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BACKGROUND Epithelial-mesenchymal transition (EMT) is an essential progress for tumor cell invasion to both epithelial and non-epithelial cancers, and zinc finger E-box-binding homeobox 1/2 (ZEB1/2) is a well-known promoter of EMT. In glioma cell lines, both ZEB1 and ZEB2 have been demonstrated to facilitate cancer cell proliferation and invasion with experiments in vitro. However, the clinical significance of ZEB1 and ZEB2 in glioblastoma (GBM) is still controversial. MATERIAL AND METHODS We detected the expression of ZEB1 and ZEB2 in 91 cases of GBM with immunohistochemistry and investigated the correlation between clinicopathological factors and ZEB family expression with Fisher test. By univariate analysis with Kaplan-Meier test, we explored the prognostic significance of ZEB1/2 expression and the clinicopathological factors in GBM. By multivariate analysis with the Cox regression model, we identified the independent prognostic factors in GBM. RESULTS The percentages of ZEB1 high expression and ZEB2 high expression were 31.9% (29/91) and 41.9% (36/91), respectively. High expression of ZEB2 was significantly associated with lower survival rate of GBM patients (P=0.001). ZEB2, lower KPS score (P=0.004), gross total resection (P<0.001) and higher Ki67 percentage (P=0.001) were notably correlated to worse prognosis of GBM. With multivariate analysis, high expression of ZEB2 was demonstrated to be an independent prognostic factor indicating unfavorable prognosis of GBM (P=0.001, HR=3.86, and 95%CI=1.61-9.23). CONCLUSIONS High expression of ZEB2 is an independent prognostic factor predicting unfavorable prognosis of GBM, indicating that ZEB2 or its downstream proteins may be potential drug targets of GBM therapy.
Whereas cardiomyocytes (CMs) in the fetal heart divide, postnatal CMs fail to undergo karyokinesis and/or cytokinesis and therefore become polyploid or binucleated, a key process in terminal CM differentiation. This switch from a diploid proliferative CM to a terminally differentiated polyploid CM remains an enigma and seems an obstacle for heart regeneration. Here, we set out to identify the transcriptional landscape of CMs around birth using single cell RNA sequencing (scRNA-seq) to predict transcription factors (TFs) involved in CM proliferation and terminal differentiation. To this end, we established an approach combining fluorescence activated cell sorting (FACS) with scRNA-seq of fixed CMs from developing (E16.5, P1, and P5) mouse hearts, and generated high-resolution single-cell transcriptomic maps of in vivo diploid and tetraploid CMs, increasing the CM resolution. We identified TF-networks regulating the G2/M phases of developing CMs around birth. ZEB1 (Zinc Finger E-Box Binding Homeobox 1), a hereto unknown TF in CM cell cycling, was found to regulate the highest number of cell cycle genes in cycling CMs at E16.5 but was downregulated around birth. CM ZEB1-knockdown reduced proliferation of E16.5 CMs, while ZEB1 overexpression at P0 after birth resulted in CM endoreplication. These data thus provide a ploidy stratified transcriptomic map of developing CMs and bring new insight to CM proliferation and endoreplication identifying ZEB1 as a key player in these processes.
Osteosarcoma (OS) is the most common bone cancer worldwide. There is evidence that microRNA-409 (miR-409-3p) is involved in tumorigenesis and cancer progression, however, its possible role in OS requires clarification. In the present study, we evaluated the expression level, clinical significance, and mode of action of miR-409-3p in OS. The miR-409-3p levels were diminished in the OS cells and tissues compared with associated adjacent non-tumor tissues and a non-cancer osteoplastic cell line. Low miR-409-3p expression levels were associated with clinical stage and distant metastasis in patients with OS. Resumption of miR-409-3p expression attenuated OS cell proliferation and invasion. Additionally, based on informatics analyses, we predicted that zinc-finger E-box-binding homeobox-1 (ZEB1) is a possible target of miR-409-3p. This hypothesis was confirmed using luciferase reporter assays, reverse transcription-quantitative real-time polymerase chain reaction, and Western blot analyses. The findings of the current study indicated that ZEB1 was up-regulated in the OS tissues and cell lines, and that this up-regulation was inversely proportional to miR-409-3p expression levels. Furthermore, down-regulation of ZEB1 decreased OS cell invasion and proliferation, illustrating that the tumor suppressive role of miR-409-3p in OS cells may be exerted via negative regulation of ZEB1. Taken together, our observations highlight the potential role of miR-409-3p as a tumor suppressor in OS partially through down-regulation of ZEB1 and suggest that miR-409-3p has potential applications in OS treatment.
As documented in numerous studies, microRNAs (miRNAs) play key roles in various biological processes associated with melanoma occurrence and development. In this study, we found that miRNA-342 (miR-342) was significantly downregulated in melanoma tissues and cell lines. Additionally, the ectopic expression of miR-342 prohibited the cell proliferation and invasion of melanoma. Moreover, zinc-finger E-box-binding homeobox 1 (ZEB1) was identified as a direct target gene of miR-342 in melanoma. Similar with the results induced by miR-342 overexpression, ZEB1 knockdown attenuated cell proliferation and invasion in melanoma. Furthermore, the restoration of ZEB1 expression reversed the suppressive effects of miR-342 on the proliferation and invasion of melanoma cells. These findings suggest that miR-342 may play tumor-suppressing roles in melanoma, at least partially, by directly inhibiting ZEB1 expression. Therefore, miR-342 may be developed as a potential candidate for the treatment of patients with this aggressive type of cancer.
Human microRNA (miR)-141 is a member of the miR‑200 family, which has been reported to be downregulated in gastric cancer, and involved in the proliferation of gastric cancer cells. However, little is currently known regarding its role in the migration of gastric cancer. The present study investigated the function of miR‑141 in gastric cancer cell migration, and evaluated the contribution of zinc finger E‑box‑binding homeobox 1 and 2 (ZEB1/2) in miR‑141 mediated migration of gastric cancer cells. The expression levels of miR‑141 and its potential ZEB1/2 targets were examined by quantitative polymerase chain reaction (qPCR) and western blotting, respectively. The migration of SGC‑7901 and HGC‑27 gastric cancer cells, which had been transfected with an miRNA precursor, was examined by cell migration and wound healing assays. A luciferase activity assay was used to validate whether ZEB1/2 was a direct target of miR‑141. The results demonstrated that overexpression of miR‑141 markedly inhibited the migration of gastric cancer cells in vitro. Forced overexpression of miR‑141 significantly reduced the luciferase activity of the 3'‑untranslated region of ZEB2 in gastric cancer cells. Furthermore, the mRNA and protein expression levels of ZEB2 were reduced in cells overexpressing miR‑141, whereas the protein expression levels of E‑cadherin were increased. In gastric tumor samples the expression levels of ZEB2 were inversely correlated with the expression of miR‑141. These results suggest that miR‑141 may be involved in the inhibition of gastric cancer cell migration, and that ZEB2 is a target gene of miR-141.
A growing body of evidence indicates that aberrant activation of epithelial-to-mesenchymal transition (EMT) plays a key role in tumor cell invasion and metastasis. Zinc finger E-box-binding homeobox factor 1 (ZEB1), as a crucial mediator of EMT, contributes to the malignant progression of various epithelial tumors. To determine whether ZEB1 is involved in the progression of ovarian cancer, we immunohistochemically evaluated the expression of ZEB1 in 238 cases of epithelial ovarian cancer (EOC) and analyzed its associations with clinicopathological parameters. Positive expression of ZEB1 was observed in 32.8% (78/238) of EOCs and it was found to be significantly associated with advanced tumor stage (P=0.001). The survival analysis indicated that the expression of ZEB1 was associated with a poor 5-year progression-free survival (PFS) (P=0.021). A similar tendency was also observed between the expression of ZEB1 and 5-year overall survival, although it did not reach statistical significance (P=0.118). Moreover, the multivariate analysis demonstrated that ZEB1 expression was an independent risk factor for 5-year PFS in ovarian cancer. Taken together, our data provide evidence that ZEB1 may play a crucial role in promoting aggressive ovarian carcinoma progression. Therefore, ZEB1 may serve as an effectively predictive marker and a potential target for therapeutic intervention in EOC.
Following cardiac injury, fibroblasts are activated and are termed as myofibroblasts, and these cells are key players in extracellular matrix (ECM) remodeling and fibrosis, itself a primary contributor to heart failure. Nutraceuticals have been shown to blunt cardiac fibrosis in both in-vitro and in-vivo studies. However, nutraceuticals have had conflicting results in clinical trials, and there are no effective therapies currently available to specifically target cardiac fibrosis. We have previously shown that expression of the zinc finger E box-binding homeobox 2 (Zeb2) transcription factor increases as fibroblasts are activated. We now show that Zeb2 plays a critical role in fibroblast activation. Zeb2 overexpression in primary rat cardiac fibroblasts is associated with significantly increased expression of embryonic smooth muscle myosin heavy chain (SMemb), ED-A fibronectin and α-smooth muscle actin (α-SMA). We found that Zeb2 was highly expressed in activated myofibroblast nuclei but not in the nuclei of inactive fibroblasts. Moreover, ectopic Zeb2 expression in myofibroblasts resulted in a significantly less migratory phenotype with elevated contractility, which are characteristics of mature myofibroblasts. Knockdown of Zeb2 with siRNA in primary myofibroblasts did not alter the expression of myofibroblast markers, which may indicate that Zeb2 is functionally redundant with other profibrotic transcription factors. These findings add to our understanding of the contribution of Zeb2 to the mechanisms controlling cardiac fibroblast activation.
Zinc finger E‑box binding homeobox 2 (ZEB2) is a member of the Zfh1 family of two‑handed zinc finger/homeodomain proteins. To date, the role of ZEB2 in human laryngeal carcinoma has not been clearly defined. In the present study, the level of ZEB2 expression in laryngeal squamous cell carcinoma (LSCC) tissues and adjacent normal tissues was evaluated using reverse transcription‑quantitative polymerase chain reaction. The effects of ZEB2 on the growth, migration, invasion, cell cycle distribution and apoptosis of laryngeal cancer cells were also explored using MTT, Transwell and flow cytometry assays. It was identified that ZEB2 was upregulated in LSCC tissues compared with normal tissues. Silencing of ZEB2 inhibited the viability, migration and invasion of LSCC cells. It was also observed that ZEB2 silencing induced cell cycle arrest and apoptosis in LSCC cells. Furthermore, ZEB2 silencing inhibited the process of epithelial‑mesenchymal transition. Overall, the results indicated that ZEB2 promotes the progression of LSCC and that it may be a potential target for the treatment of this type of cancer.
Preeclampsia (PE) is a serious pregnancy syndrome, which is mainly caused by attenuated trophoblast proliferation and invasion. It has been verified that E2F transcription factor 1 (E2F1) is lowly expressed in PE. It is identified that E2F1 binds to the promoter region of Zinc Finger E-Box Binding Homeobox 1 (ZEB1) in JASPAR datasets. ZEB1 is also a transforming factor that can facilitate EMT. The present work was designed to investigate the biological functions of E2F1 and ZEB1 on the proliferation, invasiveness and EMT of trophoblast cells and further explore the molecular mechanism underlying the participation of E2F1 and ZEB1 in the behaviors of trophoblast cells. Results revealed that upregulation of E2F1 reinforced the proliferation, invasiveness and EMT of trophoblast cells and downregulation of E2F1 exhibited opposite effects on trophoblast proliferation, invasion and EMT. It was confirmed that E2F1 bound to the promoter region of ZEB1 and two binding sites (E1 and E2) in ZEB1 promoter region to E2F1 was identified by CHIP assays. Luciferase reporter assay further verified the binding relationship between E2F1 and ZEB1. Overexpression of ZEB1 rescued the suppressing effects of E2F1 knockdown on proliferation, invasiveness and EMT of trophoblast cells. To conclude, E2F1 could promote trophoblast proliferation and invasion and strengthen EMT of trophoblast cells by enhancing ZEB1 expression.
As a common hypertensive complication of pregnancy, preeclampsia (PE) remains one of the leading causes of maternal and fetal with high morbidity and mortality worldwide. Much research has identified the vital functions of insulin-like growth factor 1 (IGF-1) in PE treatment. However, the combined roles and molecular mechanism of IGF-1 and microRNAs (miRNAs) underlying PE remain unclear. Therefore, we first measured the expression of IGF-1, zinc finger E-box binding homeobox 1 (ZEB1) and microRNA-183 (miR-183) expression in the placenta tissues of patients with PE by Western blot analysis and RT-qPCR. Interactions among IGF-1, ZEB1 and miR-183 were assessed by Western blot analysis, ChIP-PCR and dual-luciferase reporter gene assay. The effect of IGF-1 on the biological characteristics of trophoblast cells was investigated by CCK-8, colony formation assay and in vitro angiogenesis experiments after cells were transfected with si-IGF-1. Finally, a mouse eclampsia model induced by knockdown of IGF-1 was established to confirm the in vitro effect of IGF-1 on PE. We found that IGF-1, ZEB1 and miR-183 were highly expressed in the placental tissues of patients with PE. The knockdown of IGF-1 resulted in reduced proliferation and invasion of trophoblast cells and was accompanied by inhibited angiogenesis. ZEB1 was positively regulated by IGF-1 via ERK/MAPK pathway, which in turn inhibited miR-153 expression by binding to the miR-183 promoter. The in vitro experiments further confirmed that IGF-1 knockdown could induce PE. To sum up, IGF-1 knockdown elevated expression of miR-183 by downregulating ZEB1, thereby promoting deterioration of PE.
Lung cancer is a devastating cancer with high morbidity and mortality. Ubiquitin‑specific protease (USP) is a type of deubiquitinating enzyme (DUB) that has been implicated in numerous cancers, including colorectal, myeloma and breast. In the present study, the expression of USP51 was determined in the lung cancer cell line A549 and cisplatin (also known as DDP)‑resistant lung cancer strain A549/DDP. The expression of zinc‑finger E‑box binding homeobox 1 (ZEB1), a transcriptional repressor, was also examined. The effects of USP51 knockdown or overexpression on proliferation and apoptosis, as well as the impact of ZEB1 overexpression and USP51 interference on apoptosis and ubiquitination were then assessed. Notably, increased expression of USP51 and ZEB1 in A549/DDP cells was observed, and treatment with DDP significantly inhibited proliferation in A549/DDP cells. In addition, knockdown of USP51 in A549/DDP cells significantly induced apoptosis, decreased ZEB1 expression and increased cleaved poly ADP‑ribose polymerase 1 (PARP1) and cleaved caspase‑3 levels. Consistently, USP51 overexpression in A549 cells displayed the opposite effects and potently attenuated DDP‑induced apoptosis. Notably, overexpression of ZEB1 in A549/DDP cells potently attenuated the effects of USP51 knockdown on apoptosis, and co‑IP experiments further demonstrated interaction between USP51 and ZEB. Lastly, knockdown of USP51 promoted ZEB1 ubiquitination, leading to ZEB1 degradation. Collectively, the present findings demonstrated that USP51 inhibition attenuated DDP resistance in A549/DDP cells via ubiquitin‑mediated degradation of ZEB1. Hence, targeting USP51 may serve as a novel therapeutic target for DDP resistance in lung cancer.
A large number of microRNAs (miRNAs) are aberrantly expressed in cervical cancer and play crucial roles in the onset and progression of cervical cancer by acting as either an oncogene or a tumor suppressor. Therefore, investigation of the expression, biological roles, and underlying mechanisms of miRNAs in cervical cancer might provide valuable therapeutic targets in the treatment for patients with this disease. In this study, miRNA-377 (miR-377) was downregulated in cervical cancer tissues and cell lines. Decreased miR-377 expression was strongly correlated with the International Federation of Gynecology and Obstetrics (FIGO) stage, lymph node metastasis, and distant metastasis in patients with cervical cancer. Enhanced expression of miR-377 prohibited cell proliferation and invasion in cervical cancer. Bioinformatics analysis predicted that zinc finger E-box-binding homeobox 2 (ZEB2) was a potential target of miR-377. Subsequent experiments confirmed that ZEB2 is a direct target gene of miR-377 in cervical cancer. In addition, ZEB2 was overexpressed in cervical cancer tissues and was inversely related with miR-377 levels. Furthermore, the suppressive effects of miR-377 on cervical cancer proliferation and invasion were rescued by restored ZEB2 expression. Overall, our findings indicated that miR-377 decreases proliferation and invasion of cervical cancer cells by directly targeting ZEB2 and provides novel evidence of miR-377 as a novel therapeutic strategy for the therapy of patients with this malignancy.
Zinc-finger E-box-binding homeobox 1 (ZEB1) is an important regulator of epithelial-mesenchymal transition (EMT) and is involved in the maintenance of cancer stem cells (CSCs) via miR-200c and BMI1 pathway. Recent studies revealed that ZEB1 contributes to the EMT-mediated acquired resistance to gefitinib in EGFR-mutant non-small cell lung cancer (NSCLC). However, the precise role of ZEB1 in the maintenance of lung CSCs that lead to acquired resistance to gefitinib remains unclear.
Glioma is one of the important diseases that threaten human survival in today's society. WD repeat domain 5 (WDR5) belongs to the components of the lysine methyltransferase complex. WDR5 is involved in gene transcription regulation, cell senescence, cancer and other biological events through methylation modification. However, its expression and function in glioma are still unclear.
Accumulating studies have suggested that microRNAs (miRNAs) play vital roles in the pathogenesis of osteoarthritis (OA). Nevertheless, the specific function of miR-128-3p in OA remains unknown. In this study, we demonstrated that miR-128-3p was decreased and ZEB1 was increased in OA. Additionally, miR-128-3p expression was negatively correlated with ZEB1. miR-128-3p overexpression or ZEB1 silencing attenuated extracellular matrix degradation and cell apoptosis, and increased the proliferation of IL-1β-activated CHON-001 cells. Furthermore, ZEB1 was directly targeted by miR-128-3p. In addition, ZEB1 upregulation restored the effects of miR-128-3p overexpression on OA progression. Overall, our findings suggested that miR-128-3p might regulate the development of OA via targeting ZEB1.
Ischemia injury can cause cell death or impairment of neuron and astrocytes, and thus induce loss of nerve function. central nervous systems injury induces an aberrant activation of astrocytes called astrogliosis. Pyroptosis, which is a kind of programmed cell death, was proved play an important role in ischemia injury. Zinc Finger E-Box Binding Homeobox 2 (ZEB2) promoted neuron astrogliosis, which play a protected role in neuron regeneration. However, its precise mechanism remains unclear. This study investigated the mechanism of ZEB2 on astrogliosis and neuron regeneration after cerebral ischemia reperfusion condition. To confirm our hypothesis, Neurons and astrocytes were isolated from fetal Sprague Dawley rats, in vivo Middle Cerebral Artery Occlusion/reperfusion (MCAO/R) rat model and in vitro oxygen-glucose deprivation/reperfusion (OGD/R)-treated astrocytes and neurocytes model were constructed. Our results showed that ZEB2 was expressed in nucleus of astrocyte and upregulated after OGD/R induction, ZEB2 promoted astrogliosis. Further upregulation of ZEB2 promoted the astrogliosis, which promoted neuron proliferation and regeneration by decreased pyroptosis. Moreover, this finding was further confirmed in vivo MCAO/R rat model. Overexpression of ZEB2 promoted astrogliosis, which decreased infarct volume and accumulated recovery of neurological function by alleviated pyroptosis. This finding revealed that ZEB2 was a regulator of the astrogliosis after ischemia/reperfusion injury, and then astrogliosis promoted neuron regeneration via decreased neuron pyroptosis. Therefore, ZEB2 may be a potential therapeutic target for ischemia/reperfusion injury.
The fifth most common cancer is allocated to bladder cancer (BC) worldwide. Understanding the molecular mechanisms of BC invasion and metastasis to identify target therapeutic strategies will improve disease survival. So the aim of this study was to measure expression rate of zinc finger E-box binding homeobox 1 (ZEB1) and transforming growth factor-beta2 (TGF-β2) mRNA in tissue samples of patients with BC and its healthy adjacent tissue samples and their association with muscle invasion, size and grade of the tumor.
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