[Corrigendum] GATA3 is downregulated in HCC and accelerates HCC aggressiveness by transcriptionally inhibiting slug expression

433 Background: The SLUG gene plays an important role in EMT by repressing E-cadherin and promotes metastasis. Previous data suggest that overexpressed SLUG gene in pancreatic cancer (PC) showing a high frequency of metastasis and poor prognosis. As SLUG contribution to characteristics or metastatic features remains elusive, we clarified its functional roles in PC progression. Methods: A total of 2958 pancreatic tumors were analyzed using Whole Transcriptome sequencing, NextGen Sequencing (NGS) (NextSeq, 592 gene panel) or Whole Exome Sequencing (WES) (NovaSeq) (Caris Life Sciences, Phoenix, AZ). Microsatellite instability (MSI) status was tested by fragment analysis, immunohistochemistry (IHC) and NGS. PD-L1 expression was tested by IHC. Tumor mutational burden (TMB) was measured by counting all mutations found per tumor (a universal cutoff point of ≧10 mutations per MB). Immune cell fraction was calculated by quanTIseq (Finotello 2019, Genome Medicine). Results: A total of 1274 primary and 1684 metastatic pancreatic tumors were included for this study. They were divided equally into four classes in each group, according to their SLUG expression levels. Tumors in the highest quartile of SLUG expression (QH) showed significantly higher frequency in peritoneal-retroperitoneal-omentum metastasis (15.0%) compared to the lowest quartile (QL) (4.8%) (p = .0001). Similar trends were seen in the abdomen (6% vs 1%, p = .001) and bone (2.8% vs 0.0%, p = .005). However, liver (55.0% in QH vs 63.1% in QL) and lung (2.8% vs 14.1%) metastasis occurred most frequently in QL and the least frequently in QH (p = .0197 and p = .001, respectively). This data indicated that tumors with high SLUG gene expression levels tend to lead to disseminated metastasis, and with low expression levels, they tend to spread intravascularly. We detected significant differences among genetic mutations in ATM (5.7% in QL vs 1.8% in QH, p < 0.001) and APC (2.9% vs 0.5%, p < 0.001), and Wnt signaling expressions were higher in QL (4.6%) than QH (0.7%) (p < 0.001). Binary TMB-H and MSI-H tumors had higher frequencies in QL (2.7% and 2.1%) compared to QH (0.3% and 0.1%) (p < 0.001 in both). Contrastingly, PD-L1 expression levels were higher in QH (23.4%) compared to QL (11.0%) (p < 0.001) and had a linear relationship with the expression levels. The median values of the population of B cells, M1 and M2 macrophages were significantly higher in QH compared to QL, but those of myeloid dendritic and CD8+T cells conversely decrease as the SLUG expression increases. Conclusions: Our data indicated the SLUG expression level could determine the tumor characteristics in progression, especially the pattern of metastasis in PC, and it could possibly predict the prognosis and/or therapeutic effects. We also showed immune oncologic markers which have some relationships with SLUG expressions. Further investigation is warranted to better understand SLUG gene functions.

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ETS-Related Gene Expression in Healthy Femoral Arteries With Focal Calcifications

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.623782 ◽

2021 ◽

Vol 9 ◽

Author(s):

Francesco Vasuri ◽

Sabrina Valente ◽

Ilenia Motta ◽

Alessio Degiovanni ◽

Carmen Ciavarella ◽

...

Keyword(s):

Bone Development ◽

Histological Study ◽

Arterial Calcification ◽

Related Gene ◽

Mesenchymal Transition ◽

Femoral Arteries ◽

Slug Expression ◽

Chondrogenic Marker ◽

Endothelial To Mesenchymal Transition ◽

Endothelial Homeostasis

Bone development-related genes are enriched in healthy femoral arteries, which are more prone to calcification, as documented by the predominance of fibrocalcific plaques at the femoral location. We undertook a prospective histological study on the presence of calcifications in normal femoral arteries collected from donors. Since endothelial-to-mesenchymal transition (EndMT) participates in vascular remodeling, immunohistochemical (IHC) and molecular markers of EndMT and chondro-osteogenic differentiation were assessed. Transmission electron microscopy (TEM) was used to describe calcification at its inception. Two hundred and fourteen femoral arteries were enrolled. The mean age of the donors was 39.9 ± 12.9 years; male gender prevailed (M: 128). Histology showed a normal architecture; calcifications were found in 52 (24.3%) cases, without correlations with cardiovascular risk factors. Calcifications were seen on or just beneath the inner elastic lamina (IEL). At IHC, SLUG was increasingly expressed in the wall of focally calcified femoral arteries (FCFA). ETS-related gene (ERG), SLUG, CD44, and SOX-9 were positive in calcifications. RT-PCR showed increased levels of BPM-2, RUNX-2, alkaline phosphatase, and osteocalcin osteogenic transcripts and increased expression of the chondrogenic marker, SOX-9, in FCFA. TEM documented osteoblast-like cells adjacent to the IEL, releasing calcifying vesicles from the cell membrane. The vesicles were embedded in a proteoglycan-rich matrix and were entrapped in IEL fenestrations. In this study, ERG- and CD44-positive cell populations were found in the context of increased SLUG expression, thus supporting the participation of EndMT in FCFA; the increased transcript expression of osteochondrogenic markers, particularly SOX-9, reinforced the view that EndMT, osteochondrogenesis, and neoangiogenesis interact in the process of arterial calcification. Given its role as a transcription factor in the regulation of endothelial homeostasis, arterial ERG expression can be a clue of endothelial dysregulation and changes in IEL organization which can ultimately hinder calcifying vesicle diffusion through the IEL fenestrae. These results may have a broader implication for understanding arterial calcification within a disease context.

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Activation of NF-κB by TOPK upregulates Snail/Slug expression in TGF-β1 signaling to induce epithelial-mesenchymal transition and invasion of breast cancer cells

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2020.07.015 ◽

2020 ◽

Vol 530 (1) ◽

pp. 122-129 ◽

Cited By ~ 1

Author(s):

Young-Ju Lee ◽

Jung-Hwan Park ◽

Sang-Muk Oh

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Epithelial Mesenchymal Transition ◽

Mesenchymal Transition ◽

Slug Expression ◽

Tgf Β1

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Jagged1-mediated Notch activation induces epithelial-to-mesenchymal transition through Slug-induced repression of E-cadherin

Journal of Experimental Medicine ◽

10.1084/jem.20071082 ◽

2007 ◽

Vol 204 (12) ◽

pp. 2935-2948 ◽

Cited By ~ 298

Author(s):

Kevin G. Leong ◽

Kyle Niessen ◽

Iva Kulic ◽

Afshin Raouf ◽

Connie Eaves ◽

...

Keyword(s):

Tumor Growth ◽

Poor Prognosis ◽

Epithelial To Mesenchymal Transition ◽

Breast Tumors ◽

Aberrant Expression ◽

Mesenchymal Transition ◽

Slug Expression ◽

Tumor Growth And Metastasis ◽

Notch Activation ◽

E Cadherin

Aberrant expression of Jagged1 and Notch1 are associated with poor outcome in breast cancer. However, the reason that Jagged1 and/or Notch overexpression portends a poor prognosis is unknown. We identify Slug, a transcriptional repressor, as a novel Notch target and show that elevated levels of Slug correlate with increased expression of Jagged1 in various human cancers. Slug was essential for Notch-mediated repression of E-cadherin, which resulted in β-catenin activation and resistance to anoikis. Inhibition of ligand-induced Notch signaling in xenografted Slug-positive/E-cadherin–negative breast tumors promoted apoptosis and inhibited tumor growth and metastasis. This response was associated with down-regulated Slug expression, reexpression of E-cadherin, and suppression of active β-catenin. Our findings suggest that ligand-induced Notch activation, through the induction of Slug, promotes tumor growth and metastasis characterized by epithelial-to-mesenchymal transition and inhibition of anoikis.

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Characteristics of the Epithelial-Mesenchymal Transition in Primary and Paired Metastatic Canine Mammary Carcinomas

Veterinary Pathology ◽

10.1177/0300985818776054 ◽

2018 ◽

Vol 55 (5) ◽

pp. 622-633 ◽

Cited By ~ 7

Author(s):

Talita M. M. Raposo-Ferreira ◽

Becky K. Brisson ◽

Amy C. Durham ◽

Renee Laufer-Amorim ◽

Veronica Kristiansen ◽

...

Keyword(s):

Primary Tumor ◽

Epithelial Mesenchymal Transition ◽

Critical Role ◽

Cell Counting ◽

Positive Staining ◽

Primary Tumors ◽

Mesenchymal Transition ◽

Mammary Carcinomas ◽

Slug Expression ◽

E Cadherin

The epithelial-mesenchymal transition (EMT) is a dynamic process linked to metastasis in many tumor types, including mammary tumors. In this study, we evaluated E-cadherin and vimentin immunolocalization in primary canine mammary carcinomas (20 cases) and their respective metastases, as well as their relationship with the core regulators SNAIL/SLUG. To assess the number of cells undergoing the process of EMT, we quantitated double-positive (E-cadherin+/vimentin+) cells using immunofluorescence, via cell counting and image analysis. In addition, SNAIL/SLUG expression was evaluated by established immunohistochemical methods. Primary tumors had significantly more E-cadherin+/vimentin+ co-expression than their paired respective lymph node or distant metastasis, respectively. Furthermore, the percentage of E-cadherin+/vimentin+ cells in grade II and III carcinomas was significantly higher than in grade I tumors. Primary tumors had significantly higher SNAIL/SLUG expression when analyzed based on the percentage of positive cells compared with their respective distant metastases in pairwise comparisons. An inverse correlation was noted between SNAIL/SLUG immunoreactivity and percentage of E-cadherin+/vimentin+ immunopositive cells in primary tumor samples when SNAIL/SLUG immunoreactivity was grouped into 2 categories (high versus low) based on percentage-positive staining. These results show a positive correlation between E-cadherin+/vimentin+ cells and higher tumor grade, establish differences between primary tumor and their respective metastases, and provide further support that EMT plays a critical role in the metastasis of canine mammary carcinoma. Furthermore, these data suggest that modulation of this process could provide greater therapeutic control and provide support for further research to determine if E-cadherin+/vimentin+ co-immunoreactivity imparts predictive value in the clinical outcome of patients with canine mammary carcinomas.

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