Role Of ZEB2 Research Articles

ZEB2 regulates endocrine therapy sensitivity and metastasis in luminal a breast cancer cells through a non-canonical mechanism.

The transcription factors ZEB1 and ZEB2 mediate epithelial-to-mesenchymal transition (EMT) and metastatic progression in numerous malignancies including breast cancer. ZEB1 and ZEB2 drive EMT through transcriptional repression of cell-cell junction proteins and members of the tumor suppressive miR200 family. However, in estrogen receptor positive (ER +) breast cancer, the role of ZEB2 as an independent driver of metastasis has not been fully investigated. In the current study, we induced exogenous expression of ZEB2 in ER + MCF-7 and ZR-75-1 breast cancer cell lines and examined EMT gene expression and metastasis using dose-response qRT-PCR, transwell migration assays, proliferation assays with immunofluorescence of Ki-67 staining. We used RNA sequencing to identify pathways and genes affected by ZEB2 overexpression. Finally, we treated ZEB2-overexpressing cells with 17β-estradiol (E2) or ICI 182,780 to evaluate how ZEB2 affects estrogen response. Contrary to expectation, we found that ZEB2 did not increase canonical epithelial nor decrease mesenchymal gene expressions. Furthermore, ZEB2 overexpression did not promote a mesenchymal cell morphology. However, ZEB1 and ZEB2 protein expression induced significant migration of MCF-7 and ZR-75-1 breast cancer cells in vitro and MCF-7 xenograft metastasis in vivo. Transcriptomic (RNA sequencing) pathway analysis revealed alterations in estrogen signaling regulators and pathways, suggesting a role for ZEB2 in endocrine sensitivity in luminal A breast cancer. Expression of ZEB2 was negatively correlated with estrogen receptor complex genes in luminal A patient tumors. Furthermore, treatment with 17β-estradiol (E2) or the estrogen receptor antagonist ICI 182,780 had no effect on growth of ZEB2-overexpressing cells. ZEB2 is a multi-functional regulator of drug sensitivity, cell migration, and metastasis in ER + breast cancer and functions through non-canonical mechanisms.

The Role of ZEB2 in Human CD8 T Lymphocytes: Clinical and Cellular Immune Profiling in Mowat–Wilson Syndrome

The Zeb2 gene encodes a transcription factor (ZEB2) that acts as an important immune mediator in mice, where it is expressed in early-activated effector CD8 T cells, and limits effector differentiation. Zeb2 homozygous knockout mice have deficits in CD8 T cells and NK cells. Mowat–Wilson syndrome (MWS) is a rare genetic disease resulting from heterozygous mutations in ZEB2 causing disease by haploinsufficiency. Whether ZEB2 exhibits similar expression patterns in human CD8 T cells is unknown, and MWS patients have not been comprehensively studied to identify changes in CD8 lymphocytes and NK cells, or manifestations of immunodeficiency. By using transcriptomic assessment, we demonstrated that ZEB2 is expressed in early-activated effector CD8 T cells of healthy human volunteers following vaccinia inoculation and found evidence of a role for TGFß-1/SMAD signaling in these cells. A broad immunological assessment of six genetically diagnosed MWS patients identified two patients with a history of recurrent sinopulmonary infections, one of whom had recurrent oral candidiasis, one with lymphopenia, two with thrombocytopenia and three with detectable anti-nuclear antibodies. Immunoglobulin levels, including functional antibody responses to protein and polysaccharide vaccination, were normal. The MWS patients had a significantly lower CD8 T cell subset as % of lymphocytes, compared to healthy controls (median 16.4% vs. 25%, p = 0.0048), and resulting increased CD4:CD8 ratio (2.6 vs. 1.8; p = 0.038). CD8 T cells responded normally to mitogen stimulation in vitro and memory CD8 T cells exhibited normal proportions of subsets with important tissue-specific homing markers and cytotoxic effector molecules. There was a trend towards a decrease in the CD8 T effector memory subset (3.3% vs. 5.9%; p = 0.19). NK cell subsets were normal. This is the first evidence that ZEB2 is expressed in early-activated human effector CD8 T cells, and that haploinsufficiency of ZEB2 in MWS patients had a slight effect on immune function, skewing T cells away from CD8 differentiation. To date there is insufficient evidence to support an immunodeficiency occurring in MWS patients.

Zinc finger E‑box binding homeobox2 functions as an oncogene in human laryngeal squamous cell carcinoma.

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.

Neuroimaging findings in Mowat\u2013Wilson syndrome: a study of 54 patients

Purpose:Mowat–Wilson syndrome (MWS) is a genetic disease characterized by distinctive facial features, moderate to severe intellectual disability, and congenital malformations, including Hirschsprung disease, genital and eye anomalies, and congenital heart defects, caused by haploinsufficiency of the ZEB2 gene. To date, no characteristic pattern of brain dysmorphology in MWS has been defined.Methods:Through brain magnetic resonance imaging (MRI) analysis, we delineated a neuroimaging phenotype in 54 MWS patients with a proven ZEB2 defect, compared it with the features identified in a thorough review of published cases, and evaluated genotype–phenotype correlations.Results:Ninety-six percent of patients had abnormal MRI results. The most common features were anomalies of corpus callosum (79.6% of cases), hippocampal abnormalities (77.8%), enlargement of cerebral ventricles (68.5%), and white matter abnormalities (reduction of thickness 40.7%, localized signal alterations 22.2%). Other consistent findings were large basal ganglia, cortical, and cerebellar malformations. Most features were underrepresented in the literature. We also found ZEB2 variations leading to synthesis of a defective protein to be favorable for psychomotor development and some epilepsy features but also associated with corpus callosum agenesis.Conclusion:This study delineated the spectrum of brain anomalies in MWS and provided new insights into the role of ZEB2 in neurodevelopment.Genet Med advance online publication 10 November 2016

A role of Zeb2 in the development of terminally differentiated effector T cells (P1434)

Abstract Zeb2 (also known as Zfhx1b and Sip1) is a DNA-binding multi-zinc-finger transcription factor found to play a significant role in the development of cells both early in neuronal differentiation and in cancer metastasis. By binding dual E2 box enhancer elements, Zeb2 acts primarily as a transcriptional repressor and may inhibit E-protein DNA binding, although it is known to act also as a transcriptional activator. Zeb2 also binds activated Smads, the co-repressor CtBP and the NuRD chromatin remodeling complex but not all of its functions may necessarily depend on each of these interactions. While the closely related family member, dEG1/Zfhx1a/Zeb1, is known to plays an early role in lymphocyte development, the function of Sip1 in T lymphocytes remains unknown. We find that Zeb2 is upregulated in activated T cells and that antigen specific T cells show diminished expansion during an immune response. Zeb2 is selectively expressed and necessary for the development of a subset of terminally differentiated CD8+ T cells. We are currently assessing the interplay between Zeb2 and E-proteins in differentiation of naïve CD8+ T cells to cytotoxic effector cells.

Novel dermatological manifestations of Mowat–Wilson syndrome including photosensitivity and dyspigmentation

The authors update on a previously reported patient with Mowat–Wilson syndrome (MWS) with unusual dermatological features including photosensitivity and skin dyspigmentation.1 An 18-month-old Afro-Caribbean boy with Hirschsprung9s disease, hypospadias, delayed visual maturation, microcephaly, developmental delay, seizures and dysmorphic facial features was referred to the dermatology department. Since birth he displayed persistent skin dyspigmentation with patchy macular hypo- and hyperpigmentation involving the face and neck, upper limbs, trunk, perineum and right ankle. There was no history of preceding inflammation or eczema. Following the original report, his parents have described photosensitivity since the age of 2 years, with sunburn-like erythema occurring within minutes of sun exposure despite application of high-factor sunblock. Investigations including lupus serology and porphyria screen were normal. The patient is currently awaiting formal phototesting. Genetic analysis previously identified a heterozygous truncating mutation in exon 8 of the ZEB2 (formerly ZFHXIB; Zinc finger homeobox 1B) gene, confirming MWS. MWS was first described in 1998, comprising characteristic facial dysmorphism, profound learning difficulties, epilepsy, Hirschprung9s disease and other congenital abnormalities, mapped to a locus at chromosome 2q21–q23.2 In 2001 the causative gene, ZEB2 was identified.3 Subsequently, over 100 pathogenetic heterozygous mutations or deletions are described.4 The distinctive evolving facial phenotype has been recently reviewed.5 ZEB2 encodes Smad interacting protein (SIP1), a ubiquitous transcription factor with an important role in embryological development including the neural crest. “Raindrop” pigmentation has been previously reported in a 9-year-old patient with MWS.6 This indicates that MWS should be added to the spectrum of neurocutaneous disorders comprising dyspigmentation and Hirschprung9s. We can speculate that dyspigmentation results from ZEB2 haploinsufficiency disrupting neural crest melanocyte development or migration. Our case is the first record of photosensitivity in MWS, raising the possibility of an additional role of ZEB2 in regulating the cutaneous response to ultraviolet radiation.

The influence of dexamethasone on postoperative pain following lumbar discectomy — A double-blind study

Mowat–Wilson syndrome (MWS) is a genetic disease characterized by distinctive facial features, moderate to severe intellectual disability, and congenital malformations, including Hirschsprung disease, genital and eye anomalies, and congenital heart defects, caused by haploinsufficiency of the ZEB2 gene. To date, no characteristic pattern of brain dysmorphology in MWS has been defined.Through brain magnetic resonance imaging (MRI) analysis, we delineated a neuroimaging phenotype in 54 MWS patients with a proven ZEB2 defect, compared it with the features identified in a thorough review of published cases, and evaluated genotype–phenotype correlations.Ninety-six percent of patients had abnormal MRI results. The most common features were anomalies of corpus callosum (79.6% of cases), hippocampal abnormalities (77.8%), enlargement of cerebral ventricles (68.5%), and white matter abnormalities (reduction of thickness 40.7%, localized signal alterations 22.2%). Other consistent findings were large basal ganglia, cortical, and cerebellar malformations. Most features were underrepresented in the literature. We also found ZEB2 variations leading to synthesis of a defective protein to be favorable for psychomotor development and some epilepsy features but also associated with corpus callosum agenesis.This study delineated the spectrum of brain anomalies in MWS and provided new insights into the role of ZEB2 in neurodevelopment.Genet Med advance online publication 10 November 2016