Gene Summary

Gene:ZEB2; zinc finger E-box binding homeobox 2
Aliases: SIP1, SIP-1, ZFHX1B, HSPC082, SMADIP1
Summary:The protein encoded by this gene is a member of the Zfh1 family of 2-handed zinc finger/homeodomain proteins. It is located in the nucleus and functions as a DNA-binding transcriptional repressor that interacts with activated SMADs. Mutations in this gene are associated with Hirschsprung disease/Mowat-Wilson syndrome. Alternatively spliced transcript variants have been found for this gene.[provided by RefSeq, Jan 2010]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:zinc finger E-box-binding homeobox 2
Source:NCBIAccessed: 01 September, 2019


What does this gene/protein do?
Show (19)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Wnt Signaling Pathway
  • Epithelial-Mesenchymal Transition
  • Neoplasm Metastasis
  • Lung Cancer
  • Disease Progression
  • Long Noncoding RNA
  • Neoplasm Invasiveness
  • Virus Latency
  • siRNA
  • RT-PCR
  • Stromal Cells
  • RNA Interference
  • MicroRNAs
  • Gene Knockdown Techniques
  • Risk Factors
  • Stomach Cancer
  • Down-Regulation
  • Biomarkers, Tumor
  • Gene Expression Profiling
  • snail family transcription factors
  • Cancer Stem Cells
  • Signal Transduction
  • Neoplasm Proteins
  • Squamous Cell Carcinoma of Head and Neck
  • Apoptosis
  • Kidney Cancer
  • Cell Movement
  • Homeodomain Proteins
  • Up-Regulation
  • Transcription Factors
  • Cancer Gene Expression Regulation
  • Liver Cancer
  • DNA Methylation
  • Promoter Regions
  • Breast Cancer
  • Repressor Proteins
  • Chromosome 2
  • Xylenes
  • Western Blotting
  • Cell Proliferation
  • Cadherins
Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: ZEB2 (cancer-related)

Li Q, Ma L, Wu Z, et al.
Zinc finger E‑box binding homeobox 2 functions as an oncogene in human laryngeal squamous cell carcinoma.
Mol Med Rep. 2019; 19(6):4545-4552 [PubMed] Free Access to Full Article Related Publications
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.

Lingling J, Xiangao J, Guiqing H, et al.
SNHG20 knockdown suppresses proliferation, migration and invasion, and promotes apoptosis in non-small cell lung cancer through acting as a miR-154 sponge.
Biomed Pharmacother. 2019; 112:108648 [PubMed] Related Publications
Long noncoding RNAs (LncRNAs) play critical roles in the development and progression of cancers. However, little is known about the function and mechanism of lncRNAs in non-small cell lung cancer (NSCLC). In this study, we investigated the expression and functional role of lncRNA small nucleolar RNA host gene 20 (SNHG20) as well as its underlying mechanism in NSCLC. Our results showed that SNHG20 was significantly up-regulated in NSCLC tissues and cells. High SNHG20 expression was implicated with poor prognosis in NSCLC patients. Moreover, SNHG20 knockdown suppressed proliferation, migration and invasion, and induced apoptosis in NSCLC cells. Furthermore, SNHG20 could function as a competing endogenous RNA (ceRNA) to elevate ZEB2 and RUNX2 expression by sponging miR-154. Rescue assays revealed that miR-154 inhibition could reverse the inhibitory effect of SNHG20 silence on proliferation, migration and invasion in NSCLC cells. More importantly, SNHG20 knockdown suppressed tumor growth in NSCLC in vivo through suppressing miR-154 and elevating ZEB2 and RUNX2 expression. In summary, knockdown of lncRNA SNHG20 suppressed proliferation, migration and invasion, and promotes apoptosis through up-regulating ZEB2 and RUNX2 expression by sponging miR-154 in NSCLC, providing a promising therapeutic target for NSCLC patients.

Feng S, Cai X, Li Y, et al.
Tripartite motif-containing 14 (TRIM14) promotes epithelial-mesenchymal transition via ZEB2 in glioblastoma cells.
J Exp Clin Cancer Res. 2019; 38(1):57 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Several members of the tripartite motif-containing (TRIM) protein family have been reported to serve as vital regulators of tumorigenesis. Recent studies have demonstrated an oncogenic role of TRIM 14 in multiple human cancers; however, the importance of this protein in glioblastoma remains to be elucidated.
METHODS: The expression levels of TRIM14 were analyzed in a series of database and were examined in a variety of glioblastoma cell lines. Two independent TRIM14 shRNA were transfected into LN229 and U251 cells, and the effect of TRIM14 depletion was confirmed. Transwell assay and wound healing assay assay were carried out to assess the effect of TRIM14 depletion on glioblastoma cell invasion and migration. Western blotting was performed to screen the downstream gene of TRIM14. The stability analysis and Ubiquitylation assays and Orthotopic xenograft studies were also performed to investigate the role of TRIM14 and the relationship with downstream gene. Human glioblastoma tissues were obtained and immunohistochemical staining were carried out to confirm the clinical significance of TRIM14.
RESULTS: In this study, we showed that TRIM14 was upregulated in human glioblastoma specimens and cell lines, and correlated with glioblastoma progression and shorter patient survival times. Functional experiments showed that decreased TRIM14 expression reduced glioblastoma cell invasion and migration. Furthermore, we identified that zinc finger E-box binding homeobox 2 (ZEB2), a transcription factor involved in epithelial-mesenchymal transition, is a downstream target of TRIM14. Further investigation revealed that TRIM14 inactivation significantly facilitated ZEB2 ubiquitination and proteasomal degradation, which led to aggressive invasion and migration. Our findings provide insight into the specific biological role of TRIM14 in tumor invasion.
CONCLUSIONS: Our findings provide insight into the specific biological role of TRIM14 in tumor invasion, and suggest that targeting the TRIM14/ZEB2 axis might be a novel therapeutic approach for blocking glioblastoma.

Zhu D, Gu L, Li Z, et al.
MiR-138-5p suppresses lung adenocarcinoma cell epithelial-mesenchymal transition, proliferation and metastasis by targeting ZEB2.
Pathol Res Pract. 2019; 215(5):861-872 [PubMed] Related Publications
BACKGROUND: MiR-138-5p is regarded as a tumour suppressor in many cancers. Transforming growth factor beta (TGF-β) often acts as a tumor promotor at the late stages of human cancers. However, the function of miR-138-5p on lung adenocarcinoma cells induced by TGF-β remains to be further confirmed.
METHODS: RT-qPCR was used to detect the expression of human lung adenocarcinoma tissues, adjacent normal tissues, and relative cell lines. When the lung adenocarcinoma cells A549 and H1299 were transfected with negative control (NC), miR-138-5p mimics and miR-138-5p inhibitor by lipofectamine3000 and treated with or without TGF-β1, the lung adenocarcinoma cell function was detected by Immunofluorescence, Western blotting (WB), cell counting Kit-8 (CCK8), colony formation, EdU, Wound-healing and Transwell assays. The relation between miR-138-5p and zinc finger E-box-binding homeobox 2 (ZEB2) was detected by RT-qPCR, WB, and Luciferase reporter assays. When ZEB2 was knocked down, the lung adenocarcinoma cell function was detected by WB, CCK8 and Transwell assays.
RESULTS: The expression of miR-138-5p was decreased in lung adenocarcinoma tissues and cell lines. When treated with or without TGF-β1, overexpression of miR-138-5p suppressed EMT, proliferation and metastasis of A549 and H1299. ZEB2 was verified as the direct target of miR-138-5p. Downregulation of ZEB2 suppressed EMT, proliferation and metastasis of lung adenocarcinoma cell, which could be reversed by miR-138-5p inhibitor.
CONCLUSIONS: MiR-138-5p inhibits epithelial-mesenchymal transition, growth and metastasis of lung adenocarcinoma cells through targeting ZEB2.

Wang F, Zhu W, Yang R, et al.
LncRNA ZEB2-AS1 contributes to the tumorigenesis of gastric cancer via activating the Wnt/β-catenin pathway.
Mol Cell Biochem. 2019; 456(1-2):73-83 [PubMed] Related Publications
Studies have shown that long noncoding RNA Zinc finger E-box-binding homeobox 2 antisense RNA 1 (ZEB2-AS1) is involved in the progression of lung cancer, bladder cancer, and hepatocellular carcinoma. However, its role in the pathogenesis of gastric cancer remains unknown. The Wnt/β-catenin pathway contributes to the development of gastric cancer. ZEB2-AS1 expression was firstly detected in the gastric carcinoma tissue samples as well as in gastric cancer cells. Knockdown of ZEB2-AS1 was performed by ZEB2-AS1-shRNA, and the viability, migration, invasion, and apoptosis of gastric cancer cells were determined by CCK-8, scratch assay, transwell, and flow cytometry, respectively. Furthermore, levels of Ki-67, PCNA, VEGF, MMP9, epithelial-mesenchymal transition (EMT) markers (E-cadherin, Vimentin and ZEB2), cleaved caspase 3/8/9 and PARP, active β-catenin, c-Myc, cyclinD1, and AXIN2 were assayed by Western blot or real-time PCR. Additionally, the role and mechanism of ZEB2-AS1 were confirmed in a xenograft nude mouse model. We found ZEB2-AS1 expression was increased in gastric carcinoma samples, and it was correlated with tumor progression. Also, its expression was elevated in gastric cancer cells. Knockdown of ZEB2-AS1 reduced the proliferation, migration, invasion, and EMT, but increased the apoptosis of gastric carcinoma cells. Furthermore, ZEB2-AS1 downregulation remarkably suppressed the expression of Ki-67, PCNA, VEGF and MMP9, and the activation of Wnt/β-catenin signaling, whereas elevated the levels of cleaved caspase 3/8/9 and PARP in gastric cancer cells. And ZEB2 overexpression reversed the effects of ZEB2-AS1 downregulation on the proliferation, EMT and inactivation of Wnt/β-catenin signaling. Additionally, ZEB2-AS1 knockdown inhibited tumor growth, Ki-67 staining, and the expression of VEGF, MMP9, active β-catenin, c-Myc, cyclinD1, and AXIN2 in mice. In conclusion, ZEB2-AS1 promotes the tumorigenesis of gastric carcinoma that is related to the upregulation of ZEB2 and the activation of the Wnt/β-catenin pathway.

Ji H, Sang M, Liu F, et al.
miR-124 regulates EMT based on ZEB2 target to inhibit invasion and metastasis in triple-negative breast cancer.
Pathol Res Pract. 2019; 215(4):697-704 [PubMed] Related Publications
BACKGROUND: Triple-negative breast cancer (TNBC) is highly invasive and aggressive and lacks specific molecular targets to improve the prognosis. MicroRNAs (miRNAs) serve a role in promoting and suppressing tumors in various types of malignant cancer, including TNBC. However, the regulatory mechanism of miR-124 in TNBC has still remains unclear.
METHODS: Reverse transcription quantitative polymerase chain reaction (RT-qPCR) was used to detect the expression of miR-124. Cell viability was analyzed with CCK-8 assay. Cell colony formation ability was detected with colony formation assay. Cell invasion was measured with transwell assay. Dual luciferase reporter assay was conducted to verify whether ZEB2 is a target gene of miR-124. The mRNA and protein expression levels of ZEB2 and EMT markers were detected by quantitative real time PCR and western blot, respectively.
RESULTS: Our results showed that miR-124 was down-regulated in TNBC tissues and cells. Overexpression of miR-124 inhibited the proliferation, metastasis and epithelial-mesenchymal transition (EMT) of TNBC cells. Furthermore, ZEB2 3'UTR was considered to be a direct target of miR-124 with luciferase reporter assay. Rescue experiments confirmed that EMT was regulated by miR-124 via suppression of ZEB2.
CONCLUSION: miR-124 suppresses EMT and metastasis via ZEB2. Therefore, miR-124 may represent a potential therapeutic target for TNBC.

Zhang X, Xu X, Ge G, et al.
miR‑498 inhibits the growth and metastasis of liver cancer by targeting ZEB2.
Oncol Rep. 2019; 41(3):1638-1648 [PubMed] Free Access to Full Article Related Publications
MicroRNAs (miRNAs) play critical roles in the growth, metastasis and therapeutic resistance of liver cancer. Accumulating evidence suggests that miR‑498 is aberrantly expressed in several human malignancies. However, the role and underlying mechanism of miR‑498 in liver cancer remain unclear. In the present study, we investigated the potential roles and clinical value of miR‑498 in liver cancer. We found that the miR‑498 expression level was significantly lower in liver cancer patient tissues than that in healthy control tissues. The expression of miR‑498 was also decreased in liver cancer cell lines compared to that noted in a normal human normal liver cell line. miR‑498 overexpression markedly inhibited liver cancer cell proliferation, migration and invasion. miR‑498 overexpression induced cell cycle arrest and apoptosis while it suppressed epithelial‑mesenchymal transition (EMT) in liver cancer cells. Bioinformatic analysis and luciferase reporter assay further identified zinc finger E‑box binding homeobox 2 (ZEB2) as a novel target of miR‑498. Furthermore, ZEB2 knockdown recapitulated the inhibitory effects of miR‑498 overexpression in liver cancer cells. ZEB2 overexpression rescued the inhibition of liver cancer cell proliferation, migration, and invasion by miR‑498, indicating that ZEB2 acts as a downstream effector of miR‑498 in liver cancer cells. Thus, we demonstrated that miR‑498 suppresses the growth and metastasis of liver cancer cells, partly at least, by directly targeting ZEB2, suggesting that miR‑498 may serve as a potential biomarker for the diagnosis and therapy of liver cancer.

Gasinska A, Jaszczynski J, Adamczyk A, et al.
Biomarkers of epithelial-mesenchymal transition in localized, surgically treated clear-cell renal cell carcinoma.
Folia Histochem Cytobiol. 2018; 56(4):195-206 [PubMed] Related Publications
INTRODUCTION: It has been suggested that the metastatic potential of neoplastic cells can be predicted on the basis of their biological features, including expression of proteins involved in the epithelial to mesenchymal transition (EMT). Therefore, the purpose of this work was to (1) evaluate the expression of EMT markers: ZEB2, vimentin, N-cadherin, TWIST, PTEN, survivin, E-cadherin, Ki-67 and GLUT-1, (2) assess mutation status of two genes: PIK3CA and KRAS, and (3) investigate the potential relationships between the studied biomarkers and clinicopathological factors in clear-cell renal cell carcinoma (ccRCC).
MATERIAL AND METHODS: Tumor tissue samples (embedded in paraffin blocks) from 159 patients undergoing radical nephrectomy were analyzed. Proteins expression was evaluated immunohistochemically. DNA mutations were analyzed on DNA isolated from tumor tissue and amplified by real-time PCR detection using suitable fluorescent labeled TaqMan assays.
RESULTS: One hundred and seven men and 52 women of mean age of 63.1years were enrolled. Fifty four cancers at pTNM stage I-II and 98 at pTNM III-IV stage were diagnosed. There were 30 Fuhrman grade G1, 61 Fuhrman G2, 49 Fuhrman G3 and 19 Fuhrman G4 tumors. A negative correlation between ZEB2 (p = 0.047, r = -0.172) or E-cadherin expression (p = 0.027, r = -0.191) and TNM was observed. Positive association between grade and Ki-67 (p < 0.001), survivin (p < 0.001), vimentin (p < 0.001) immunoreactivity and negative association between TWIST expression (p = 0.029) or PTEN expression (p = 0.013) were found. Ki-67 expression was positively correlated with survivin (p < 0.001, r = 0.617), vimentin (p = 0.001, r = 0.251) and N-cadherin (p = 0,009, r = 0.207) immunoreactivity which can suggest tumor aggressiveness. TWIST was negatively correlated with E-cadherin (p < 0.001, r = -0.284), vimentin (p < 0.001, r = -0.297) and N-cadherin (p < 0.002, r = -0.241). ZEB2 was not associated with ccRCC grade but was negatively correlated with E-cadherin (p = 0.055, r= -0.153) and PTEN (p = 0.006). GLUT-1 expression was inversely linked to E-cadherin expression (p = 0.022, r= -0.182). Mutations in PIK3CA and KRAS genes were not found in any of the studied ccRCC tumors.
CONCLUSIONS: Low-grade tumors showed higher expression of ZEB2 and TWIST proteins than high-grade tumors, which can suggest that EMT in ccRCC begins at early stages of tumor development and, therefore, evaluation of these proteins, together with other biomarkers, may be useful for assessment of the tumor metastatic potential.

Matsunuma R, Chan DW, Kim BJ, et al.
DPYSL3 modulates mitosis, migration, and epithelial-to-mesenchymal transition in claudin-low breast cancer.
Proc Natl Acad Sci U S A. 2018; 115(51):E11978-E11987 [PubMed] Free Access to Full Article Related Publications
A Clinical Proteomic Tumor Analysis Consortium (CPTAC) proteogenomic analysis prioritized dihydropyrimidinase-like-3 (DPYSL3) as a multilevel (RNA/protein/phosphoprotein) expression outlier specific to the claudin-low (CLOW) subset of triple-negative breast cancers. A PubMed informatics tool indicated a paucity of data in the context of breast cancer, which further prioritized DPYSL3 for study. DPYSL3 knockdown in DPYSL3-positive ([Formula: see text]) CLOW cell lines demonstrated reduced proliferation, yet enhanced motility and increased expression of epithelial-to-mesenchymal transition (EMT) markers, suggesting that DPYSL3 is a multifunctional signaling modulator. Slower proliferation in DPYSL3-negative ([Formula: see text]) CLOW cells was associated with accumulation of multinucleated cells, indicating a mitotic defect that was associated with a collapse of the vimentin microfilament network and increased vimentin phosphorylation. DPYSL3 also suppressed the expression of EMT regulators SNAIL and TWIST and opposed p21 activated kinase 2 (PAK2)-dependent migration. However, these EMT regulators in turn induce DPYSL3 expression, suggesting that DPYSL3 participates in negative feedback on EMT. In conclusion, DPYSL3 expression identifies CLOW tumors that will be sensitive to approaches that promote vimentin phosphorylation during mitosis and inhibitors of PAK signaling during migration and EMT.

Li JF, Dai YT, Lilljebjörn H, et al.
Transcriptional landscape of B cell precursor acute lymphoblastic leukemia based on an international study of 1,223 cases.
Proc Natl Acad Sci U S A. 2018; 115(50):E11711-E11720 [PubMed] Free Access to Full Article Related Publications
Most B cell precursor acute lymphoblastic leukemia (BCP ALL) can be classified into known major genetic subtypes, while a substantial proportion of BCP ALL remains poorly characterized in relation to its underlying genomic abnormalities. We therefore initiated a large-scale international study to reanalyze and delineate the transcriptome landscape of 1,223 BCP ALL cases using RNA sequencing. Fourteen BCP ALL gene expression subgroups (G1 to G14) were identified. Apart from extending eight previously described subgroups (G1 to G8 associated with

Li X, Tian Y, Hu Y, et al.
CircNUP214 sponges miR-145 to promote the expression of ZEB2 in thyroid cancer cells.
Biochem Biophys Res Commun. 2018; 507(1-4):168-172 [PubMed] Related Publications
Circular (circ)RNAs have been implicated in cancer development. However, few studies have examined the role of circRNAs in papillary thyroid cancer (PTC). In this study we found that circNUP214 was upregulated in clinical PTC specimens relative to adjacent normal tissue. In vitro analyses showed that circNUP214 knockdown suppressed PTC cell proliferation, invasion, migration, and tumorigenesis. A luciferase reporter assay confirmed that circNUP214 binds to miR-145, which directly targets zinc finger E-box binding homeobox (ZEB)2. Thus, circNUP214 may play an oncogenic role in PTC by acting as a sponge for miR-145, leading to upregulation of ZEB2. These results provide evidence for a new regulatory mechanism in PTC development involving circNUP214, which can serve as a potential therapeutic target in PTC treatment.

Zou Y, Ouyang Q, Wei W, et al.
FAT10 promotes the invasion and migration of breast cancer cell through stabilization of ZEB2.
Biochem Biophys Res Commun. 2018; 506(3):563-570 [PubMed] Related Publications
FAT10, an ubiquitin-like protein, functions as a potential tumor promoter in several caners. However, the function and clinical significance of FAT10 in breast cancer (BC) remains unclear. Here, we found that high FAT10 expression was detected frequently in primary BC tissues, and was closely associated with malignant phenotype and shorter survival among the BC patients. Multivariate analyses also revealed that FAT10 overexpression was independent prognostic factors for poor outcome of patients with BC. Function assay demonstrated that FAT10 knockdown significantly inhibited the metastasis abilities and the epithelial-mesenchymal transition (EMT) of breast cancer cell. Further investigation revealed that FAT10 directly bound ZEB2 and decreased its ubiquitination to enhance the protein stability of ZEB2 in BC cells. Moreover, our data shown that the pro-metastasis effect of FAT10 in BC is partially dependent on ZEB2 enhancement. Collectively, our data suggest that FAT10 plays a crucial oncogenic role in BC metastasis, and we provide a novel evidence that FAT10 may be serve as a prognostic and therapeutic target for BC patients.

Wang S, Zhang G, Zheng W, et al.
MiR-454-3p and miR-374b-5p suppress migration and invasion of bladder cancer cells through targetting ZEB2.
Biosci Rep. 2018; 38(6) [PubMed] Free Access to Full Article Related Publications
Bladder cancer (BCa) threatens human health due to the high occurrence and mortality. Nowadays, more and more researchers focussed on the molecular mechanisms and biological functions of miRNAs in human cancers. The present study aims to study the biological role of miR-454-3p and miR-374b-5p in BCa. The expression levels of miR-454-3p and miR-374b-5p were detected in BCa tissues and cell lines by qRT-PCR analysis. Kaplan-Meier analysis revealed that the expression levels of miR-454-3p and miR-374b-5p were positively correlated with the overall survival (OS) rate of BCa patients. Gain-of-function assays were conducted to demonstrate the inhibitory effects of miR-454-3p and miR-374b-5p on the invasion, migration, and epithelial-mesenchymal transition (EMT) of BCa cells. Mechanically, ZEB2 was found to be a target of both miR-454-3p and miR-374b-5p. Rescue assays revealed that ZEB2 reversed the inhibitory effects of miR-454-3p and miR-374b-5p on the invasion and migration of BCa cell lines. In summary, miR-454-3p and miR-374b-5p negatively regulated invasion and migration of BCa cell lines via targetting ZEB2.

Zhang Y, Li J, Jia S, et al.
Down-regulation of lncRNA-ATB inhibits epithelial-mesenchymal transition of breast cancer cells by increasing miR-141-3p expression.
Biochem Cell Biol. 2019; 97(2):193-200 [PubMed] Related Publications
Long noncoding RNA activated by transforming growth factor-beta (lnc-ATB) is abnormally expressed in a number of tumor types. The aim of this study was to investigate the expression of lnc-ATB and miR-141-3p, and to determine whether lnc-ATB can regulate epithelial-mesenchymal transition (EMT) by miR-141-3p in breast cancer. Here, we found that lnc-ATB was highly expressed, whereas there was low expression of miR-141-3p in breast cancer tissues and cells. Knockdown of lnc-ATB in two breast cancer cell lines (MDA-MB-231 and BT549) significantly increased miR-141-3p expression. Down-regulation of lnc-ATB resulted in a morphological change of breast cancer cells from spindle-like to a round shape, and in a remarkable inhibition of cell migration and invasion, which were reversed by miR-141-3p inhibitor. Furthermore, we demonstrated that lnc-ATB knockdown decreased ZEB1, ZEB2, N-cadherin, and vimentin expression, and promoted E-cadherin expression, while miR-141-3p inhibitor could reverse those effects. Moreover, we proved that miR-141-3p directly bound to the 3' untranslated region (UTR) of ZEB1 and ZEB2 and negatively regulated ZEB1 and ZEB2 expression. Taken together, our results show that knockdown of lnc-ATB significantly inhibits the EMT process of breast cancer cells by increasing the expression of miR-141-3p, indicating that lnc-ATB might serve as a novel therapeutic target for breast cancer.

Ma J, Zhang J, Weng YC, Wang JC
EZH2-Mediated microRNA-139-5p Regulates Epithelial-Mesenchymal Transition and Lymph Node Metastasis of Pancreatic Cancer.
Mol Cells. 2018; 41(9):868-880 [PubMed] Free Access to Full Article Related Publications
Pancreatic cancer (PC) is one of the most aggressive cancers presenting with high rates of invasion and metastasis, and unfavorable prognoses. The current study aims to investigate whether EZH2/miR-139-5p axis affects epithelial-mesenchymal transition (EMT) and lymph node metastasis (LNM) in PC, and the mechanism how EZH2 regulates miR-139-5p. Human PC and adjacent normal tissues were collected to determine expression of EZH2 and miR-139-5p, and their relationship with clinicopathological features of PC. Human PC cell line was selected, and treated with miR-139-5p mimics/inhibitors, EZH2 vector or shEZH2 in order to validate the regulation of EZH2-mediated miR-139-5p in PC cells

Meyer-Schaller N, Heck C, Tiede S, et al.
Foxf2 plays a dual role during transforming growth factor beta-induced epithelial to mesenchymal transition by promoting apoptosis yet enabling cell junction dissolution and migration.
Breast Cancer Res. 2018; 20(1):118 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The most life-threatening step during malignant tumor progression is reached when cancer cells leave the primary tumor mass and seed metastasis in distant organs. To infiltrate the surrounding tissue and disseminate throughout the body, single motile tumor cells leave the tumor mass by breaking down cell-cell contacts in a process called epithelial to mesenchymal transition (EMT). An EMT is a complex molecular and cellular program enabling epithelial cells to abandon their differentiated phenotype, including cell-cell adhesion and cell polarity, and to acquire mesenchymal features and invasive properties.
METHODS: We employed gene expression profiling and functional experiments to study transcriptional control of transforming growth factor (TGF)β-induced EMT in normal murine mammary gland epithelial (NMuMG) cells.
RESULTS: We identified that expression of the transcription factor forkhead box protein F2 (Foxf2) is upregulated during the EMT process. Although it is not required to gain mesenchymal markers, Foxf2 is essential for the disruption of cell junctions and the downregulation of epithelial markers in NMuMG cells treated with TGFβ. Foxf2 is critical for the downregulation of E-cadherin by promoting the expression of the transcriptional repressors of E-cadherin, Zeb1 and Zeb2, while repressing expression of the epithelial maintenance factor Id2 and miRNA 200 family members. Moreover, Foxf2 is required for TGFβ-mediated apoptosis during EMT by the transcriptional activation of the proapoptotic BH3-only protein Noxa and by the negative regulation of epidermal growth factor receptor (EGFR)-mediated survival signaling through direct repression of its ligands betacellulin and amphiregulin. The dual function of Foxf2 during EMT is underscored by the finding that high Foxf2 expression correlates with good prognosis in patients with early noninvasive stages of breast cancer, but with poor prognosis in advanced breast cancer.
CONCLUSIONS: Our data identify the transcription factor Foxf2 as one of the important regulators of EMT, displaying a dual function in promoting tumor cell apoptosis as well as tumor cell migration.

Wang Y, Song W, Kan P, et al.
Overexpression of Epsin 3 enhances migration and invasion of glioma cells by inducing epithelial‑mesenchymal transition.
Oncol Rep. 2018; 40(5):3049-3059 [PubMed] Related Publications
Epsin 3 (EPN3) expression is limited to gastric parietal cells and wounded or pathological tissue rather than normal brain tissue, and although it has been identified as an oncogene in estrogen receptor‑positive breast cancer and non‑small cell lung cancer, its function in cancer is poorly understood. The present study aimed to investigate the association of EPN3 expression with the clinicopathological features of patients with glioma, as well as the effects of EPN3 on glioblastoma cells and the potential molecular mechanisms for its effects on glioblastoma cell behavior. EPN3 expression was assessed by immunohistochemistry in tissue samples from 167 patients with glioma, as well as by western blotting in 5 glioblastoma cell lines. The U87 and U251 glioblastoma cell lines were used to investigate the effects of EPN3 on glioblastoma cell invasion and migration through gain and loss of EPN3 expression experiments; expression levels were further investigated by reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) and western blot analyses. The results demonstrated that EPN3 expression levels were upregulated in high‑grade glioma tissues compared with low‑grade tissues, and there were varying expression levels of EPN3 in the five glioblastoma cell lines. No significant differences were observed in EPN3 expression in relation to patient age, sex or tumor size. Overexpression of EPN3 promoted glioblastoma cell migration and invasion, which we hypothesized was through affecting epithelial‑mesenchymal transition (EMT). RT‑qPCR and western blotting revealed that EPN3 upregulation increased the expression of Notch1 intracellular domain, β‑catenin, Slug, Twist and zinc‑finger E‑box‑binding homeobox (ZEB)‑1. These results suggested that EPN3 enhances the migration and invasion of glioblastoma cells by activating the transcription factors Slug, Twist and ZEB1, but not Snail 1 or ZEB2, to induce EMT in glioma cells; EPN3 involvement in the Notch and WNT/β‑catenin signaling pathways may contribute to this process.

Zhang DD, Li Y, Xu Y, et al.
Phosphodiesterase 7B/microRNA-200c relationship regulates triple-negative breast cancer cell growth.
Oncogene. 2019; 38(7):1106-1120 [PubMed] Related Publications
Members of microRNA-200 (miRNA-200) family have a regulatory role in epithelial to mesenchymal transition (EMT) by suppressing Zeb1 and Zeb2 expression. Consistent with its role in suppressing EMT, Hsa-miR-200c-3p (miR-200c), a member of miR-200 family is poorly expressed in mesenchymal-like triple-negative breast cancer (TNBC) cells and ectopic miR-200c expression suppresses cell migration. In this study, we demonstrated that miR-200c potently inhibited TNBC cell growth and tumor development in a mechanism distinct from its ability to downregulate Zeb1 and Zeb2 expression, because silencing them only marginally affected TNBC cell growth. We identified phosphodiesterase 7B (PDE7B) as a bona fide miR-200c target. Importantly, miR-200c-led inhibition in cell growth and tumor development was prevented by forcing PDE7B transgene expression, while knockdown of PDE7B effectively inhibited cell growth. These results suggest that miR-200c inhibits cell growth by targeting PDE7B mRNA. To elucidate mechanism underlying miR-200c/PDE7B regulation of TNBC cell growth, we showed that cAMP concentration was lower in TNBC cells compared with estrogen receptor-positive (ER + ) cells, and that both miR-200c and PDE7B siRNAs were able to increase cAMP concentration in TNBC cells. High level of cellular cAMP has been shown to induce cell cycle arrest and apoptosis in TNBC cells. Our observation that ectopic expression of miR-200c triggered apoptosis indicates that it does so by elevating level of cellular cAMP. Analysis of breast tumor gene expression datasets revealed an inverse association between miR-200c and PDE7B expression. Especially, both low miR-200c and high PDE7B expression were correlated with poor survival of breast cancer patients. Our study supports a critical role of miR-200c/PDE7B relationship in TNBC tumorigenesis.

Liu C, Hu W, Li LL, et al.
Roles of miR-200 family members in lung cancer: more than tumor suppressors.
Future Oncol. 2018; 14(27):2875-2886 [PubMed] Related Publications
miRNAs are a class of single-stranded noncoding RNAs, which have no coding potential, but modulate many molecular mechanisms including cancer pathogenesis. miRNAs participate in cell proliferation, differentiation, apoptosis, as well as carcinogenesis or cancer progression, and their involvement in lung cancer has been recently shown. They are suggested to have bidirectional functions on important cancer-related genes so as to enhance or attenuate tumor genesis. Epithelial-mesenchymal transition (EMT) is a fundamental process which contributes to integrity of organogenesis and tissue differentiation as well as tissue repair, organ fibrosis and the progression of carcinoma, and several miRNAs were suggested to form the network regulating EMT in lung cancer, among which, miR-200 family members (miR-200a, miR-200b, miR-200c, miR-429 and miR-141) play crucial roles in the suppression of EMT.

Huo H, Tian J, Wang R, et al.
Long non-coding RNA NORAD upregulate SIP1 expression to promote cell proliferation and invasion in cervical cancer.
Biomed Pharmacother. 2018; 106:1454-1460 [PubMed] Related Publications
Long non-coding RNAs (lncRNAs) play important roles in tumor progression. Recently, increasing evidence showed that lncRNA NORAD could be used as an important regulator in tumor progression. However, the roles and underlying mechanism of NORAD in cervical cancer (CC) remain unclear. In the present study, we found that NORAD expression was significantly up-regulated in CC tissues and cell lines. High NORAD expression was correlated with advanced FIGO stage, lymph nodes metastasis, vascular invasion, and poor overall survival of CC patients. In vitro function assays, we showed that NORAD suppression reduced CC cells proliferation, invasion, and epithelial-mesenchymal transition (EMT) processes. Furthermore, the underlying mechanism studies showed that lncRNA NORAD could sponge miR-590-3p to promote the proliferation and invasion of CC cells via upregulating SIP1 expression. In addition, we showed that NORAD inhibition could reduce CC cells growth in vivo. Taken together, these results suggested that NORAD could serve as a ceRNA in CC progression by modulating miR-590-3p/SIP1 axis and act as a therapeutic target for the treatment of CC.

Lorenzo-Martín LF, Citterio C, Menacho-Márquez M, et al.
Vav proteins maintain epithelial traits in breast cancer cells using miR-200c-dependent and independent mechanisms.
Oncogene. 2019; 38(2):209-227 [PubMed] Free Access to Full Article Related Publications
The bidirectional regulation of epithelial-mesenchymal transitions (EMT) is key in tumorigenesis. Rho GTPases regulate this process via canonical pathways that impinge on the stability of cell-to-cell contacts, cytoskeletal dynamics, and cell invasiveness. Here, we report that the Rho GTPase activators Vav2 and Vav3 utilize a new Rac1-dependent and miR-200c-dependent mechanism that maintains the epithelial state by limiting the abundance of the Zeb2 transcriptional repressor in breast cancer cells. In parallel, Vav proteins engage a mir-200c-independent expression prometastatic program that maintains epithelial cell traits only under 3D culture conditions. Consistent with this, the depletion of endogenous Vav proteins triggers mesenchymal features in epithelioid breast cancer cells. Conversely, the ectopic expression of an active version of Vav2 promotes mesenchymal-epithelial transitions using E-cadherin-dependent and independent mechanisms depending on the mesenchymal breast cancer cell line used. In silico analyses suggest that the negative Vav anti-EMT pathway is operative in luminal breast tumors. Gene signatures from the Vav-associated proepithelial and prometastatic programs have prognostic value in breast cancer patients.

Romero S, Musleh M, Bustamante M, et al.
Polymorphisms in
Anticancer Res. 2018; 38(7):3871-3877 [PubMed] Related Publications
BACKGROUND/AIM: Epithelial-mesenchymal transition (EMT) program has been linked as a driver of metastatic dissemination by conferring migratory and invasive capacity to cancer cells. Gastric cancer (GC) patients with tumors expressing altered levels of EMT markers have low survival. This study aimed to assess if polymorphisms of CDH1, TWIST1, SNAIL2, ZEB1 and ZEB2 genes are associated with survival in GC patients.
PATIENTS AND METHODS: A total of 153 individuals with diagnosis of GC were recruited in Santiago, Chile. All patients were genotyped using Infinium Global Screening Array (GSA). Twenty Tag SNPs of the studied genes were retrieved.
RESULTS: Three SNPs were associated with survival: rs2526614 (TWIST1) (genotype CA + AA, adjusted HR=0.58, 95%CI=0.37-0.93), rs6953766 (TWIST1) (genotype GG, crude HR=2.02, 95%CI=1.06-3.82, adjusted HR=2.14, 95%CI=1.07-4.25), and rs431073 (ZEB1) (genotype AC + CC, crude HR=1.62, 95%CI=1.01-2.59, adjusted HR=1.96, 95%CI=1.18-3.25).
CONCLUSION: To the best of our knowledge, this is the first study proposing a role of these SNPs in cancer prognosis. Their use as prognostic markers of GC survival warrants further investigation.

Liu Y, Siles L, Lu X, et al.
Mitotic polarization of transcription factors during asymmetric division establishes fate of forming cancer cells.
Nat Commun. 2018; 9(1):2424 [PubMed] Free Access to Full Article Related Publications
A model of K-Ras-initiated lung cancer was used to follow the transition of precancerous adenoma to adenocarcinoma. In hypoxic, Tgf-β1-rich interiors of adenomas, we show that adenoma cells divide asymmetrically to produce cancer-generating cells highlighted by epithelial mesenchymal transition and a CD44/Zeb1 loop. In these cells, Zeb1 represses the Smad inhibitor Zeb2/Sip1, causing Pten loss and launching Tgf-β1 signaling that drives nuclear translocation of Yap1. Surprisingly, the nuclear polarization of transcription factors during mitosis establishes parent and daughter fates prior to cytokinesis in sequential asymmetric divisions that generate cancer cells from precancerous lesions. Mutation or knockdown of Zeb1 in the lung blocked the production of CD44

Chen J, Gong C, Mao H, et al.
E2F1/SP3/STAT6 axis is required for IL-4-induced epithelial-mesenchymal transition of colorectal cancer cells.
Int J Oncol. 2018; 53(2):567-578 [PubMed] Free Access to Full Article Related Publications
Colorectal cancer (CRC) is a type of cancer with a mortality rate among the highest worldwide owing to its high rate of metastasis. Therefore, inflammation-associated metastasis in the development of CRC is currently a topic of considerable interest. In the present study, the pro-inflammatory cytokine interleukin-4 (IL-4) was identified to promote the epithelial-mesenchymal transition (EMT) of CRC cells. However, the enhancing effect of IL-4 was more evident in HCT116 cells compared with in RKO cells. Accordingly, an increased expression level of STAT6 was observed in HCT116 cells compared with RKO cells. Further investigations identified that E2F1 was required for maintaining the level of signal transducer and activator of transcription 6 (STAT6) in HCT116 cells. Mechanistically, E2F1 induced specificity protein 3 (SP3) directly by binding to the promoter of the STAT6 gene and activating its transcription in CRC cells. As a result, phosphorylation-activated STAT6 increased the expression of several EMT drivers, including zinc finger E-box-binding homeobox (Zeb)1 and Zeb2, which serve a critical function in IL-4-induced EMT. Rescue experiments further confirmed that IL-4-induced EMT relied on an intact E2F1/SP3/STAT6 axis in CRC cells. Finally, analysis of clinical CRC specimens revealed a positive correlation between E2F1, SP3 and STAT6. The ectopically expressed E2F1/SP3/STAT6 axis indicated a poor prognosis in patients with CRC. In conclusion, the E2F1/SP3/STAT6 pathway was identified to be essential for IL-4 signaling-induced EMT and aggressiveness of CRC cells.

Karaosmanoğlu O, Banerjee S, Sivas H
Identification of biomarkers associated with partial epithelial to mesenchymal transition in the secretome of slug over-expressing hepatocellular carcinoma cells.
Cell Oncol (Dordr). 2018; 41(4):439-453 [PubMed] Related Publications
BACKGROUND: Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. Complete epithelial to mesenchymal transition (EMT) has long been considered as a crucial step for metastasis initiation. It has, however, become apparent that many carcinoma cells can metastasize without complete loss of epithelial traits or with incomplete gain of mesenchymal traits, i.e., partial EMT. Here, we aimed to determine the similarities and differences between complete and partial EMT through over-expression of the EMT-associated transcription factor Slug in different HCC-derived cell lines.
METHODS: Slug over-expressing HCC-derived HepG2 and Huh7 cells were assessed for their EMT, chemo-resistance and stemness features using Western blotting, qRT-PCR, neutral red uptake, doxorubicin accumulation and scratch wound healing assays. We also collected conditioned media from Slug over-expressing HCC cells and analyzed its exosomal protein content for the presence of chemo-resistance and partial EMT markers using MALDI-TOF/TOF and ELISA assays, respectively.
RESULTS: We found that Slug over-expression resulted in the induction of both complete and partial EMT in the different HCC-derived cell lines tested. Complete EMT was characterized by downregulation of E-cadherin and upregulation of ZEB2. Partial EMT was characterized by upregulation of E-cadherin and downregulation of vimentin and ZEB2. Interestingly, we found that Slug induced chemo-resistance through downregulation of the ATP binding cassette (ABC) transporter ABCB1 and upregulation of the ABC transporter ABCG2, as well as through expression of CD133, a stemness marker that exhibited a similar expression pattern in cells with either a complete or a partial EMT phenotype. In addition, we found that Slug-mediated partial EMT was associated with enhanced exosomal secretion of post-translationally modified fibronectin 1 (FN1), collagen type II alpha 1 (COL2A1) and native fibrinogen gamma chain (FGG).
CONCLUSIONS: From our data we conclude that the exosomal proteins identified may be considered as potential non-invasive biomarkers for chemo-resistance and partial EMT in HCC.

Takei Y, Shen G, Morita-Kondo A, et al.
MicroRNAs Associated with Epithelial-Mesenchymal Transition Can Be Targeted to Inhibit Peritoneal Dissemination of Human Scirrhous Gastric Cancers.
Pathobiology. 2018; 85(4):232-246 [PubMed] Related Publications
OBJECTIVES: Scirrhous gastric cancers grow rapidly, and frequently invade the peritoneum. Such peritoneal dissemination properties markedly reduce patient survival. Thus, an effective means for inhibiting peritoneal dissemination is urgently required.
METHODS: We previously established a cell line, HSC-58, from a scirrhous gastric cancer patient, and further successfully isolated a metastatic line, 58As9, in nude mice upon orthotopic inoculation. Using the lines, we examined the mechanism underlying peritoneal dissemination from the viewpoint of microRNA (miRNA) expression.
RESULTS: miRNA array and qRT-PCR analysis showed that the expressions of epithelial-mesenchymal transition (EMT)-associated miRNAs such as miR-200c and miR-141 were significantly low in 58As9. Using 58As9 with stably overexpressing miR-200c, miR-141, or both, together with a luciferase reporter assay, we found that miR-200c targeted zinc finger E-box-binding homeobox 1 (ZEB1) and miR-141 targeted ZEB2. The overexpressed lines reversed the EMT status from mesenchymal to epithelial in 58As9, and significantly reduced the invasion activity and peritoneal dissemination for a significant prolongation of survival in the orthotopic tumor models in nude mice.
CONCLUSIONS: EMT-associated miRNAs such as miR-200c and miR-141 and their target genes ZEB1/ZEB2 have good potential for antiperitoneal dissemination therapy in patients with scirrhous gastric cancers.

Lili LN, Huang AD, Zhang M, et al.
Time-course analysis of microRNA-induced mesenchymal-to-epithelial transition underscores the complexity of the underlying molecular processes.
Cancer Lett. 2018; 428:184-191 [PubMed] Related Publications
Expression levels of the miR-200 family of miRNAs are significantly reduced during the epithelial-to-mesenchymal transition (EMT) and consequent metastasis of ovarian and other cancers. Consistently, ectopic over-expression of miR-200 family miRNAs in mesenchymal-like cells reverses the process by converting treated cells to an epithelial phenotype, thereby reducing invasiveness and increasing sensitivity to chemotherapeutic drugs. To better understand the dynamics and molecular processes underlying miRNA-induced mesenchymal-to mesenchymal transition (MET), a time-course study was conducted where miRNA-induced morphological and molecular changes associated with MET were monitored over a period of 144 h. Morphological transition from an elongated mesenchymal-like to a cuboidal epithelial-like phenotype is maximized at 48 h with cells returning to the elongated phenotype by 144 h. Changes in the expression of >3000 genes, including many previously associated with epithelial-to-mesenchymal transition (EMT), are most pronounced at 48 h, and approach starting levels of expression by 144 h. The majority of these genes are not direct targets of miR-429. Targeted (siRNA) inhibition of key miR-429 regulated genes previously implicated as drivers of EMT/MET, do not recapitulate miR-429 induced MET indicating that the underlying molecular processes are complex.

Yang H, Li G, Cheng B, Jiang R
ZFAS1 functions as an oncogenic long non-coding RNA in bladder cancer.
Biosci Rep. 2018; 38(3) [PubMed] Free Access to Full Article Related Publications
Long non-coding RNA (lncRNA) ZFAS1 (zinc finger antisense 1) has been suggested to have an oncogenic role in the tumorigenesis of human malignant tumors. However, the expression status and biological function of ZFAS1 in bladder cancer is still unknown. Thus, the purpose of the present study is to explore the clinical value of ZFAS1 in bladder cancer patients, and the biological function of ZFAS1 in bladder cancer cell. In the present study, we found ZFAS1 expression was increased in bladder cancer tissues compared with paired adjacent normal tissues through analyzing the Cancer Genome Atlas (TCGA) database. Furthermore, we confirmed that levels of ZFAS1 expression were elevated in bladder cancer tissues and cell lines compared with normal bladder tissues and normal uroepithelium cell line, respectively. Then, we observed that the expression level of ZFAS1 was positively associated with clinical stag, muscularis invasion, lymph node metastasis, and distant metastasis in bladder cancer patients. The experiments

Colacino JA, Azizi E, Brooks MD, et al.
Heterogeneity of Human Breast Stem and Progenitor Cells as Revealed by Transcriptional Profiling.
Stem Cell Reports. 2018; 10(5):1596-1609 [PubMed] Free Access to Full Article Related Publications
During development, the mammary gland undergoes extensive remodeling driven by stem cells. Breast cancers are also hierarchically organized and driven by cancer stem cells characterized by CD44

Ye C, Hu Y, Wang J
MicroRNA-377 Targets Zinc Finger E-box-Binding Homeobox 2 to Inhibit Cell Proliferation and Invasion of Cervical Cancer.
Oncol Res. 2019; 27(2):183-192 [PubMed] Related Publications
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.

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