Targeting EMT using low-dose Teniposide by downregulating ZEB2-driven activation of RNA polymerase I in breast cancer.

Metastatic dissemination from the primary tumor is a complex process that requires crosstalk between tumor cells and the surrounding milieu and involves the interplay between numerous cellular-signaling programs. Epithelial-mesenchymal transition (EMT) remains at the forefront of orchestrating a shift in numerous cellular programs, such as stemness, drug resistance, and apoptosis that allow for successful metastasis. Till date, there is limited success in therapeutically targeting EMT. Utilizing a high throughput screen of FDA-approved compounds, we uncovered a novel role of the topoisomerase inhibitor, Teniposide, in reversing EMT. Here, we demonstrate Teniposide as a potent modulator of the EMT program, specifically through an IRF7-NMI mediated response. Furthermore, Teniposide significantly reduces the expression of the key EMT transcriptional regulator, Zinc Finger E-Box Binding Homeobox 2 (ZEB2). ZEB2 downregulation by Teniposide inhibited RNA polymerase I (Pol I) activity and rRNA biogenesis. Importantly, Teniposide treatment markedly reduced pulmonary colonization of breast cancer cells. We have uncovered a novel role of Teniposide, which when used at a very low concentration, mitigates mesenchymal-like invasive phenotype. Overall, its ability to target EMT and rRNA biogenesis makes Teniposide a viable candidate to be repurposed as a therapeutic option to restrict breast cancer metastases.

ZEB2 alleviates Hirschsprung's-associated enterocolitis by promoting the proliferation and differentiation of enteric neural precursor cells via the Notch-1/Jagged-2 pathway.

BACKGROUND: Hirschsprung's-associated enterocolitis (HAEC) is a prevalent complication of Hirschsprung's disease (HSCR). Zinc finger E-box binding homeobox 2 (ZEB2) and Notch-1/Jagged-2 are dysregulated in HSCR, but their role in HAEC progression remains poorly understood. We aimed to explore the role and underlying mechanism of enteric neural precursor cells (ENPCs) and the ZEB2/Notch-1/Jagged-2 pathway in HAEC development. METHODS: Colon tissues were collected from HSCR and HAEC patients. ENPCs were isolated from the HAEC group and stimulated by lipopolysaccharide (LPS). The expressions of ZEB2/Notch-1/Jagged-2 were measured using RT-qPCR and Western blot. Immunofluorescence and cell counting kit-8 assays were performed to assess the differentiation and proliferation of ENPCs. Inflammatory factors were measured by ELISA kits. Co-immunoprecipitation and bioinformatic analysis were used to explore the interaction between ZEB2 and Notch-1. Small interfering RNA and overexpression vectors were used to investigate the role and mechanism of ZEB2 and Notch-1 in regulating ENPCs' proliferation and differentiation during HAEC progression. RESULTS: We observed increased LPS in the colon tissues of HAEC, with downregulated ZEB2 expression and upregulated Notch-1/Jagged-2 expression. ZEB2 interacts with Notch-1. LPS treatment downregulated ZEB2 expression, upregulated Notch-1/Jagged-2 expression, and induced proliferation and differentiation disorders in ENPCs, which were reversed by the knockdown of Notch-1. Furthermore, overexpression of ZEB2 inhibited Notch-1/Jagged-2 signaling and ameliorated inflammation and dysfunction in LPS-induced ENPCs. Notch-1 overexpression enhanced LPS-induced dysfunction, but this effect was antagonized by the overexpression of ZEB2. CONCLUSION: Overexpression of ZEB2 ameliorates LPS-induced ENPCs' dysfunction via the Notch-1/Jagged-2 pathway, thus playing a role in HAEC.

ABCs begin with ZEB2.

Age-associated B cells (ABCs) are a stable subset of memory B lymphocytes that develop during microbial infections and in autoimmune diseases. Despite growing appreciation of their phenotypic and functional characteristics, the transcriptional networks involved in ABC fate commitment and maintenance have remained elusive. In their recent publication, Dai et al. tackle this problem, leveraging both mouse models and human diseases to reveal zinc finger E-box-binding homeobox 2 (ZEB2) as a key transcriptional regulator of ABC lineage specification. In aggregate, their results show that ZEB2, a member of the zinc finger E homeobox binding family, promotes ABC differentiation by repressing alternative differentiative fates and targeting genes important for ABC character and function. Moreover, their results strengthen the case for causal links between ABC fate and function in autoimmune pathologies.

Age-associated CD4+ T cells with B cell-promoting functions are regulated by ZEB2 in autoimmunity.

Aging is a significant risk factor for autoimmunity, and many autoimmune diseases tend to onset during adulthood. We conducted an extensive analysis of CD4+ T cell subsets from 354 patients with autoimmune disease and healthy controls via flow cytometry and bulk RNA sequencing. As a result, we identified a distinct CXCR3midCD4+ effector memory T cell subset that expands with age, which we designated "age-associated T helper (THA) cells." THA cells exhibited both a cytotoxic phenotype and B cell helper functions, and these features were regulated by the transcription factor ZEB2. Consistent with the highly skewed T cell receptor usage of THA cells, gene expression in THA cells from patients with systemic lupus erythematosus reflected disease activity and was affected by treatment with a calcineurin inhibitor. Moreover, analysis of single-cell RNA sequencing data revealed that THA cells infiltrate damaged organs in patients with autoimmune diseases. Together, our characterization of THA cells may facilitate improved understanding of the relationship between aging and autoimmune diseases.

Entero-toxigenic Bacteroides fragilis contributes to intestinal barrier injury and colorectal cancer progression by mediating the BFT/STAT3/ZEB2 pathway.

Our previous findings confirmed the high enrichment of Bacteroides fragilis (BF) in fecal samples from patients with colorectal cancer (CRC). The intestinal mucosal barrier is the first defense of the organism against commensal flora and intestinal pathogens and is closely associated with the occurrence and development of CRC. Therefore, this study aimed to investigate the molecular mechanisms through which BF mediates intestinal barrier injury and CRC progression. SW480 cells and a Caco2 intestinal barrier model were treated with entero-toxigenic BF (ETBF), its enterotoxin (B. fragilis toxin, BFT), and non-toxigenic BF (NTBF). Cell counting kit-8, flow cytometry, wound healing and transwell assays were performed to analyze the proliferation, apoptosis, migration, and invasion of SW480 cells. Transmission electron microscopy, FITC-dextran, and transepithelial electrical resistance (TEER) were used to analyze damage in the Caco2 intestinal barrier model. The Azoxymethane/Dextran Sulfate Sodium (AOM/DSS) animal model was established to evaluate the effect of ETBF on intestinal barrier injury and CRC progression in vivo. ETBF and BFT enhanced the viability, wound healing ratio, invasion, and EMT of SW480 cells. In addition, ETBF and BFT disrupted the tight junctions and villus structure in the intestinal barrier model, resulting in increased permeability and reduced TEER. Similarly, the expression of intestinal barrier-related proteins (MUC2, Occludin and Zo-1) was restricted by ETBF and BFT. Interestingly, the STAT3/ZEB2 axis was activated by ETBF and BFT, and treatment with Brevilin A (a STAT3 inhibitor) or knockdown of ZEB2 limited the promotional effect of ETBF and BFT on the SW480 malignant phenotype. In vivo experiments also confirmed that ETBF colonization accelerated tumor load, carcinogenesis, and intestinal mucosal barrier damage in the colorectum of the AOM/DSS animal model, and that treatment with Brevilin A alleviated these processes. ETBF-secreted BFT accelerated intestinal barrier damage and CRC by activating the STAT3/ZEB2 axis. Our findings provide new insights and perspectives for the application of ETBF in CRC treatment.

IKBKE promotes the ZEB2-mediated EMT process by phosphorylating HMGA1a in glioblastoma.

IKBKE (Inhibitor of Nuclear Factor Kappa-B Kinase Subunit Epsilon) is an important oncogenic protein in a variety of tumors, which can promote tumor growth, proliferation, invasion and drug resistance, and plays a critical regulatory role in the occurrence and progression of malignant tumors. HMGA1a (High Mobility Group AT-hook 1a) functions as a cofactor for proper transcriptional regulation and is highly expressed in multiple types of tumors. ZEB2 (Zinc finger E-box Binding homeobox 2) exerts active functions in epithelial mesenchymal transformation (EMT). In our current study, we confirmed that IKBKE can increase the proliferation, invasion and migration of glioblastoma cells. We then found that IKBKE can phosphorylate HMGA1a at Ser 36 and/or Ser 44 sites and inhibit the degradation process of HMGA1a, and regulate the nuclear translocation of HMGA1a. Crucially, we observed that HMGA1a can regulate ZEB2 gene expression by interacting with ZEB2 promoter region. Hence, HMGA1a was found to promote the ZEB2-related metastasis. Consequently, we demonstrated that IKBKE can exert its oncogenic functions via the IKBKE/HMGA1a/ZEB2 signalling axis, and IKBKE may be a prominent biomarker for the treatment of glioblastoma in the future.

The transcription factor ZEB2 drives the formation of age-associated B cells.

Age-associated B cells (ABCs) accumulate during infection, aging, and autoimmunity, contributing to lupus pathogenesis. In this study, we screened for transcription factors driving ABC formation and found that zinc finger E-box binding homeobox 2 (ZEB2) is required for human and mouse ABC differentiation in vitro. ABCs are reduced in ZEB2 haploinsufficient individuals and in mice lacking Zeb2 in B cells. In mice with toll-like receptor 7 (TLR7)-driven lupus, ZEB2 is essential for ABC formation and autoimmune pathology. ZEB2 binds to +20-kb myocyte enhancer factor 2b (Mef2b)'s intronic enhancer, repressing MEF2B-mediated germinal center B cell differentiation and promoting ABC formation. ZEB2 also targets genes important for ABC specification and function, including Itgax. ZEB2-driven ABC differentiation requires JAK-STAT (Janus kinase-signal transducer and activator of transcription), and treatment with JAK1/3 inhibitor reduces ABC accumulation in autoimmune mice and patients. Thus, ZEB2 emerges as a driver of B cell autoimmunity.

Propofol Promoted the Cell Growth and Epithelial Mesenchymal Transformation of the HTR-8/SVneo Cells through Targeting the METTL3 Mediated ZEB2.

Preeclampsia (PE) belongs to hypertensive disorder complicating pregnancy, which is a serious obstetric complication. Propofol is a new type of fast and short-acting general anesthetic, which has also been demonstrated to promote the cell growth recently. Therefore, this study was carried out to explore the effects of propofol on the cell growth, migration and invasion in the HTR-8/SVneo cells. The cell biological behaviors were analyzed using CCK-8, EdU, transwell assays. The relationship between METTL3 and ZEB2 was confirmed by RIP assay. Western blot and RT-qPCR assays were carried out to detect the protein and mRNA levels. The results showed that propofol enhanced the cell viability, proliferation, migration and invasion of the HTR-8/SVneo cells. Besides, METTL3 overexpression neutralized the propofol role. Furthermore, METTL3 overexpression elevated the m6A levels of ZEB2 and decreased the mRNA levels and stability of ZEB2. ZEB2 overexpression neutralized the role of METTL3 in the propofol treated HTR-8/SVneo cells. In conclusion, this study demonstrated the effects of propofol on promoting the cell growth, migration and invasion of HTR-8/SVneo cells. Mechanistically, propofol indirectly regulated ZEB2 expression by targeting METTL3 mediated m6A methylation modification.

A positive feedback loop between ZEB2 and ACSL4 regulates lipid metabolism to promote breast cancer metastasis.

Lipid metabolism plays a critical role in cancer metastasis. However, the mechanisms through which metastatic genes regulate lipid metabolism remain unclear. Here, we describe a new oncogenic-metabolic feedback loop between the epithelial-mesenchymal transition transcription factor ZEB2 and the key lipid enzyme ACSL4 (long-chain acyl-CoA synthetase 4), resulting in enhanced cellular lipid storage and fatty acid oxidation (FAO) to drive breast cancer metastasis. Functionally, depletion of ZEB2 or ACSL4 significantly reduced lipid droplets (LDs) abundance and cell migration. ACSL4 overexpression rescued the invasive capabilities of the ZEB2 knockdown cells, suggesting that ACSL4 is crucial for ZEB2-mediated metastasis. Mechanistically, ZEB2-activated ACSL4 expression by directly binding to the ACSL4 promoter. ACSL4 binds to and stabilizes ZEB2 by reducing ZEB2 ubiquitination. Notably, ACSL4 not only promotes the intracellular lipogenesis and LDs accumulation but also enhances FAO and adenosine triphosphate production by upregulating the FAO rate-limiting enzyme CPT1A (carnitine palmitoyltransferase 1 isoform A). Finally, we demonstrated that ACSL4 knockdown significantly reduced metastatic lung nodes in vivo. In conclusion, we reveal a novel positive regulatory loop between ZEB2 and ACSL4, which promotes LDs storage to meet the energy needs of breast cancer metastasis, and identify the ZEB2-ACSL4 signaling axis as an attractive therapeutic target for overcoming breast cancer metastasis.

The adaptive antioxidant response during fasting-induced muscle atrophy is oppositely regulated by ZEB1 and ZEB2.

Reactive oxygen species (ROS) serve important homeostatic functions but must be constantly neutralized by an adaptive antioxidant response to prevent supraphysiological levels of ROS from causing oxidative damage to cellular components. Here, we report that the cellular plasticity transcription factors ZEB1 and ZEB2 modulate in opposing directions the adaptive antioxidant response to fasting in skeletal muscle. Using transgenic mice in which Zeb1 or Zeb2 were specifically deleted in skeletal myofibers, we show that in fasted mice, the deletion of Zeb1, but not Zeb2, increased ROS production and that the adaptive antioxidant response to fasting essentially requires ZEB1 and is inhibited by ZEB2. ZEB1 expression increased in fasted muscles and protected them from atrophy; conversely, ZEB2 expression in muscles decreased during fasting and exacerbated muscle atrophy. In fasted muscles, ZEB1 reduces mitochondrial damage and increases mitochondrial respiratory activity; meanwhile, ZEB2 did the opposite. Treatment of fasting mice with Zeb1-deficient myofibers with the antioxidant triterpenoid 1[2-cyano-3,12-dioxool-eana-1,9(11)-dien-28-oyl] trifluoro-ethylamide (CDDO-TFEA) completely reversed their altered phenotype to that observed in fasted control mice. These results set ZEB factors as potential therapeutic targets to modulate the adaptive antioxidant response in physiopathological conditions and diseases caused by redox imbalance.

Lnc NR2F1-AS1 Promotes Breast Cancer Metastasis by Targeting the MiR-25-3p/ZEB2 Axis.

Background: Long noncoding RNAs (lncRNAs) substantially affect tumor metastasis and are aberrantly expressed in various cancers. However, its role in breast cancer (BC) remains unclear. Methods: A microarray assay of differentially expressed lncRNAs in epithelial-mesenchymal transition (EMT) and non-EMT cells was performed. The prognostic value of lnc NR2F1-AS1 expression in patients with BC was analyzed using The Cancer Genome Atlas database. Lnc NR2F1-AS1 expression levels in different BC cell lines were assessed using quantitative real-time PCR. The role of lnc NR2F1-AS1 in BC cell metastasis was investigated in vitro and in vivo. Dual luciferase reporter assay and RNA immunoprecipitation were performed to investigate the relationship between lnc NR2F1-AS1, miR-25-3p, and ZEB2. Results: High levels of lnc NR2F1-AS1 were observed in BC cells undergoing EMT and were closely correlated with adverse prognosis in patients with BC. Lnc NR2F1-AS1 knockdown significantly inhibited BC cell migration, invasiveness in vitro, and metastasis in vivo. Mechanistically, lnc NR2F1-AS1 competitively binds to miR-25-3p to impede ZEB2 degradation, a positive EMT transcription factor in BC. Conclusions: Our study revealed a novel lnc NR2F1-AS1/miR-25-3p/ZEB2 axis in BC metastasis and that lnc NR2F1-AS1 may serve as a potential therapeutic target for BC metastasis.

[ZEB2 Regulates the Migration and Invasion of PANC-1 Pancreatic Cancer Cells: An Experimental Study].

Objective: To investigate the effects and mechanisms of zinc finger E-box binding homeobox transcription factor-2 ( ZEB2) on the proliferation, colony formation, migration, and invasion abilities and the epithelial-mesenchymal transition (EMT) of PANC-1 cells, a human pancreatic cancer cell line. Methods: Data on the expression of ZEB2 in pancreatic cancer tissues and paracancerous tissues from The Cancer Genome Atlas (TCGA) database were analyzed. PANC-1 pancreatic cancer cells were divided into si-NC group, si- ZEB2 group, pcDNA3.1 group, and pcDNA3.1- ZEB2 group. qRT-PCR and Western blot were conducted to confirm the effectiveness of ZEB2 knockdown or overexpression. CCK-8, colony formation, wound healing, and Transwell assays were conducted to examine the effects of ZEB2 on the proliferation, colony formation, migration, and invasion of PANC-1 cells. qRT-PCR and immunofluorescence assays were performed to examine the expression of E-cadherin and vimentin, the EMT markers, in the cells. Prediction of proteins interacting with ZEB2 was made through the STRING database. Results: TCGA database analysis showed that the expression level of ZEB2 in pancreatic cancer tissues was significantly higher than that in adjacent tissues ( P<0.05). Compared with those of cells in the control group, the proliferation, colony formation, migration, and invasion of cells in the si- ZEB2 group were decreased ( P<0.05). Compared with those of cells in the pcDNA3.1 group, the proliferation, colony formation, migration and invasion of cells in the pcDNA3.1- ZEB2 group were increased (all P<0.05). According to the results of qRT-PCR and immunofluorescence assays, compared with those of the si-NC group, the expression of E-cadherin mRNA, an epithelial marker, in the si- ZEB2 group increased, while the expression of vimentin mRNA, an mesenchymal marker, and the protein decreased. Compared with those of the pcDNA3.1 group, the expression of E-cadherin mRNA in the PANC-1 cells of the pcDNA3.1- ZEB2 group decreased, while the expression of vimentin mRNA and the protein increased (all P<0.05). Analysis with the STRING database predicted that 10 proteins had close interaction with ZEB2. Conclusion: Overexpression of ZEB2 promotes the migration, invasion, and the EMT process of PANC-1 pancreatic cancer cells.

Circular RNA circTNIK promotes tumor progression and metastasis in gastric cancer by regulating ZEB2.

BACKGROUND AND AIM: Tumor progression and distant metastasis are the main causes of deaths in gastric cancer. Growing evidence revealed that circular RNAs (circRNAs) play critical role in the pathology of malignant disease, the role of circRNAs in gastric cancer progression and metastasis is still unknown. METHODS: Differentially expressed circRNAs was identified by circRNA microarray and validated by quantitative reverse transcription polymerase reaction. The biological function of circTNIK was evaluated by in vitro and in vivo experiments after ectopic expression or siRNA mediated knockdown of circTNIK. The interaction between circTNIK and miR-138-5p was determined by luciferase activity assay, RNA immunoprecipitation, and fluorescence in situ hybridization assays. RESULTS: circTNIK rather than linear TINK mRNA was significantly upregulated in gastric cancer tissues, cell lines compared with normal controls. Higher circTNIK expression was correlated with aggressive tumor phenotypes and poor overall survival in gastric cancer patients. Ectopic circTNIK expression promoted cell proliferation, invasion, tumorigenesis, and metastasis in gastric cancer cells whereas knockdown of circTNIK inhibited cell proliferation, invasion, tumorigenesis, and metastasis in gastric cancer cells. Importantly, circTNIK functions as a molecular sponge for miR-138-5p to regulate the expression of ZEB2. CONCLUSIONS: Overall, our study demonstrates how circTNIK regulates gastric cancer progression and metastasis by sponging miR-138-5p to modulate the expression of ZEB2. CircTNIK might be used as a prognostic biomarker in gastric cancer patients.

miR-147a targets ZEB2 to regulate ox-LDL-induced monocyte adherence to HUVECs, atherosclerotic plaque formation, and stability in atherosclerosis.

The mechanisms underlying atherosclerosis (AS) that seriously affect human health, such as those involved in endothelial cell injury and monocyte/macrophage aggregation and infiltration, have not been fully elucidated. To investigate these processes, we established human umbilical vein endothelial cells (HUVECs) injured by oxidized low-density lipoprotein (ox-LDL) to mimic AS in vitro. Apolipoprotein E knockout (ApoE-/-) C57BL/6 mice were fed with a high-cholesterol diet to establish an AS model in vivo. We detected HUVEC apoptosis, and apoptosis-related proteins by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide and lactate dehydrogenase, flow cytometry, and Western blot assays, respectively, and we observed monocytes (THP-1 cells) adhering to HUVECs. Furthermore, miR-147a and its downstream target gene ZEB2 (zinc finger E-box binding homeobox 2) were predicted by bioinformatics analysis to be involved in AS, and their correlation was confirmed by several experiments. We determined the localization of miR-147a and ZEB2 within macrophages of AS mice by in situ hybridization and immunofluorescence. Atherosclerotic plaques in whole aortas were detected by histology observation. miR-147a attenuated adherence of monocytes to HUVECs and the upregulation of mononuclear chemotactic adhesion receptors in THP-1 cells induced by ox-LDL-injured HUVEC supernatants through directly downregulating ZEB2 levels. Moreover, miR-147a influenced M1/M2 macrophage polarization from THP-1 cells and the roles of their supernatants (THP-1 cells) in HUVEC apoptosis. miR-147a targeted ZEB2 to impact lipid accumulation and atherosclerotic plaque formation through regulating M1/M2 polarization and macrophage adhesion in AS mice. In summary, miR-147a attenuates ox-LDL-induced adherence of monocytes to HUVECs and modulates atherosclerotic plaque formation and stability through targeting ZEB2 during AS.

Zeb2 DNA-Binding Sites in Neuroprogenitor Cells Reveal Autoregulation and Affirm Neurodevelopmental Defects, Including in Mowat-Wilson Syndrome.

Functional perturbation and action mechanism studies have shown that the transcription factor Zeb2 controls cell fate decisions, differentiation, and/or maturation in multiple cell lineages in embryos and after birth. In cultured embryonic stem cells (ESCs), Zeb2's mRNA/protein upregulation is necessary for the exit from primed pluripotency and for entering general and neural differentiation. We edited mouse ESCs to produce Flag-V5 epitope-tagged Zeb2 protein from one endogenous allele. Using chromatin immunoprecipitation coupled with sequencing (ChIP-seq), we mapped 2432 DNA-binding sites for this tagged Zeb2 in ESC-derived neuroprogenitor cells (NPCs). A new, major binding site maps promoter-proximal to Zeb2 itself. The homozygous deletion of this site demonstrates that autoregulation of Zeb2 is necessary to elicit the appropriate Zeb2-dependent effects in ESC-to-NPC differentiation. We have also cross-referenced all the mapped Zeb2 binding sites with previously obtained transcriptome data from Zeb2 perturbations in ESC-derived NPCs, GABAergic interneurons from the ventral forebrain of mouse embryos, and stem/progenitor cells from the post-natal ventricular-subventricular zone (V-SVZ) in mouse forebrain, respectively. Despite the different characteristics of each of these neurogenic systems, we found interesting target gene overlaps. In addition, our study also contributes to explaining developmental disorders, including Mowat-Wilson syndrome caused by ZEB2 deficiency, and also other monogenic syndromes.

Umbilical cord mesenchymal stem cell-derived exosomes reverse endometrial fibrosis by the miR-145-5p/ZEB2 axis in intrauterine adhesions.

RESEARCH QUESTION: What is the specific mechanism of umbilical cord mesenchymal stem cell-derived exosomes (UCMSC-exos) in regulating endometrial repair and regeneration? DESIGN: In this study, UCMSC-exos were harvested by differential ultracentrifugation from umbilical cord mesenchymal stem cell culture supernatant and identified with western blotting, transmission electron microscopy and nanoparticle tracking analysis. Transforming growth factor-ß1 (TGFß1) at different concentrations was used to construct the intrauterine adhesions cell model. The fibrotic markers were assessed by quantitative reverse transcription-polymerase chain reaction and western blotting. The effects of miR-145-5p over-expression on endometrial fibrosis were assessed. Dual luciferase assay was performed to verify the relationship between miR-145-5p and zinc finger E-box binding homeobox 2 (ZEB2). RESULTS: The isolated UCMSC-exos had a typical cup-shaped morphology, expressed the specific exosomal markers Alix, CD63 and TSG101, and were approximately 50-150 nm in diameter. TGFß1 at 10 ng/ml significantly promoted endometrial fibrosis, which was reversed by 20 µg/ml UCMSC-exos. Exosomal miR-145-5p ameliorated TGFß1-induced endometrial fibrosis. ZEB2 was inversely regulated by exosomal miR-145-5p as a direct target. CONCLUSIONS: UCMSC-exos might reverse endometrial stromal cell fibrosis by regulating the miR-145-5p/ZEB2 axis, representing a potential novel strategy to promote endometrial repair.

The Long Noncoding RNA ZEB2-AS1 Contributes to Proliferation and Epithelial-to-Mesenchymal Transition of Osteosarcoma.

Background: Long non-coding RNA Zinc finger E-box binding homeobox 2 (ZEB2) antisense RNA 1 (ZEB2-AS1) has been shown to promote tumor progression. However, the clinical significance and fundamental function role of ZEB2-AS1 in osteosarcoma (OS) has been poorly understood. Methods: The expression of ZEB2-AS1 was determined in tumor tissues and matched normal tissues from 67 OS patients using quantitative reverse transcriptase PCR analysis. Clinical value of ZEB2-AS1 was evaluated by χ2 test and Kaplan-Meier method. Cell proliferation was analyzed using CCK-8 assay, colony formation. Cell apoptosis status was determined by caspase-3 activity assay. Cell migration, invasion and epithelial-mesenchymal transition (EMT) were investigated by scratch wound healing, transwell invasion assays and Western blotting. Results: Clinical association analysis revealed that high ZEB2-AS1 expression correlated with tumor size, distant metastasis and poor prognosis of OS patients. Moreover, ZEB2-AS1 expression was identified as an independent prognostic factor for OS patients. Loss-of-function assays demonstrated that ZEB2-AS1 knockdown suppressed the proliferation and induced apoptosis in OS cells. In addition, ZEB2-AS1 knockdown inhibited cell migration, invasion, EMT of OS cells in vitro. Conclusions: Taken together, our data demonstrate that ZEB2-AS1 serves a putative oncogenic role and associates with unfavorable prognosis in OS.

Post-Translational Modification of ZEB Family Members in Cancer Progression.

Post-translational modification (PTM), the essential regulatory mechanisms of proteins, play essential roles in physiological and pathological processes. In addition, PTM functions in tumour development and progression. Zinc finger E-box binding homeobox (ZEB) family homeodomain transcription factors, such as ZEB1 and ZEB2, play a pivotal role in tumour progression and metastasis by induction epithelial-mesenchymal transition (EMT), with activation of stem cell traits, immune evasion and epigenetic reprogramming. However, the relationship between ZEB family members' post-translational modification (PTM) and tumourigenesis remains largely unknown. Therefore, we focussed on the PTM of ZEBs and potential therapeutic approaches in cancer progression. This review provides an overview of the diverse functions of ZEBs in cancer and the mechanisms and therapeutic implications that target ZEB family members' PTMs.

The correlation of long non-coding RNAs IFNG-AS1 and ZEB2-AS1 with IFN-γ and ZEB-2 expression in PBMCs and clinical features of patients with coronary artery disease.

BACKGROUND: Aberrant expression of long non-coding RNAs (lncRNAs) can contribute to the pathogenesis of coronary artery disease (CAD). In this study, we aimed to evaluate the expression of lncRNA interferon γ-antisense 1 (IFNG-AS1), zinc finger E-box binding homeobox 2 antisense RNA 1 (ZEB2-AS1), and their direct target genes (IFN-γ and ZEB2, respectively) in peripheral blood mononuclear cell (PBMC) from CAD and healthy individuals. METHODS AND RESULTS: We recruited 40 CAD patients and 40 healthy individuals. After doing some bioinformatics analyses, the expressions of IFNG-AS1/ ZEB2-AS1 lncRNAs and IFN-γ/ ZEB2 in PBMCs were measured using quantitative real-time PCR. The possible correlation between the putative lncRNAs and disease severity was also assessed. Receiver operating characteristic (ROC) curve analysis was used to evaluate the predictive role of lncRNAs as diagnostic biomarkers in CAD patients. The expressions of IFNG-AS1 lncRNA as well as IFN-γ and ZEB2 genes were significantly reduced in CAD patients compared to healthy subjects. In contrast, the expression of ZEB2-AS1 was up-regulated in these patients. Linear regression analysis unveiled that there is a positive correlation between the expression of IFNG-AS1 and IFN-γ, also similarly, ZEB2-AS1 and ZEB2 in PBMCs of subjects. Moreover, the expression of IFNG-AS1 and ZEB2-AS1 correlated with the Gensini score. The area under the ROC curves ranged from 0.633-0.742 for ZEB2-AS1/ZEB2 and IFNG-AS1/IFN-γ, respectively. CONCLUSIONS: Our results indicated that the dysregulation of IFNG-AS1/IFN-γ and ZEB2-AS1/ZEB2 in PBMCs of CAD patients may be involved in CAD pathogenesis.