipitation and colocalization analyses confirmed the interaction of TG2 and Zbtb7a in the nucleus of astrocytes. Overexpression or knockdown of Zbtb7a levels in WT and TG2−/− astrocytes revealed that Zbtb7a robustly influenced astrocytic morphology and the ability of astrocytes to support neuronal outgrowth, which was significantly modulated by the presence of TG2. These findings support our hypothesis that astrocytic TG2 acts as a transcriptional regulator to influence astrocytic function, with greater influence under injury conditions that increase its expression, and Zbtb7a likely contributes to the overall effects observed with astrocytic TG2 deletion. [ABSTRACT FROM AUTHOR]

ZBTB7A, alternatively referred to Pokemon, FBI-1, LRF, and OCZF, is classified as a member of POK/ZBTB protein family of transcriptional repressors. ZBTB7A binds to targeted DNA via C-terminal zinc fingers and recruits co-compression complexes through N-terminal BTB ⁄ POZ domain to impede transcription. ZBTB7A regulates a range of fundamental biological processes such as cell proliferation, differentiation and apoptosis, B- and T-lymphocyte fate determination and thymic insulin expression and self-tolerance. Accumulating evidence has demonstrated an important role of ZBTB7A in the initiation and advancement of tumors, thus making ZBTB7A emerge as an appealing target. This review examines the functions and regulatory mechanisms of ZBTB7A in a range of common solid tumors, including hepatocellular carcinoma, breast cancer, prostate cancer and lung cancer, as well as hematological malignancies. Notably, the review concludes with a summary of the recent applications of targeting ZBTB7A in clinical treatments through gene silencing, immunotherapy and chemotherapeutic approaches to halt or slow tumor progression. We focus on the functional role and regulatory mechanisms of ZBTB7A in cancer with the goal of providing new insights for the development of more effective cancer therapeutic strategies. • The transcription factor ZBTB7A regulates cell proliferation and differentiation, apoptosis, cell cycle and metabolism. • ZBTB7A plays a key role in a range of common solid tumors as well as hematological malignancies. • ZBTB7A as a key target for cancer therapy by directly targeting ZBTB7A or indirectly targeting its upstream regulators. • ZBTB7A as a therapeutic target for clinical use through gene silencing, immunotherapy and chemotherapy to stop or slow tumor progression. [ABSTRACT FROM AUTHOR]

Our previous studies suggested a potential interaction between the POK erythroid myeloid ontogenic factor ZBTB7A and glucose transporter 1 (GLUT1) in nasopharyngeal carcinoma (NPC). This study was designed to confirm the interaction and further evaluate the precise mechanism by which ZBTB7A and GLUT1 regulate NPC development. The binding sites between ZBTB7A and the promoter of GLUT1 were predicted by bioinformatics. Gene expression was measured by quantitative real-time polymerase chain reaction (qPCR), western blotting, and immunohistochemistry. The activities of key glycolysis enzymes, including hexokinase (HK), pyruvate kinase (PK), lactate dehydrogenase (LDH), and lactate, were detected using specific enzyme-linked immunosorbent assay kits. The connection between ZBTB7A and GLUT1 was analyzed by dual-luciferase reporter assay and chromatin immunoprecipitation--qPCR. The vitality, proliferation, and tumorigenicity of the cells expressing different levels of ZBTB7A were tested by adding the glycolysis inhibitor 2-deoxy-D-glucose (2-DG), followed by MTT, colorimetric focus forming, and xenograft assays, respectively. Our results showed that high expression of GLUT1 was associated with late-stage NPC. After constructing stably transfected cells with lentiviruses, ZBTB7A was effectively knocked down in 5-8F cells (RNAi-5-8F) and overexpressed in 6-10B cells (ZBTB7A-6-10B). The up- or downregulation of GLUT1 secondary to ZBTB7A changes was also limited. The vitality and proliferation of the cells expressing low ZBTB7A were notably blocked by 2-DG. The cells expressing high ZBTB7A were not very sensitive to 2-DG. The growth of RNAi-5-8F xenografts was strongly suppressed by 2-DG. The activities of HK, PK, and LDH were suppressed by 2-DG in the cells expressing low ZBTB7A. RNAi-5-8F cells had the lowest 2-DG-induced lactate production. ZBTB7A directly suppressed the promoter region of GLUT1 to regulate GLUT1 expression. Thus, ZBTB7A controls the 2-DG-induced inhibition of glycolysis by affecting GLUT1. [ABSTRACT FROM AUTHOR]

Gastric cancer is malignant cancer with high morbidity and mortality worldwide. Milk fat globule EGF and factor V/VIII domain containing (MFGE8) was involved in many cancers. Nevertheless, the role of MFGE8 in gastric cancer remained indistinct. To probe the role of MFGE8 in gastric cancer and further explore the regulating mechanism. GEPIA was employed for analysis of MFGE8 expression and survival of gastric cancer patients. MFGE8 expression in gastric cancer was determined by immunohistochemistry, PCR, and western blot. The effect of MFGE8 on gastric cancer cells were evaluated by a series of cell function experiments. The mechanism of MFGE8 on gastric cancer was analyzed by GSEA and verified by in vitro and in vivo experiments. MFGE8 was over-expressed in gastric cancer. Silence of MFGE8 suppressed cell viability, proliferated ability, migrated and invasive ability, and EMT, but accelerated cell apoptosis. The opposite results were obtained in MFGE8-overexpressed gastric cancer cells. Zinc finger and BTB domain containing 7 A (ZBTB7A) was a transcription factor of MFGE8. ZBTB7A overexpression eliminated the effect of MFGE8 on gastric cancer cells. MFGE8 activated the IL-6/JAK/STAT3 signaling. Inhibition of IL-6/JAK/STAT3 signaling by Stattic (pathway inhibitor) could eliminate the promoting effect of MFGE8 on IL-6/JAK/STAT3 signaling. In addition, MFGE8 shRNA inhibited tumor growth. MFGE8 promoted cell proliferation, EMT progress, and tumor growth of gastric cancer by activating the IL-6/JAK/STAT3 signaling. • MFGE8 is over-expressed in gastric cancer. • MFGE8 accelerates gastric cancer cell proliferation but inhibits apoptosis in vitro. • MFGE8 reverses ZBTB7A-induced proliferation, apoptosis and migration of gastric cancer cells. • MFGE8 promotes the proliferation and inhibits the apoptosis via IL-6/JAK/STAT3 signaling in gastric cancer cells. • Silencing of MFGE8 inhibits gastric cancer tumor growth in xenograft mouse models. [ABSTRACT FROM AUTHOR]

Background: Zinc finger and BTB domain-containing 7A (ZBTB7A) is a member of the POK family of transcription factors that plays an oncogenic or tumor-suppressive role in different cancers depending on the type and genetic context of cancer. However, the function and molecular mechanism of ZBTB7A in bladder cancer (BC) remain elusive. Methods: The role of ZBTB7A in bladder cancer was detected by colony formation, transwell, and tumor formation assays. The expression levels of ZBTB7A, HIC1, and miR-144-3p were analyzed by qRT-PCR and Western blot. Bioinformatics analysis and a dual-luciferase reporter assay were used to assess the effect of ZBTB7A on the promoter activity of HIC1. Results: The present study revealed that knockdown of ZBTB7A suppressed BC cell growth and migration, as indicated by an approximately 50% reduction in the number of colonies and an approximately 70% reduction in the number of migrated cells. Loss of ZBTB7A inhibited tumor growth in vivo, resulting in a 75% decrease in tumor volume and an 80% decrease in tumor weight. Further mechanistic studies revealed that ZBTB7A bound to the hypermethylated in cancer 1 (HIC1) promoter and downregulated HIC1 expression, accelerating the malignant behavior of BC. Increased expression of ZBTB7A in BC tissues was negatively corrected with the expression of HIC1. Moreover, ZBTB7A was a target of miR-144-3p, which decreased ZBTB7A expression in BC. Conclusion: Our data demonstrate that ZBTB7A, a targeted gene of miR-144-3p, promoted tumorigenesis of BC through downregulating HIC1 expression. [ABSTRACT FROM AUTHOR]

Objective(s): This study aimed to verify whether curcumol combined with paclitaxel exerted synergistic antiproliferative and proapoptotic effects in MDA-MB-231 mammary cancer cells. Materials and Methods: The effects of different concentrations of CC, PTX, and their combination on the proliferation of MDA-MB-231 mammary cancer cells were determined by CCK-8 laboratory tests. Combination index (CI) was calculated using CompuSyn software. Colony formation assays, Hoechst 33258 immunofluorescence staining, and flow cytometry were carried out to observe proliferation and apoptosis in each group. The protein expression of PCNA, Bcl-2, Bax, ZBTB7A, p-p65, and NFƙB p65 was detected by western blotting. The xenograft tumor volume and body mass of nude mice were measured. Immunohistochemistry was used to detect the expression of PCNA, NF-κB p65 and ZBTB7A. TUNEL and DAPI staining were used to detect the apoptosis of tumor cells. Results: Curcumol combined with paclitaxel exerted a significant inhibitory effect on proliferation of MDA-MB-231 cells in the CCK-8 laboratory test. Hoechst 33258 immunofluorescence staining, flow cytometry, TUNEL, and DAPI apoptosis staining demonstrated that cell apoptosis was the highest in the CC+PTX group in vivo and in vitro. Expression of PCNA, Bcl-2, ZBTB7A, p-p65, and NF-κB p65 was lowest in the CC+PTX group, while the expression of Bax was highest. The growth of xenograft tumors in the CC+PTX group was most notably suppressed. Immunohistochemistry showed that expression of PCNA, ZBTB7A, and NF-ƙB p65 was the lowest in the CC+PTX group. Conclusion: Curcumol combined with paclitaxel exerted a synergistic antiproliferative and proapoptotic effect on triple-negative breast cancer cells. [ABSTRACT FROM AUTHOR]

Purpose: Tumor budding (TB) is reported to predict nodal involvement and recurrence in multiple human malignancies. However, it is not clear how TB forms. The purpose of this study is to find markers related to TB formation in gastric cancer and to investigate the underlying mechanisms. Methods: TB was scored on hematoxylin–eosin staining slides in 122 gastric cancer cases. Immunostaining score of CREB1, GAGE12I, CTNND1, KIF26B and ZBTB7A both at the invasive front and in the center of the tumor were assigned to each case. Spearman's correlation with the TB score was performed to find the TB-related markers. In vitro study and RNA-seq using gastric cancer cell lines were done to unveil the mechanisms. Results: TB could predict lymph node metastasis and is negatively associated with overall survival of the patients. The expression of ZBTB7A in the invasive front, rather than the other four markers, was much higher than that in the tumor center and was positively correlated with TB score. ZBTB7A could enhance migration and invasion of gastric cancer cells in vitro. RNA-seq data followed by RT-qPCR and western blot verification demonstrated the activation of EGFR-MAPK-ERK and PI3K-AKT-mTOR pathways and increased expression of EMT related markers upon ZBTB7A over-expression. Conclusion: Higher ZBTB7A expression in the tumor margin may contribute to the dissociation of tumor cells from the tumor mass to form TB by initiating EMT via EGFR-MEK-ERK and PI3K-AKT-mTOR pathway. [ABSTRACT FROM AUTHOR]

ZBTB7A is a member of the POK family of transcription factors that possesses a POZ-domain at the N-terminus and Krüppel-like zinc-finger at the c-terminus. ZBTB7A was initially isolated as a protein that binds to the inducer of the short transcript of HIV-1 virus TAT gene promoter. The protein forms a homodimer through protein-protein interaction via the N-terminus POZ-domains. ZBTB7A typically binds to the DNA elements through its zinc-finger domains and represses transcription both by modification of the chromatin organization and through the direct recruitment of transcription factors to gene regulatory regions. ZBTB7A is involved in several fundamental biological processes including cell proliferation, differentiation, and development. It also participates in hematopoiesis, adipogenesis, chondrogenesis, cellular metabolism and alternative splicing of BCLXL, DNA repair, development of oligodendrocytes, osteoclast and unfolded protein response. Aberrant ZBTB7A expression promotes oncogenic transformation and tumor progression, but also maintains a tumor suppressive role depending on the type and genetic context of cancer. In this comprehensive review we provide information about the structure, function, targets, and regulators of ZBTB7A and its role as an oncogenic driver and transcriptional repressor in various human diseases. [ABSTRACT FROM AUTHOR]

It has been generally confirmed that zinc finger and BTB domain containing 7A (ZBTB7A) plays an important role in the occurrence and progression of malignant tumours, but the promotion or inhibition effect is related to tumour type. The mechanism between ZBTB7A and breast cancer is not well understood, so further research is needed. In this study, we first investigated the expression of ZBTB7A in tissue samples of clinical breast cancer patients, MDA-MB-231, MCF-7 and MCF-10A cells. Second, we overexpressed the ZBTB7A in MCF-7 cells and silenced the ZBTB7A in MDA-MB-231 cells using lentivirus transfection technology, respectively, and verified the effect of ZBTB7A on migration and invasion of breast cancer cell lines through in vitro cell function experiments, such as wound-healing assay, migration and invasion assay, quantitative real time reverse transcriptase (qRT-PCR) and western blot. Then, the correlation between the above influences, epithelial–mesenchymal transition (EMT) and NF-κB was analysed. Finally, in vivo tumour transplantation model in nude mice was established to verified the effect of ZBTB7A on metastasis of breast cancer MDA-MB-231 cells. In conclusion, ZBTB7A is highly expressed in cancer tissue, breast cancer cell line MDA-MB-231 and MCF-7. Meanwhile, the high expression of ZBTB7A may promote cell migration, invasion and tumour metastasis, which may be related to EMT events by regulating NF-κB. [ABSTRACT FROM AUTHOR]

Many studies have uncovered the essential role of ZBTB7A in regulating tumourigenesis. However, its functional significance in cell responses to endoplasmic reticulum stress (ER stress) remains poorly understood. Here we report that ZBTB7A functions as an important prosurvival factor in osteosarcoma cells undergoing pharmacological ER stress-induced by tunicamycin (TM) or thapsigargin (TG). The downregulation of ZBTB7A expression by ER stress promoted cell apoptosis in vitro and in vivo. ZBTB7A expression levels were increased in osteosarcoma tissues and elevated ZBTB7A was associated with osteosarcoma metastasis. Further mechanistic studies revealed that miR-663a induced by ER stress directly bound to the 3'UTR of ZBTB7A and contributed to ER stress-induced ZBTB7A downregulation in osteosarcoma cells. Additionally, our data revealed that ZBTB7A bound to the promoter of LncRNA GAS5 and transcriptionally suppressed LncRNA GAS5 expression, leading to a decline in ER stress-induced cell apoptosis. Collectively, our findings reveal the prosurvival role of ZBTB7A in osteosarcoma adaptation to ER stress and suggest that the miR-663a-ZBTB7A-LncRNAGAS5 pathway is essential for the survival of human osteosarcoma cells under ER stress. [ABSTRACT FROM AUTHOR]

We analyzed the clinical significance and genetic features of ASXL2 and ZBTB7A mutations, and the alternatively spliced isoform of the RUNX1-RUNX1T1 transcript, which is also called AML1-ETO9a (AE9a), in Japanese CBF-AML patients enrolled in the JALSG AML201 study. ASXL2 and ZBTB7A genes were sequenced using bone marrow samples of 41 AML patients with t(8;21) and 14 with inv(16). The relative expression levels of AE9a were quantified using the real-time PCR assay in 23 AML patients with t(8;21). We identified ASXL2 (34.1%) and ZBTB7A (9.8%) mutations in only AML patients with t(8;21). ASXL2-mutated patients had a significantly higher WBC count at diagnosis (P = 0.04) and a lower frequency of sex chromosome loss than wild-type patients (33 vs. 76%, respectively, P = 0.01). KIT mutations were the most frequently accompanied with both ASXL2 (36%) and ZBTB7A (75%) mutations. Neither ASXL2 nor ZBTB7A mutations had an impact on overall or event-free survival. Patients harboring cohesin complex gene mutations expressed significantly higher levels of AE9a than unmutated patients (P = 0.03). In conclusion, ASXL2 and ZBTB7A mutations were frequently identified in Japanese AML patients with t(8;21), but not in those with inv(16). Further analysis is required to clarify the detailed biological mechanism of AE9a regulation of the cohesin complex. [ABSTRACT FROM AUTHOR]

The present study aimed to determine the association between changes in Zbtb7a expression levels and heterogeneity of nasopharyngeal carcinoma (NPC) CNE3 sublines. CNE3 sublines were established by screening of serial dilution and continuous passage. Proliferative ability and tumorigenicity of the sublines were analyzed separately by soft-agar colony formation and mouse studies. The NPC tissues from mice were analyzed by histological evaluation and immunohistochemistry. The expression levels of Zbtb7a mRNA and protein were analyzed separately by quantitative reverse transcription polymerase chain reaction and western blotting. According to findings from the soft-agar colony formation and mouse studies, two sublines with increased tumorigenicity compared with other sublines were transfected transiently with Zbtb7a short hairpin RNA (shRNA) recombinant plasmid. The changes in viability, migration and invasion abilities were evaluated separately by MTT, colorimetric focus-formation, Transwell migration and invasion assays. The sublines CNE3-GX6 and CNE3-GX11 were selected for subsequent study due to increased tumorigenicity and increased Zbtb7a expression levels compared with the other sublines. High metastatic potency was not observed in all of the sublines. Zbtb7a expression levels were positively associated with tumorigenic degree of the sublines. The growth, migration and invasion abilities of the sublines transfected with Zbtb7a shRNA plasmid were decreased compared with the cells transfected with empty vector in the negative control group. The findings suggest Zbtb7a expression levels may be associated with heterogeneity of CNE3 sublines. Therefore, Zbtb7a may have an important role in the regulatory mechanism of NPC heterogeneity. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) that negatively regulated gene expression have emerged as novel therapeutic target for non-small-cell lung cancer (NSCLC) treatment. In this study, we investigated the potential role of miR-520e and examined its functional role in NSCLCs. Loss-and-gain of function assays show that miR-520e significantly modulated NSCLC cell growth, cell invasion and cell migration via directly targeting the 3’-untranslated region (UTR) of Zbtb7a and therefore reduced Zbtb7a protein level. These effects of miR-520e on NSCLC progression could be rescued by Zbtb7a overexpression in A549 cells. Furthermore, both of miR-520e level and Zbtb7a level were correlated with Wnt signaling in NSCLC cells. Taken together, these results indicate that overexpressing miR-520e is involved in regulating the NSCLC cell growth, invasion and migration by targeting Zbtb7a partly depending on Wnt signaling. [ABSTRACT FROM AUTHOR]

MicroRNAs have been reported to play key roles in various human cancers, including gastric cancer. However, understanding of the expression of miR-100 and its regulatory mechanisms in human gastric cancer remains elusive. In this study, we reveal that miR-100 is downregulated in gastric cancer samples and gastric cancer cell lines. Furthermore, lower miR-100 expression was found in primary gastric cancer samples with lymphatic metastasis compared to those without lymphatic metastasis. Overexpression of miR-100 suppressed tumor growth in vivo and inhibited gastric cancer invasion and metastasis in vitro and in vivo. Furthermore, we demonstrated that miR-100 reduced gastric cancer aggressiveness by directly targeting ZBTB7A. Knockdown of ZBTB7A by siRNA disrupted gastric cancer progression by impairing tumor invasion and metastasis. High expression of ZBTB7A was significantly correlated with poorer prognosis in gastric cancer patients. Our results also showed that the transcription factor CCAAT/enhancer-binding protein alpha (C/EBPα) could induce the expression of miR-100 by binding to the putative promoter region of miR-100. This study demonstrated that miR-100 could be induced by C/EBPα and may act as a tumor suppressor gene by inhibiting ZBTB7A. [ABSTRACT FROM AUTHOR]

Elevated glycolysis is a common metabolic trait of cancer, but what drives such metabolic reprogramming remains incompletely clear. We report here a novel transcriptional repressor-mediated negative regulation of glycolysis. ZBTB7A, a member of the POK (POZ/BTB and Krüppel) transcription repressor family, directly binds to the promoter and represses the transcription of critical glycolytic genes, including GLUT3, PFKP, and PKM. Analysis of The Cancer Genome Atlas (TCGA) data sets reveals that the ZBTB7A locus is frequently deleted in many human tumors. Significantly, reduced ZBTB7A expression correlates with up-regulation of the glycolytic genes and poor survival in colon cancer patients. Remarkably, while ZBTB7A-deficient tumors progress exceedingly fast, they exhibit an unusually heightened sensitivity to glycolysis inhibition. Our study uncovers a novel tumor suppressor role of ZBTB7A in directly suppressing glycolysis. [ABSTRACT FROM AUTHOR]

Backgroud: ZBTB protein is an important member of the C2H2 zinc finger protein family. As a transcription factor, it is widely involved in the transcriptional regulation of genes, cell proliferation, differentiation, and apoptosis. The ZBTB7A has been largely linked to different kinds of tumors due to its diverse function. However, the value for ZBTB7A in uterine corpus endometrial carcinoma (UCEC) is unclear. Methods: In our work, we assessed the importance of ZBTB7A in UCEC. Firstly, Using Oncomine and Tumor Immunoassay Resource (TIMER) databases to evaluate the expression of ZBTB7A. Secondly, we explored the co-expression network of ZBTB7A through the cBioPortal online tool, Metascape, and LinkedOmics. TIMER was also used to explore the relationship between ZBTB7A and tumor immune invasion, and to detect the correlation between the ZBTB7A and the marker genes related to immune infiltration. Finally, CCK8, migration, ChIP assays were introduced to partly validate ZBTB7A function in endometrial cancer cells. Results: We found the ZBTB7A expression in TIMER was associated with various cancers, especially UCEC. The decreased expression of ZBTB7A was markedly related to the stage and prognosis of UCEC. Furthermore, ZBTB7A was also related to the expression of various immune markers such as Neutrophils, Dendritic cell, T cell (general), Th1, Th2, and Treg. Finally, we verified that ZBTB7A repressed E2F4 transcription and inhibited cells proliferation and migration. These results indicate that ZBTB7A may play a vital role in regulating immune cell infiltration in UCEC, and is a valuable prognostic marker. Conclusions: In summary, we demonstrate that ZBTB7A is notably downregulated in UCEC, plays a vital role in regulating immune cell infiltration, possesses diagnostic and prognostic values and attenuates E2F4 transcription and cell proliferation, migration in vitro. [ABSTRACT FROM AUTHOR]

Background: Despite zinc finger and BTB domain-containing 7A (ZBTB7A) documented importance in multiple tumors, the function and clinical value in Colorectal cancer (CRC) remain elusive. The aim of this study was to evaluate the functional roles and the clinical value of ZBTB7A in CRC progression.Methods: The level of ZBTB7A was detected in a large cohort of CRC patients (n = 189) by immunohistochemistry (IHC), and we analyzed the diagnostic and prognostic value of the protein. In addition, the functional roles of ZBTB7A on CRC were explored in vitro and in vivo.Results: Survival analyses indicated that patients with high ZBTB7A expression made the prognosis worse (P = 0.024). Functionally, knockdown of ZBTB7A could markedly inhibit tumor proliferation in vitro and in vivo, whereas ZBTB7A overexpression displayed the opposite results.Conclusions: ZBTB7A was associated with poor survival outcomes and functioned as an oncogene in CRC patients, indicating that it is a potential prognostic biomarker and therapeutic target for CRC patients. [ABSTRACT FROM AUTHOR]

ZBTB7A, a transcriptional repressor, accelerates the breast cancer progression. Over 70% of breast cancer samples are identified as ER-α positive. Due to the function of ZBTB7A in ER-α positive breast cancer incompletely known, we aimed to determine the role of ZBTB7A in ER-α positive cancer and explore the underlying mechanisms. In this study, the correlation between ZBTB7A and ER-α was confirmed by tissue microarray-based and TCGA database. Then, we explore if ZBTB7A maintains ER-α′s level via targeting ER-α′s expression or degradation. Finally, we examined the effect of ZBTB7A on the proliferation of breast cancer cells. We further confirmed that ZBTB7A shows a significant positive correlation with ER-α in clinical breast cancer samples by tissue microarray-based analysis. Mechanically, we identified that the inhibition of ZBTB7A could upregulate E3 ligase TRIM25 leading to enhancement of ER-α ubiquitination and proteasomal degradation, which could partly explain the correlation between ZBTB7A and ER-α. Besides, we uncovered that ZBTB7A could also transcriptionally increase the expression of ER-α via indirectly binding to the region +146 to +461 bp downstream of the transcription start site of ESR1 (ERpro315) in breast cancer cells. Furthermore, ZBTB7A is found to stimulate the expression of ER-α′s downstream genes, and promote the growth of estrogen receptor alpha (ER-α)-positive breast cancer cells. Our data revealed the novel mechanisms through which ZBTB7A manipulates ER-α level and might provide a new avenue for endocrine therapy in breast cancer. [ABSTRACT FROM AUTHOR]