FOXA1 Induces E-Cadherin Expression at the Protein Level &lt;i&gt;via&lt;/i&gt; Suppression of Slug in Epithelial Breast Cancer Cells

Anzai, Erina; Hirata, Kensuke; Shibazaki, Misato; Yamada, Chiaki; Morii, Mariko; Honda, Takeshi; Yamaguchi, Naoto; Yamaguchi, Noritaka

doi:10.1248/bpb.b17-00307

Cited by 26 publications

(17 citation statements)

References 24 publications

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“…Our data showed that the expression of FOXA1 correlated positively with E-cadherin which is in line with previous reports [39,40]. Anzai et al reported that FOXA1 promotes E-cadherin expression at the protein level by suppressing Slug expression in MCF7 cells [41]. Similarly, in gastric cancer cells, FOXA1 regulates the EMT in cancer cells, by inducing the E-cadherin expression and decreasing the vimentin protein level [42].…”

Section: Biomed Research Internationalsupporting

confidence: 92%

FOXA1 Expression in Nasopharyngeal Carcinoma: Association with Clinicopathological Characteristics and EMT Markers

Ammous-Boukhris

Ayadi

Derbel

et al. 2020

BioMed Research International

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The forkhead box (FOXA) family of transcription factors regulates gene expression and chromatin structure during tumorigenesis and embryonic development. Until now, the relationship between FOXA1 and the nasopharyngeal carcinoma (NPC) has not yet been reported. Therefore, our purpose is to analyze the expression of FOXA1 in 56 NPC patients compared to 10 normal nasopharyngeal mucosae and to correlate the expression with the clinicopathological features. Besides, we investigated the association between FOXA1 and LMP1 gene expression, as well as the EMT markers namely the E-cadherin and Twist1. Among 56 NPC tissues, 34 (60.7%) cases were positive for FOXA1. Furthermore, we noticed that FOXA1 expression correlated with TNM (p=0.037), and age at diagnosis (p=0.05). Moreover, positive expression of FOXA1 is likely to be associated with prolonged disease-free survival and overall survival rates. On the other hand, we observed a positive association between the expression of E-cadherin and FOXA1 (p=0.0051) whereas Twist1 correlated negatively with FOXA1 (p=0.004). Furthermore, knowing that LMP1 plays a key role in the pathogenesis of NPC, we explored the association of FOXA1 with the LMP1 gene expression in both NPC cell lines and tissues. We found that, in the C666-1 which displays low levels of LMP1, the expression of FOXA1 is high, and inversely in the C15 cell line that expresses a high level of LMP1, the level of FOXA1 is low. Besides, in accordance to our results, we found that in NPC tissues there is a negative association between LMP1 and FOXA1. In conclusion, our results suggest that the overexpression of FOXA1 is associated with a nonaggressive behavior and favorable prognosis in NPC patients. FOXA1 could contribute in the EMT process through key factors as E-cadherin, Twist1, and LMP1.

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Section: Biomed Research Internationalsupporting

confidence: 92%

FOXA1 Expression in Nasopharyngeal Carcinoma: Association with Clinicopathological Characteristics and EMT Markers

Ammous-Boukhris

Ayadi

Derbel

et al. 2020

BioMed Research International

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“…STAT3 is reported to increase invasion and metastasis by inducing matrix metalloproteinase (MMP) expression [22]. STAT3 can also bind to an antisilencer element in the VIMENTIN promoter to enhance VIMENTIN gene expression and can directly or indirectly target certain transcriptional regulators of E-CADHERIN, such as HIF-1 and SLUG, to regulate EMT progression in cancer [20,21]. Consistent with the above findings, we found that the levels of JAK2, p-JAK2 (Tyr1007/1008), and p-STAT3 (Tyr705) were upregulated in REX1-overexpressing cervical cancer cells (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…To the best of our knowledge, these classical EMT-related genes are downstream targets of the JAK2/STAT3-signaling pathway, which is negatively regulated by the SOCS family [20][21][22][23][24][25][26][27]. Therefore, we investigated the expression of the key proteins of the JAK2/STAT3 pathway in the present study.…”

Section: Rex1 Activates the Jak2/stat3 Pathway By Downregulating Socsmentioning

confidence: 99%

REX1 promotes EMT-induced cell metastasis by activating the JAK2/STAT3-signaling pathway by targeting SOCS1 in cervical cancer

et al. 2019

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ZFP42 zinc finger protein (REX1), a pluripotency marker in mouse pluripotent stem cells, has been identified as a tumor suppressor in several human cancers. However, the function of REX1 in cervical cancer remains unknown. Both IHC and western blot assays demonstrated that the expression of REX1 protein in cervical cancer tissue was much higher than that in normal cervical tissue. A xenograft assay showed that REX1 overexpression in SiHa and HeLa cells facilitated distant metastasis but did not significantly affect tumor formation in vivo. In addition, in vitro cell migration and invasion capabilities were also promoted by REX1. Mechanistically, REX1 overexpression induced epithelial-to-mesenchymal transition (EMT) by upregulating VIMENTIN and downregulating E-CADHERIN. Furthermore, the JAK2/STAT3signaling pathway was activated in REX1-overexpressing cells, which also exhibited increased levels of p-STAT3 and p-JAK2, as well as downregulated expression of SOCS1, which is an inhibitor of the JAK2/STAT3-signaling pathway, at both the transcriptional and translational levels. A dual-luciferase reporter assay and qChIP assays confirmed that REX1 transsuppressed the expression of SOCS1 by binding to two specific regions of the SOCS1 promoter. Therefore, all our data suggest that REX1 overexpression could play a crucial role in the metastasis and invasion of cervical cancer by upregulating the activity of the JAK2/STAT3 pathway by trans-suppressing SOCS1 expression.

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“…In MDA-MB-231 cells, Snail was necessary for binding of Slug to the ZEB1 promoter and its activation indicating that Slug alone may not drive EMT in the absence of Snail (Ye et al, 2015 ). On the other hand, Slug can attenuate E-cadherin levels indirectly by post-transcriptional mechanisms through miR-221 and by promoting protein degradation (Pan et al, 2016 ; Anzai et al, 2017 ). Using oncogene-transformed human mammary epithelial cells (HMLER), Kroger et al showed that Slug protein expression in such epithelial cells was similar to that in mesenchymal and hybrid E/M cells.…”

Section: Slug and Emt: Guilty By Association?mentioning

confidence: 99%

Slug and E-Cadherin: Stealth Accomplices?

Sterneck

Poria

Balamurugan

2020

Front. Mol. Biosci.

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During physiological epithelial-mesenchymal transition (EMT), which is important for embryogenesis and wound healing, epithelial cells activate a program to remodel their structure and achieve a mesenchymal fate. In cancer cells, EMT confers increased invasiveness and tumor-initiating capacity, which contribute to metastasis and resistance to therapeutics. However, cellular plasticity that navigates between epithelial and mesenchymal states and maintenance of a hybrid or partial E/M phenotype appears to be even more important for cancer progression. Besides other core EMT transcription factors, the well-characterized Snail-family proteins Snail (SNAI1) and Slug (SNAI2) play important roles in both physiological and pathological EMT. Often mentioned in unison, they do, however, differ in their functions in many scenarios. Indeed, Slug expression does not always correlate with complete EMT or loss of E-cadherin (CDH1). For example, Slug plays important roles in mammary epithelial cell progenitor cell lineage commitment and differentiation, DNA damage responses, hematopoietic stem cell self-renewal, and in pathologies such as pulmonary fibrosis and atherosclerosis. In this Perspective, we highlight Slug functions in mammary epithelial cells and breast cancer as a "non-EMT factor" in basal epithelial cells and stem cells with focus reports that demonstrate co-expression of Slug and E-cadherin. We speculate that Slug and E-cadherin may cooperate in normal mammary gland and breast cancer/stem cells and advocate for functional assessment of such Slug + /E-cadherin low/+ (SNAI2 + /CDH1 low/+) "basal-like epithelial" cells. Thus, Slug may be regarded as less of an EMT factor than driver of the basal epithelial cell phenotype.

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FOXA1 Induces E-Cadherin Expression at the Protein Level <i>via</i> Suppression of Slug in Epithelial Breast Cancer Cells

Cited by 26 publications

References 24 publications

FOXA1 Expression in Nasopharyngeal Carcinoma: Association with Clinicopathological Characteristics and EMT Markers

FOXA1 Expression in Nasopharyngeal Carcinoma: Association with Clinicopathological Characteristics and EMT Markers

REX1 promotes EMT-induced cell metastasis by activating the JAK2/STAT3-signaling pathway by targeting SOCS1 in cervical cancer

Slug and E-Cadherin: Stealth Accomplices?

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