Tissue remodeling in eosinophilic esophagitis

Eosinophilic esophagitis (EoE) is a recently recognized, immune-mediated disease characterized clinically by symptoms of esophageal dysfunction and histologically by eosinophil-predominant inflammation. The chronic esophageal eosinophilia of EoE is associated with tissue remodeling that includes epithelial hyperplasia, subepithelial fibrosis, and hypertrophy of esophageal smooth muscle. This remodeling causes the esophageal rings and strictures that frequently complicate EoE and underlies the mucosal fragility that predisposes to painful mucosal tears in the EoE esophagus. The pathogenesis of tissue remodeling in EoE is not completely understood, but emerging studies suggest that secretory products of eosinophils and mast cells, as well as cytokines produced by other inflammatory cells, epithelial cells, and stromal cells in the esophagus, all contribute to the process. Interleukin (IL)-4 and IL-13, Th2 cytokines overproduced in allergic disorders, have direct profibrotic and remodeling effects in EoE. The EoE esophagus exhibits increased expression of transforming growth factor (TGF)-β1, which is a potent activator of fibroblasts and a strong inducer of epithelial-mesenchymal transition. In addition, IL-4, IL-13, and TGF-β all have a role in regulating periostin, an extracellular matrix protein that might influence remodeling by acting as a ligand for integrins, by its effects on eosinophils or by activating fibrogenic genes in the esophagus. Presently, few treatments have been shown to affect the tissue remodeling that causes EoE complications. This report reviews the potential roles of fibroblasts, eosinophils, mast cells, and profibrotic cytokines in esophageal remodeling in EoE and identifies potential targets for future therapies that might prevent EoE complications.

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Baicalein inhibits fibronectin-induced epithelial–mesenchymal transition by decreasing activation and upregulation of calpain-2

Cell Death and Disease ◽

10.1038/s41419-019-1572-7 ◽

2019 ◽

Vol 10 (5) ◽

Cited By ~ 4

Author(s):

Yan Chen ◽

Lin Chen ◽

Duanyang Hong ◽

Zongyue Chen ◽

Jingyu Zhang ◽

...

Keyword(s):

Breast Cancer ◽

Extracellular Matrix ◽

Cellular Response ◽

Matrix Protein ◽

Epithelial Mesenchymal Transition ◽

T Antigen ◽

Extracellular Matrix Protein ◽

Mesenchymal Transition ◽

Calpain 2 ◽

E Cadherin

AbstractThe extracellular matrix protein fibronectin (FN) facilitates tumorigenesis and the development of breast cancer. Inhibition of the FN-induced cellular response is a potential strategy for breast cancer treatment. In the present study, we investigated the effects of the flavonoid baicalein on FN-induced epithelial–mesenchymal transition (EMT) in MCF-10A breast epithelial cells and in a transgenic mouse MMTV-polyoma middle T antigen breast cancer model (MMTV-PyMT). Baicalein inhibited FN-induced migration, invasion, and F-actin remodeling. Baicalein also suppressed FN-induced downregulation of the epithelial markers E-cadherin and ZO-1 and upregulation of the mesenchymal markers N-cadherin, vimentin, and Snail. Further investigation revealed that calpain-2 was involved in baicalein suppression of FN-induced EMT. Baicalein significantly decreased FN-enhanced calpain-2 expression and activation by suppressing its plasma membrane localization, substrate cleavage, and degradation of its endogenous inhibitor calpastatin. Overexpression of calpain-2 in MCF-10A cells by gene transfection partially blocked the inhibitory effect of baicalein on FN-induced EMT changes. In addition, baicalein inhibited calpain-2 by decreasing FN-increased intracellular calcium ion levels and extracellular signal-regulated protein kinases activation. Baicalein significantly decreased tumor onset, growth, and pulmonary metastasis in a spontaneous breast cancer MMTV-PyMT mouse model. Baicalein also reduced the expression of FN, calpain-2, and vimentin, but increased E-cadherin expression in MMTV-PyMT mouse tumors. Overall, these results revealed that baicalein markedly inhibited FN-induced EMT by inhibiting calpain-2, thus providing novel insights into the pharmacological action and mechanism of baicalein. Baicalein may therefore possess therapeutic potential for the treatment of breast cancer though interfering with extracellular matrix–cancer cell interactions.

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EDIL3 promotes epithelial–mesenchymal transition and paclitaxel resistance through its interaction with integrin αVβ3 in cancer cells

Cell Death Discovery ◽

10.1038/s41420-020-00322-x ◽

2020 ◽

Vol 6 (1) ◽

Author(s):

J. Gasca ◽

M. L. Flores ◽

R. Jiménez-Guerrero ◽

M. E. Sáez ◽

I. Barragán ◽

...

Keyword(s):

Tumor Progression ◽

Cancer Cells ◽

Matrix Protein ◽

Epithelial Mesenchymal Transition ◽

Chemotherapy Resistance ◽

Integrin Αvβ3 ◽

Extracellular Matrix Protein ◽

Paclitaxel Resistance ◽

Mesenchymal Transition ◽

Breast And Prostate Cancer

Abstract Epithelial–mesenchymal transition (EMT) has recently been associated with tumor progression, metastasis, and chemotherapy resistance in several tumor types. We performed a differential gene expression analysis comparing paclitaxel-resistant vs. paclitaxel-sensitive breast cancer cells that showed the upregulation of EDIL3 (EGF Like Repeats and Discoidin I Like Domains Protein 3). This gene codifies an extracellular matrix protein that has been identified as a novel regulator of EMT, so we studied its role in tumor progression and paclitaxel response. Our results demonstrated that EDIL3 expression levels were increased in paclitaxel-resistant breast and prostate cancer cells, and in subsets of high-grade breast and prostate tumors. Moreover, we observed that EDIL3 modulated the expression of EMT markers and this was impaired by cilengitide, which blocks the EDIL3–integrin αVβ3 interaction. EDIL3 knockdown reverted EMT and sensitized cells to paclitaxel. In contrast, EDIL3 overexpression or the culture of cells in the presence of EDIL3-enriched medium induced EMT and paclitaxel resistance. Adding cilengitide resensitized these cells to paclitaxel treatment. In summary, EDIL3 may contribute to EMT and paclitaxel resistance through autocrine or paracrine signaling in cancer cells. Blockade of EDIL3–integrin αVβ3 interaction by cilengitide restores sensitivity to paclitaxel and reverts EMT in paclitaxel-resistant cancer cells. Combinations of cilengitide and taxanes could be beneficial in the treatment of subsets of breast and prostate cancers.

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Detection and analysis of long noncoding RNA expression profiles related to epithelial–mesenchymal transition in keloids

BioMedical Engineering OnLine ◽

10.1186/s12938-022-00976-x ◽

2022 ◽

Vol 21 (1) ◽

Author(s):

Zhixiong Chen ◽

Xi Chu ◽

Jinghong Xu

Keyword(s):

Differential Expression ◽

Noncoding Rna ◽

Matrix Protein ◽

Epithelial Mesenchymal Transition ◽

Expression Profiles ◽

Normal Skin ◽

Differentially Expressed ◽

Extracellular Matrix Protein ◽

Mesenchymal Transition ◽

Promote Cell Proliferation

Abstract Background The role of epithelial-mesenchymal transition (EMT) in the pathogenesis of keloids is currently raising increasing attention. Long noncoding RNAs (lncRNAs) govern a variety of biological processes, such as EMT, and their dysregulation is involved in many diseases including keloid disease. The aim of this study was to identify differentially expressed EMT-related lncRNAs in keloid tissues versus normal tissues and to interpret their functions. Results Eleven lncRNAs and 16 mRNAs associated with EMT were identified to have differential expression between keloid and normal skin tissues (fold change > 1.5, P < 0.05). Gene Ontology (GO) analysis showed that these differentially expressed mRNAs functioned in the extracellular matrix, protein binding, the positive regulation of cellular processes, the Set1C/COMPASS complex and histone acetyltransferase activity. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis demonstrated that these mRNAs are involved in pathways in cancer. The lncRNA, XLOC_000587 may promote cell proliferation and migration by enhancing the expression of ENAH, while AF268386 may facilitate the invasive growth of keloids by upregulating DDR2. Conclusions We characterized the differential expression profiles of EMT-related lncRNAs and mRNAs in keloids, which may contribute to preventing the occurrence and development of keloids by targeting the corresponding signaling pathways. These lncRNAs and mRNAs may provide biomarkers for keloid diagnosis and serve as potential targets for the treatment of this disease.

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FSIP1 binds HER2 directly to regulate breast cancer growth and invasiveness

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1621486114 ◽

2017 ◽

Vol 114 (29) ◽

pp. 7683-7688 ◽

Cited By ~ 9

Author(s):

Tong Liu ◽

Hao Zhang ◽

Li Sun ◽

Danyu Zhao ◽

Peng Liu ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Matrix Protein ◽

Epithelial Mesenchymal Transition ◽

Gene Signature ◽

Extracellular Matrix Protein ◽

Breast Cancers ◽

Fibrous Sheath ◽

Mesenchymal Transition

Fibrous sheath interacting protein 1 (FSIP1), a spermatogenesis-related testicular antigen, is expressed in abundance in breast cancers, particularly in those overexpressing human epidermal growth factor receptor 2 (HER2); however, little is known about its role in regulating the growth and metastasis of breast cancer cells. We and others have shown previously that FSIP1 expression in breast cancer correlates positively with HER2-positivity, recurrence, and metastases and negatively with survival. Here, using coimmunoprecipitation and microscale thermophoresis, we find that FSIP1 binds to the intracellular domain of HER2 directly. We further show that shRNA-inducedFSIP1knockdown in SKBR3 and MCF-7 breast cancer cells inhibits proliferation, stimulates apoptosis, attenuates epithelial–mesenchymal transition, and impairs migration and invasiveness. Consistent with reduced proliferation and enhanced apoptosis, xenotransplantation of SKBR3 cells stably transfected with sh-FSIP1intonu/numice results in reduced tumor volumes compared with sh-NC transplants. Furthermore, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) mapping using sh-FSIP1gene signature yielded associations with extracellular matrix protein pathways, and a reduction in SNAI2 protein expression was confirmed on Western blot analysis. Complementarily, interrogation of the Connectivity Map using the same gene signature yielded, as top hits, chemicals known to inhibit epithelial–mesenchymal transition, including rapamycin, 17-N-allylamino-17-demethoxygeldanamycin, and LY294002. These compounds phenocopy the effects of sh-FSIP1on SKBR3 cell viability. Thus, FSIP1 suppression limits oncogenesis and invasiveness in breast cancer cells and, considering its absence in most other tissues, including normal breast, may become a potential target for breast cancer therapy.

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Prognostic and predictive significance of osteopontin in malignant neoplasms

Advances in molecular oncology ◽

10.17650/2313-805x-2021-8-2-23-28 ◽

2021 ◽

Vol 8 (2) ◽

pp. 23-28

Author(s):

E. Yu. Zubareva ◽

M. A. Senchukova

Keyword(s):

Functional Role ◽

Matrix Protein ◽

Epithelial Mesenchymal Transition ◽

Immunological Tolerance ◽

Extracellular Matrix Protein ◽

Malignant Neoplasms ◽

Biological Processes ◽

Mesenchymal Transition ◽

Different Types ◽

Integrated Study

Osteopontin is an extracellular matrix protein which is produced by different types of cells and plays an important functional role in many biological processes. This review discusses the main functions of osteopontin, its role in the progression and chemoresistance of malignant neoplasms, in the regulation of epithelial-mesenchymal transition, angiogenesis, and the body’s immune response to the tumor. The article considers the currently known mechanisms by which osteopontin affects to the survival, mobility and invasion of tumor cells, to tumor sensitivity to drug treatment, as well as the prospects for a integrated study of the predictive significance of osteopontin, markers of hypoxia, angiogenesis, epithelial- mesenchymal transition, and immunological tolerance.

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C3a and C5a Stimulate Chemotaxis of Human Mast Cells

Blood ◽

10.1182/blood.v89.8.2863 ◽

1997 ◽

Vol 89 (8) ◽

pp. 2863-2870 ◽

Cited By ~ 204

Author(s):

Karin Hartmann ◽

Beate M. Henz ◽

Sabine Krüger-Krasagakes ◽

Jörg Köhl ◽

Reinhard Burger ◽

...

Keyword(s):

Growth Factor ◽

Mast Cells ◽

Matrix Protein ◽

Transforming Growth Factor ◽

Extracellular Matrix Protein ◽

Human Mast Cell ◽

Free Calcium ◽

Human Cord Blood ◽

Human Mast Cells ◽

Chemotactic Factors

Abstract The factors that control migration of mast cells to sites of inflammation and tissue repair remain largely undefined. Whereas several recent studies have described chemotactic factors that induce migration of murine mast cells, only stem cell factor (SCF ) is known to induce migration of human mast cells. We report here that the anaphylatoxins C3a and C5a are chemotactic factors for the human mast cell line HMC-1, human cord blood-derived mast cells (CBMC) and cutaneous mast cells in vitro. The presence of an extracellular matrix protein, laminin, was required for chemotaxis in response to complement peptides. Migration of mast cells towards C3a and C5a was dose-dependent, peaking at 1 μg/mL (100 nmol/L), and was inhibited by specific antibodies. Pretreatment with pertussis toxin inhibited the anaphylatoxin-mediated migration of HMC-1 cells, indicating that Gi proteins are involved in complement-activated signal transduction pathways in human mast cells. Both C3a and C5a also induced a rapid and transient mobilization of intracellular free calcium ([Ca2+]i ) in HMC-1 cells. Besides SCF, other chemotactic factors tested, such as interleukin-3, nerve growth factor, transforming growth factor β, RANTES (regulated upon activation, normal T cell expressed and secreted), monocyte chemotactic protein-1 (MCP-1), MCP-2, MCP-3, macrophage inflammatory protein-1α (MIP-1α), and MIP-1β, failed to stimulate migration of human mast cells. In summary, these findings indicate that C3a and C5a serve as chemotaxins for human mast cells. Anaphylatoxin-mediated recruitment of mast cells might play an important role in hypersensitivity and inflammatory processes.

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Bisphenol A-induced epithelial-mesenchymal transition was reversed with a phytoestrogen, genistein via oestrogen receptor and downregulation of transforming growth factor-beta signalling pathway

Endocrine Abstracts ◽

10.1530/endoabs.37.oc2.5 ◽

2015 ◽

Author(s):

Ye-Seul Kim ◽

Kyung-A Hwang ◽

Kyung-Chul Choi

Keyword(s):

Growth Factor ◽

Bisphenol A ◽

Transforming Growth Factor Beta ◽

Oestrogen Receptor ◽

Transforming Growth Factor ◽

Epithelial Mesenchymal Transition ◽

Signalling Pathway ◽

Mesenchymal Transition ◽

Growth Factor Beta

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Different macrophages equally induce EMT in endometria of adenomyosis and normal

Reproduction ◽

10.1530/rep-17-0174 ◽

2017 ◽

Vol 154 (1) ◽

pp. 79-92 ◽

Cited By ~ 7

Author(s):

Min An ◽

Dong Li ◽

Ming Yuan ◽

Qiuju Li ◽

Lu Zhang ◽

...

Keyword(s):

Epithelial Cells ◽

Transforming Growth Factor ◽

Epithelial Mesenchymal Transition ◽

Quantitative Polymerase Chain Reaction ◽

Immunohistochemical Analysis ◽

Secretory Phase ◽

Normal Endometrium ◽

Mesenchymal Transition ◽

Expression Levels ◽

Endometrial Cells

Endometrial cells and microenvironment are two important factors in the pathogenesis of adenomyosis. Our previous study demonstrated that macrophages can induce eutopic epithelial cells of adenomyosis to suffer from epithelial–mesenchymal transition (EMT). The aim of this study is to detect whether macrophages interacting with epithelial cells equally induce the EMT process in normal and eutopic endometria of healthy and adenomyotic patients; and whether macrophages parallelly polarize to M2. We investigated the expression levels of epithelial cadherin (E-cadherin), neural cadherin (N-cadherin), cytokeratin7 (CK7), vimentin, transforming growth factor-β1 (TGFB1), SMAD3 and pSMAD3 using immunohistochemistry and western blot, and then estimated the genetic levels of CD163, IL10 and MMP12 using real-time quantitative polymerase chain reaction (RT-PCR) in macrophages. Eutopic and normal endometrial tissues were obtained from 20 patients with adenomyosis and 11 control patients without adenomyosis, respectively. The immunohistochemical analysis shows distinct EMT in eutopic endometria in secretory phase; the expression levels of TGFB1, SMAD3 and pSMAD3 that indicate signal pathway of EMT were also higher in secretory phase. Macrophages can induce EMT process in primary endometrial epithelial cells derived from normal and eutopic endometria. After co-culturing, THP-1-derived macrophages polarized to M2. Compared with the eutopic endometrium group, further polarization to M2 was observed in the normal endometrium group. These results indicate that adenomyosis may be promoted by the pathologic EMT of epithelial cells, which is induced by macrophages that incapably polarize to M2.

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