Modulation of Epithelial to Mesenchymal Transition Signaling Pathways by Olea Europaea and Its Active Compounds

Epithelial-mesenchymal transition (EMT) is a significant dynamic process that causes changes in the phenotype of epithelial cells, changing them from their original phenotype to the mesenchymal cell phenotype. This event can be observed during wound healing process, fibrosis and cancer. EMT-related diseases are usually caused by inflammation that eventually leads to tissue remodeling in the damaged tissue. Prolonged inflammation causes long-term EMT activation that can lead to tissue fibrosis or cancer. Due to activation of EMT by its signaling pathway, therapeutic approaches that modulate that pathway should be explored. Olea europaea (OE) is well-known for its anti-inflammatory effects and abundant beneficial active compounds. These properties are presumed to modulate EMT events. This article reviews recent evidence of the effects of OE and its active compounds on EMT events and EMT-related diseases. Following evidence from the literature, it was shown that OE could modulate TGFβ/SMAD, AKT, ERK, and Wnt/β-catenin pathways in EMT due to a potent active compound that is present therein.

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Metastatic EMT Phenotype Is Governed by MicroRNA-200-Mediated Competing Endogenous RNA Networks

Cells ◽

10.3390/cells11010073 ◽

2021 ◽

Vol 11 (1) ◽

pp. 73

Author(s):

Sara Uhan ◽

Nina Hauptman

Keyword(s):

Large Scale ◽

Transcriptional Control ◽

Epithelial Mesenchymal Transition ◽

Mesenchymal Cell ◽

Cell Phenotype ◽

Competing Endogenous Rna ◽

Protein Coding ◽

Factors Affecting ◽

Mesenchymal Transition ◽

Metastatic Dissemination

Epithelial–mesenchymal transition (EMT) is a fundamental physiologically relevant process that occurs during morphogenesis and organ development. In a pathological setting, the transition from epithelial toward mesenchymal cell phenotype is hijacked by cancer cells, allowing uncontrolled metastatic dissemination. The competing endogenous RNA (ceRNA) hypothesis proposes a competitive environment resembling a large-scale regulatory network of gene expression circuits where alterations in the expression of both protein-coding and non-coding genes can make relevant contributions to EMT progression in cancer. The complex regulatory diversity is exerted through an array of diverse epigenetic factors, reaching beyond the transcriptional control that was previously thought to single-handedly govern metastatic dissemination. The present review aims to unravel the competitive relationships between naturally occurring ceRNA transcripts for the shared pool of the miRNA-200 family, which play a pivotal role in EMT related to cancer dissemination. Upon acquiring more knowledge and clinical evidence on non-genetic factors affecting neoplasia, modulation of the expression levels of diverse ceRNAs may allow for the development of novel prognostic/diagnostic markers and reveal potential targets for the disruption of cancer-related EMT.

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Identification of Circulating Tumor Cell Phenotype in Differentiated Thyroid Carcinoma

Journal of Biomaterials and Tissue Engineering ◽

10.1166/jbt.2022.2957 ◽

2022 ◽

Vol 12 (4) ◽

pp. 813-819

Author(s):

Huiling Wang ◽

Mian Lv ◽

Yonghong Huang ◽

Xiaoming Pan ◽

Changyuan Wei

Keyword(s):

Thyroid Carcinoma ◽

Epithelial To Mesenchymal Transition ◽

Epithelial Mesenchymal Transition ◽

Circulating Tumor Cell ◽

Differentiated Thyroid Carcinoma ◽

Clinicopathological Characteristics ◽

Cell Phenotype ◽

Mesenchymal Transition ◽

Male Patients ◽

Emt Markers

Objective: Circulating tumor cells (CTCs) have been considered as the origin of tumor metastasis and recurrence, which always indicate a poor prognosis. There are three phenotypes of CTCs according on different epithelial-to-mesenchymal transition (EMT) markers, including epithelial, mesenchymal, and epithelial/mesenchymal (mixed phenotypic) CTCs. We intended to explore the relationship among CTC phenotypes and the clinicopathological characteristics of patients with differentiated thyroid carcinoma (DTC). Methods: Peripheral blood samples from 58 patients with DTC were collected, and CTCs were isolated by cell sizes. To identify phenotypes of CTCs, branched DNA signal amplification technology was adopted to capture and amplify target sequences, and then multiplex RNA-in situ hybridization (RNA-ISH) assay was used to identify CTC phenotypes depended on epithelial-mesenchymal transition (EMT) markers. Results: The positive rate of CTCs was 77.59% in 58 DTC patients. Totally, 488 CTCs with detective phenotype were found. Among them, there were 121 (24.80%) epithelial CTCs, 67 (13.72%) mesenchymal CTCs, and 300 (61.48%) mixed phenotypic CTCs. An obvious increased epithelial CTCs was observed in male patients compared with female. Notably, CTCs were more prevailing in younger male patients with ETI and bilateral focus. Conclusions: The CTCs are common in DTC patients, and mixed phenotypic is the major phenotype, indicating that EMT is prevalent in DTC even though its prognosis was better than other epithelial tumors. Detection of CTC and its phenotypes might independently predict the prognosis of DTC.

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The potential of Olea europaea extracts to prevent TGFβ1-induced epithelial to mesenchymal transition in human nasal respiratory epithelial cells

BMC Complementary and Alternative Medicine ◽

10.1186/s12906-018-2250-5 ◽

2018 ◽

Vol 18 (1) ◽

Cited By ~ 3

Author(s):

Rabiatul Adawiyah Razali ◽

Nik Ahmad Hafiz Nik Ahmad Eid ◽

Turkambigai Jayaraman ◽

Muhammad Asyrafi Amir Hassan ◽

Nabilah Qistina Azlan ◽

...

Keyword(s):

Epithelial Cells ◽

Olea Europaea ◽

Epithelial To Mesenchymal Transition ◽

Respiratory Epithelial Cells ◽

Mesenchymal Transition ◽

Respiratory Epithelial ◽

Olea Europaéa

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Mini Review : Liver Fibrosis Mechanism

KnE Life Sciences ◽

10.18502/kls.v3i6.1141 ◽

2017 ◽

Vol 3 (6) ◽

pp. 327

Author(s):

Wiwik Misaco Yuniarti ◽

Hardany Primarizky

Keyword(s):

Bone Marrow ◽

Wound Healing ◽

Liver Fibrosis ◽

Chronic Condition ◽

Epithelial To Mesenchymal Transition ◽

Healing Process ◽

Wound Healing Process ◽

Mesenchymal Transition ◽

Liver Fibrogenesis ◽

Severe Disorder

Liver fibrosis is the process of wound healing in the liver that caused by a various causes. The longer time of wound healing process, the more severe disorder will be. This chronic condition is characterized by excessive deposition of extracellular matrix then ended with fribrosis. This mini review describes about the phase of liver fibrogenesis. Even though there are many variations of fibrogenesis in animals and human, in general there are three fibrogenic cells that involved in fibrogenesis. These three cells are fibroblast or endogenous fibroblast like-cells, epithelial to mesenchymal transition (EMT), and fibrocytes that derived from bone-marrow. Keywords : liver, fibrosis, fibroblast, EMT, fibrocytes, collagen

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Fibroblast growth factor 2 accelerates the epithelial–mesenchymal transition in keratinocytes during wound healing process

Scientific Reports ◽

10.1038/s41598-020-75584-7 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Yuta Koike ◽

Mariko Yozaki ◽

Atsushi Utani ◽

Hiroyuki Murota

Keyword(s):

Wound Healing ◽

Growth Factor ◽

Fibroblast Growth Factor ◽

Wound Closure ◽

Epithelial Mesenchymal Transition ◽

Healing Process ◽

Wound Healing Process ◽

Fibroblast Growth ◽

Wound Edge ◽

Mesenchymal Transition

Abstract In the wound healing process, the morphology of keratinocytes at the wound edge temporarily changes to a spindle morphology, which is thought to occur due to an epithelial–mesenchymal transition (EMT). Fibroblast growth factor (FGF) 2, also called basic FGF, has the potential to accelerate wound closure by activating vascular endothelial cells and fibroblasts. We examined the effects of FGF2 on keratinocyte morphology and EMT in wounded skin. Histological examination of murine wounds treated with FGF2 revealed that wound edge keratinocytes formed thickened and multilayered epithelia. In addition, we detected wound edge keratinocytes migrating individually toward the wound center. These migrating keratinocytes exhibited not only spindle morphology but also down-regulated E-cadherin and up-regulated vimentin expression, which is characteristic of EMT. In FGF2-treated wounds, a PCR array revealed the upregulation of genes related to EMT, including transforming growth factor (TGF) signaling. Further, FGF2-treated wound edge keratinocytes expressed EMT-associated transcription factors, including Snai2, and showed translocation of β-catenin from the cell membrane to the cytoplasm/nucleus. However, in vitro examination of keratinocytes revealed that FGF2 alone did not activate EMT in keratinocytes, but that FGF2 might promote EMT in combination with TGFβ1. These findings suggest that FGF2 treatment of wounds could promote keratinocyte EMT, accelerating wound closure.

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Antifibrotic Effect of Smad Decoy Oligodeoxynucleotide in a CCl4-Induced Hepatic Fibrosis Animal Model

Molecules ◽

10.3390/molecules23081991 ◽

2018 ◽

Vol 23 (8) ◽

pp. 1991 ◽

Cited By ~ 4

Author(s):

Mi-Gyeong Gwon ◽

Jung-Yeon Kim ◽

Hyun-Jin An ◽

Woon-Hae Kim ◽

Hyemin Gu ◽

...

Keyword(s):

Hepatic Fibrosis ◽

Epithelial Mesenchymal Transition ◽

Healing Process ◽

Wound Healing Process ◽

Complementary Sequence ◽

Mesenchymal Transition ◽

Synthetic Dna ◽

Ccl4 Treatment ◽

End Stage ◽

Histological Results

Hepatic fibrosis is the wound-healing process of chronic hepatic disease that leads to the end-stage of hepatocellular carcinoma and demolition of hepatic structures. Epithelial–mesenchymal transition (EMT) has been identified to phenotypic conversion of the epithelium to mesenchymal phenotype that occurred during fibrosis. Smad decoy oligodeoxynucleotide (ODN) is a synthetic DNA fragment containing a complementary sequence of Smad transcription factor. Thus, this study evaluated the antifibrotic effects of Smad decoy ODN on carbon tetrachloride (CCl4)-induced hepatic fibrosis in mice. As shown in histological results, CCl4 treatment triggered hepatic fibrosis and increased Smad expression. On the contrary, Smad decoy ODN administration suppressed fibrogenesis and EMT process. The expression of Smad signaling and EMT-associated protein was markedly decreased in Smad decoy ODN-treated mice compared with CCl4-injured mice. In conclusion, these data indicate the practicability of Smad decoy ODN administration for preventing hepatic fibrosis and EMT processes.

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Role of the ABL tyrosine kinases in the epithelial–mesenchymal transition and the metastatic cascade

Cell Communication and Signaling ◽

10.1186/s12964-021-00739-6 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Jillian Hattaway Luttman ◽

Ashley Colemon ◽

Benjamin Mayro ◽

Ann Marie Pendergast

Keyword(s):

Solid Tumors ◽

Tyrosine Kinases ◽

Epithelial To Mesenchymal Transition ◽

Kinase Inhibitors ◽

Epithelial Mesenchymal Transition ◽

Therapeutic Effects ◽

Mesenchymal Transition ◽

Metastatic Cascade ◽

Abl Kinases ◽

Treatment Paradigm

AbstractThe ABL kinases, ABL1 and ABL2, promote tumor progression and metastasis in various solid tumors. Recent reports have shown that ABL kinases have increased expression and/or activity in solid tumors and that ABL inactivation impairs metastasis. The therapeutic effects of ABL inactivation are due in part to ABL-dependent regulation of diverse cellular processes related to the epithelial to mesenchymal transition and subsequent steps in the metastatic cascade. ABL kinases target multiple signaling pathways required for promoting one or more steps in the metastatic cascade. These findings highlight the potential utility of specific ABL kinase inhibitors as a novel treatment paradigm for patients with advanced metastatic disease.

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The Epithelial–Mesenchymal Transcription Factor SNAI1 Represses Transcription of the Tumor Suppressor miRNA let-7 in Cancer

Cancers ◽

10.3390/cancers13061469 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1469

Author(s):

Hanmin Wang ◽

Evgeny Chirshev ◽

Nozomi Hojo ◽

Tise Suzuki ◽

Antonella Bertucci ◽

...

Keyword(s):

Ovarian Cancer ◽

Stem Cell ◽

Cancer Cells ◽

Epithelial Mesenchymal Transition ◽

Tumor Burden ◽

Cell Phenotype ◽

Mesenchymal Transition ◽

Carcinoma Cell Lines ◽

Future Work

We aimed to determine the mechanism of epithelial–mesenchymal transition (EMT)-induced stemness in cancer cells. Cancer relapse and metastasis are caused by rare stem-like cells within tumors. Studies of stem cell reprogramming have linked let-7 repression and acquisition of stemness with the EMT factor, SNAI1. The mechanisms for the loss of let-7 in cancer cells are incompletely understood. In four carcinoma cell lines from breast cancer, pancreatic cancer, and ovarian cancer and in ovarian cancer patient-derived cells, we analyzed stem cell phenotype and tumor growth via mRNA, miRNA, and protein expression, spheroid formation, and growth in patient-derived xenografts. We show that treatment with EMT-promoting growth factors or SNAI1 overexpression increased stemness and reduced let-7 expression, while SNAI1 knockdown reduced stemness and restored let-7 expression. Rescue experiments demonstrate that the pro-stemness effects of SNAI1 are mediated via let-7. In vivo, nanoparticle-delivered siRNA successfully knocked down SNAI1 in orthotopic patient-derived xenografts, accompanied by reduced stemness and increased let-7 expression, and reduced tumor burden. Chromatin immunoprecipitation demonstrated that SNAI1 binds the promoters of various let-7 family members, and luciferase assays revealed that SNAI1 represses let-7 transcription. In conclusion, the SNAI1/let-7 axis is an important component of stemness pathways in cancer cells, and this study provides a rationale for future work examining this axis as a potential target for cancer stem cell-specific therapies.

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Associations between the Epithelial-Mesenchymal Transition Phenotypes of Circulating Tumor Cells and the Clinicopathological Features of Patients with Colorectal Cancer

Disease Markers ◽

10.1155/2017/9474532 ◽

2017 ◽

Vol 2017 ◽

pp. 1-6 ◽

Cited By ~ 7

Author(s):

Fengjie Wu ◽

Jun Zhu ◽

Yongjiang Mao ◽

Xiaomei Li ◽

Baoguang Hu ◽

...

Keyword(s):

Colorectal Cancer ◽

Peripheral Blood ◽

Epithelial Mesenchymal Transition ◽

Mesenchymal Cell ◽

Blood Samples ◽

Mesenchymal Transition ◽

Enrichment Technique ◽

Tumor Node Metastasis Stage ◽

Mesenchymal Cell Marker ◽

Circulating Tumor Microemboli

In this study, we identified CTCs using the previously reported CanPatrol CTC enrichment technique from peripheral blood samples of 126 patients with colorectal cancer (CRC) and found that CTCs could be classified into three subpopulations based on expression of epithelial cell adhesion molecule (EpCAM) (E-CTCs), the mesenchymal cell marker vimentin (M-CTCs), or both EpCAM and vimentin (biphenotypic E/M-CTCs). Circulating tumor microemboli (CTMs) were also identified in peripheral blood samples. Meanwhile, E-CTCs, M-CTCs, E/M-CTCs, and CTMs were detected in 76.98%, 42.06%, 56.35%, and 36.51% of the 126 patients, respectively. Interestingly, the presence of CTMs and each CTC subpopulation was significantly associated with blood lymphocyte counts and tumor-node-metastasis stage (P<0.001). Lymphocyte counts and the neutrophil-to-lymphocyte ratio (NLR) in patients lacking CTCs were significantly different from those in patients testing positive for CTMs and each CTC subpopulation (P<0.001). Our results indicate that tumor metastasis is more significantly associated with the presence of CTMs and M-CTCs than with other CTC subpopulations and suggest that EMT may be involved in CTC evasion of lymphocyte-mediated clearance.

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Cytoplasmic NOTCH and membrane-derived β-catenin link cell fate choice to epithelial-mesenchymal transition during myogenesis

eLife ◽

10.7554/elife.14847 ◽

2016 ◽

Vol 5 ◽

Cited By ~ 21

Author(s):

Daniel Sieiro ◽

Anne C Rios ◽

Claire E Hirst ◽

Christophe Marcelle

Keyword(s):

Cell Fate ◽

Epithelial To Mesenchymal Transition ◽

Epithelial Mesenchymal Transition ◽

Mesenchymal Transition ◽

Epithelial Plasticity ◽

Cellular Environment ◽

Muscle Formation ◽

Fate Decision ◽

Gsk 3Β ◽

Coupling Cell

How cells in the embryo coordinate epithelial plasticity with cell fate decision in a fast changing cellular environment is largely unknown. In chick embryos, skeletal muscle formation is initiated by migrating Delta1-expressing neural crest cells that trigger NOTCH signaling and myogenesis in selected epithelial somite progenitor cells, which rapidly translocate into the nascent muscle to differentiate. Here, we uncovered at the heart of this response a signaling module encompassing NOTCH, GSK-3β, SNAI1 and β-catenin. Independent of its transcriptional function, NOTCH profoundly inhibits GSK-3β activity. As a result SNAI1 is stabilized, triggering an epithelial to mesenchymal transition. This allows the recruitment of β-catenin from the membrane, which acts as a transcriptional co-factor to activate myogenesis, independently of WNT ligand. Our results intimately associate the initiation of myogenesis to a change in cell adhesion and may reveal a general principle for coupling cell fate changes to EMT in many developmental and pathological processes.

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