scholarly journals A molecular and cellular analysis of human embryonic optic fissure closure related to the eye malformation coloboma

Development ◽  
2020 ◽  
Vol 147 (24) ◽  
pp. dev193649
Author(s):  
Aara Patel ◽  
Glenn Anderson ◽  
Gabriel L. Galea ◽  
Monika Balys ◽  
Jane C. Sowden
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Gene Set Enrichment ◽  
Mesenchymal Transition ◽  
Signature Genes ◽  
Cellular Analysis ◽  
Expression Of Genes ◽  
Optic Cup ◽  
Epithelial Fusion ◽  
Epithelial Layers ◽  
Laser Capture

ABSTRACTOcular coloboma is a congenital eye malformation, resulting from a failure in optic fissure closure (OFC) and causing visual impairment. There has been little study of the epithelial fusion process underlying closure in the human embryo and coloboma aetiology remains poorly understood. We performed RNAseq of cell populations isolated using laser capture microdissection to identify novel human OFC signature genes and probe the expression profile of known coloboma genes, along with a comparative murine analysis. Gene set enrichment patterns showed conservation between species. Expression of genes involved in epithelial-to-mesenchymal transition was transiently enriched in the human fissure margins during OFC at days 41-44. Electron microscopy and histological analyses showed that cells transiently delaminate at the point of closure, and produce cytoplasmic protrusions, before rearranging to form two continuous epithelial layers. Apoptosis was not observed in the human fissure margins. These analyses support a model of human OFC in which epithelial cells at the fissure margins undergo a transient epithelial-to-mesenchymal-like transition, facilitating cell rearrangement to form a complete optic cup.

scholarly journals Specific Gene- and MicroRNA-Expression Pattern Contributes to the Epithelial to Mesenchymal Transition in a Rat Model of Experimental Colitis

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Éva Boros ◽  
Marianna Csatári ◽  
Csaba Varga ◽  
Balázs Bálint ◽  
István Nagy
Keyword(s):  
Expression Pattern ◽  
Rat Model ◽  
Epithelial To Mesenchymal Transition ◽  
Experimental Colitis ◽  
Microrna Expression ◽  
Specific Gene ◽  
Mesenchymal Transition ◽  
Expression Of Genes ◽  
Epithelial Marker ◽  
Male Wistar Rats

The aim of this study was to determine the gene- and microRNA-expression profile contributing to epithelial to mesenchymal transition in a rat model of experimental colitis. For this, inflammation was induced by injecting 2,4,6-trinitrobenzene sulphonic acid to the colon of male Wistar rats. Samples were taken from both inflamed and uninflamed regions of the same colon, total RNA was isolated, and the mRNA and microRNA expressions were monitored. We have determined that the expression of genes responsible for inducing mesenchymal phenotype, such as Egr1, Fgf2, Fgf7, Jak2, Notch2, Hif1α, Zeb2, Mmp9, Lox, and Vim, was all significantly induced in the inflamed regions of the affected colons while the epithelial marker E-cadherin (Cdh1) was downregulated. In contrast, the expression of microRNAs miR-192, miR-143, miR-375, miR-30a, miR-107, and miR-200b responsible for the regulation of the above mentioned genes was significantly downregulated in inflamed colon. Importantly, we detected moderate induction in the expression of five out of six tested microRNAs in the uninflamed regions. In summary, we identified numerous interacting genes and microRNAs with mutually exclusive expression pattern in inflamed regions of colitis-induced rats. These findings suggest that—among others—an important step in the epithelial to mesenchymal transition in experimental colitis is the dysregulated microRNA expression.

scholarly journals Interplay among SNAIL Transcription Factor, MicroRNAs, Long Non-Coding RNAs, and Circular RNAs in the Regulation of Tumor Growth and Metastasis

Cancers ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 209 ◽  
Author(s):  
Klaudia Skrzypek ◽  
Marcin Majka
Keyword(s):  
Transcription Factor ◽  
Tumor Growth ◽  
Epithelial To Mesenchymal Transition ◽  
Cell Metabolism ◽  
Circular Rnas ◽  
Mesenchymal Transition ◽  
Expression Of Genes ◽  
Non Coding Rnas ◽  
Tumor Growth And Metastasis ◽  
Novel Therapeutic Strategies

SNAIL (SNAI1) is a zinc finger transcription factor that binds to E-box sequences and regulates the expression of genes. It usually acts as a gene repressor, but it may also activate the expression of genes. SNAIL plays a key role in the regulation of epithelial to mesenchymal transition, which is the main mechanism responsible for the progression and metastasis of epithelial tumors. Nevertheless, it also regulates different processes that are responsible for tumor growth, such as the activity of cancer stem cells, the control of cell metabolism, and the regulation of differentiation. Different proteins and microRNAs may regulate the SNAIL level, and SNAIL may be an important regulator of microRNA expression as well. The interplay among SNAIL, microRNAs, long non-coding RNAs, and circular RNAs is a key event in the regulation of tumor growth and metastasis. This review for the first time discusses different types of regulation between SNAIL and non-coding RNAs with a focus on feedback loops and the role of competitive RNA. Understanding these mechanisms may help develop novel therapeutic strategies against cancer based on microRNAs.

scholarly journals Thymidylate synthase maintains the de-differentiated state of aggressive breast cancers

2018 ◽  
Author(s):  
Aarif Siddiqui ◽  
Paradesi Gollavilli ◽  
Annemarie Schwab ◽  
Maria Eleni Vazakidou ◽  
Pelin G Ersan ◽  
...  
Keyword(s):  
Thymidylate Synthase ◽  
Epithelial To Mesenchymal Transition ◽  
Nucleotide Metabolism ◽  
Strongly Correlated ◽  
Breast Cancers ◽  
Mesenchymal Transition ◽  
Signature Genes ◽  
Differentiated Cells

ABSTRACTCancer cells frequently boost nucleotide metabolism (NM) to support their increased proliferation, but the consequences of elevated NM on tumor de-differentiation are mostly unexplored. Here, we identified a role for thymidylate synthase (TS), a NM enzyme and established drug target, in cancer cell de-differentiation and investigated its clinical significance in breast cancer (BC).In vitro, TS knockdown increased the population of CD24+differentiated cells, and attenuated migration and sphere-formation. RNA-seq profiling indicated a repression of epithelial-to-mesenchymal transition (EMT) signature genes upon TS knockdown, and TS-deficient cells showed an increased ability to invade and metastasizein vivo, consistent with the occurrence of a partial EMT phenotype. Mechanistically, TS enzymatic activity was found essential for the maintenance of the EMT/stem-like state by fueling a DPYD-dependent pyrimidine catabolism. In patient tissues, TS levels were found significantly higher in poorly differentiated and in triple negative BC (TNBC), and strongly correlated with worse prognosis. The present study provides therationaleto study in-depth the role of NM at the crossroads of proliferation and differentiation, and depicts new avenues for the design of novel drug combinations for the treatment of BC.

scholarly journals Nonmuscle myosin IIA and IIB differentially modulate migration and alter gene expression in primary mouse tumorigenic cells

2019 ◽  
Vol 30 (12) ◽  
pp. 1463-1476 ◽  
Author(s):  
Debdatta Halder ◽  
Shekhar Saha ◽  
Raman K. Singh ◽  
Indranil Ghosh ◽  
Ditipriya Mallick ◽  
...  
Keyword(s):  
Gene Expression ◽  
Epithelial To Mesenchymal Transition ◽  
Pcr Analysis ◽  
Nonmuscle Myosin ◽  
Altered Expression ◽  
Mesenchymal Transition ◽  
Expression Of Genes ◽  
Primary Mouse ◽  
Perinuclear Area

Though many cancers are known to show up-regulation of nonmuscle myosin (NM) IIA and IIB, the mechanism by which NMIIs aid in cancer development remains unexplored. Here we demonstrate that tumor-generating, fibroblast-like cells isolated from 3-methylcholanthrene (3MC)-induced murine tumor exhibit distinct phospho-dependent localization of NMIIA and NMIIB at the perinuclear area and tip of the filopodia and affect cell migration differentially. While NMIIA-KD affects protrusion dynamics and increases cell directionality, NMIIB-KD lowers migration speed and increases filopodial branching. Strategically located NMIIs at the perinuclear area colocalize with the linker of nucleoskeleton and cytoskeleton (LINC) protein Nesprin2 and maintain the integrity of the nuclear-actin cap. Interestingly, knockdown of NMIIs results in altered expression of genes involved in epithelial-to-mesenchymal transition, angiogenesis, and cellular senescence. NMIIB-KD cells display down-regulation of Gsc and Serpinb2, which is strikingly similar to Nesprin2-KD cells as assessed by quantitative PCR analysis. Further gene network analysis predicts that NMIIA and NMIIB may act on similar pathways but through different regulators. Concomitantly, knockdown of NMIIA or NMIIB lowers the growth rate and tumor volume of 3MC-induced tumor in vivo. Altogether, these results open a new window to further investigate the effect of LINC-associated perinuclear actomyosin complex on mechanoresponsive gene expression in the growing tumor.

scholarly journals Polysome Profiling of a Human Glioblastoma Reveals Intratumoral Heterogeneity

2019 ◽  
Vol 20 (9) ◽  
pp. 2177 ◽  
Author(s):  
Fernanda Cristina Sulla Lupinacci ◽  
Hellen Kuasne ◽  
Martin Roffé ◽  
Julia Avian Vassalakis ◽  
Fernanda Ferreira da Silva ◽  
...  
Keyword(s):  
Translational Control ◽  
Tumor Heterogeneity ◽  
Epithelial To Mesenchymal Transition ◽  
Molecular Classification ◽  
High Grade ◽  
Translation Rate ◽  
Mesenchymal Transition ◽  
Expression Of Genes ◽  
Polysome Profiling

Glioblastoma (GBM) is one of the most aggressive cancers, with median survival of less than 2 years. Despite of considerable advance in molecular classification of GBMs, no improvements in therapy have been described. The scenario is further complicated by tumor heterogeneity and the relationship among genetic, transcriptional and functional findings. Classically, gene expression has been evaluated by steady-state mRNA, however, this does not take translational control into consideration, which contributes considerably to the composition of the proteome. In this study, we evaluated the transcriptomic and translatomic signature of a GBM obtained from a single patient focusing in tumor heterogeneity. In a sampling of eight fragments, we investigated the translation rates, mTORC1 and ERK1/2 pathways and identified both total and polysome associated mRNAs. An increased translation rate was observed in fragments with high-grade histological features. High-grade histology was also associated with the expression of genes related to extracellular matrix (ECM) and angiogenesis, in both transcriptomes and translatomes. However, genes associated with epithelial to mesenchymal transition and stress response, were observed only in translatomes from high-grade fragments. Overall, our results demonstrate that isolation of translated mRNA can be used to identify biomarkers and reveal previously unrecognized determinants of heterogeneity in GBMs.

scholarly journals Standard of Care and Promising New Agents for the Treatment of Mesenchymal Triple-Negative Breast Cancer

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1080
Author(s):  
Silvia Mezi ◽  
Andrea Botticelli ◽  
Giulia Pomati ◽  
Bruna Cerbelli ◽  
Simone Scagnoli ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Epithelial To Mesenchymal Transition ◽  
Triple Negative ◽  
Current Knowledge ◽  
Standard Of Care ◽  
Transition Process ◽  
Breast Cancer Patients ◽  
Mesenchymal Transition ◽  
Expression Of Genes

The pathologic definition of triple negative breast cancer (TNBC) relies on the absence of expression of estrogen, progesterone and HER2 receptors. However, this BC subgroup is distinguished by a wide biological, molecular and clinical heterogeneity. Among the intrinsic TNBC subtypes, the mesenchymal type is defined by the expression of genes involved in the epithelial to mesenchymal transition, stromal interaction and cell motility. Moreover, it shows a high expression of genes involved in proliferation and an immune-suppressive microenvironment. Several molecular alterations along different pathways activated during carcinogenesis and tumor progression have been outlined and could be involved in immune evasion mechanisms. Furthermore, reverting epithelial to mesenchymal transition process could lead to the overcoming of immune-resistance. This paper reviews the current knowledge regarding the mesenchymal TNBC subtype and its response to conventional therapeutic strategies, as well as to some promising molecular target agents and immunotherapy. The final goal is a tailored combination of cytotoxic drugs, target agents and immunotherapy in order to restore immunocompetence in mesenchymal breast cancer patients.

scholarly journals The Impact of the Nephrotoxin Ochratoxin A on Human Renal Cells Studied by a Novel Co-Culture Model Is Influenced by the Presence of Fibroblasts

Toxins ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 219
Author(s):  
Gerald Schwerdt ◽  
Michael Kopf ◽  
Michael Gekle
Keyword(s):  
Ochratoxin A ◽  
Energy Homeostasis ◽  
Epithelial To Mesenchymal Transition ◽  
Cell Types ◽  
Toxic Substances ◽  
Mesenchymal Transition ◽  
Expression Of Genes ◽  
Culture Model ◽  
Tubule Cells ◽  
The Impact

The kidney is threatened by a lot of potentially toxic substances. To study the influence of the nephrotoxin ochratoxin A (OTA) we established a cell co-culture model consisting of human renal proximal tubule cells and fibroblasts. We studied the effect of OTA on cell survival, the expression of genes and/or proteins related to cell death, extracellular matrix and energy homeostasis. OTA-induced necrosis was enhanced in both cell types in the presence of the respective other cell type, whereas OTA-induced apoptosis was independent therefrom. In fibroblasts, but not in tubule cells, a co-culture effect was visible concerning the expression of the cell-cycle-related protein p21. The expression of the epithelial-to-mesenchymal transition-indicating protein vimentin was independent from the culture-condition. The expression of the OTA-induced lncRNA WISP1-AS1 was enhanced in co-culture. OTA exposure led to alterations in the expression of genes related to energy metabolism with a glucose-mobilizing effect and a reduced expression of mitochondrial proteins. Together we demonstrate that the reaction of cells can be different in the presence of cells which naturally are close-by, thus enabling a cellular cross-talk. Therefore, to evaluate the toxicity of a substance, it would be an advantage to consider the use of co-cultures instead of mono-cultures.

scholarly journals The EMT regulator Zeb2/Sip1 is essential for murine embryonic hematopoietic stem/progenitor cell differentiation and mobilization

Blood ◽  
2011 ◽  
Vol 117 (21) ◽  
pp. 5620-5630 ◽  
Author(s):  
Steven Goossens ◽  
Viktor Janzen ◽  
Sonia Bartunkova ◽  
Tomomasa Yokomizo ◽  
Benjamin Drogat ◽  
...  
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Fetal Liver ◽  
Transcriptional Repressors ◽  
Adhesive Properties ◽  
Hematopoietic Stem ◽  
Mesenchymal Transition ◽  
Cellular Analysis ◽  
Conditional Deletion ◽  
E Box ◽  
Angiopoietin 1

Abstract Zeb2 (Sip1/Zfhx1b) is a member of the zinc-finger E-box–binding (ZEB) family of transcriptional repressors previously demonstrated to regulate epithelial-to-mesenchymal transition (EMT) processes during embryogenesis and tumor progression. We found high Zeb2 mRNA expression levels in HSCs and hematopoietic progenitor cells (HPCs), and examined Zeb2 function in hematopoiesis through a conditional deletion approach using the Tie2-Cre and Vav-iCre recombination mouse lines. Detailed cellular analysis demonstrated that Zeb2 is dispensable for hematopoietic cluster and HSC formation in the aorta-gonadomesonephros region of the embryo, but is essential for normal HSC/HPC differentiation. In addition, Zeb2-deficient HSCs/HPCs fail to properly colonize the fetal liver and/or bone marrow and show enhanced adhesive properties associated with increased β1 integrin and Cxcr4 expression. Moreover, deletion of Zeb2 resulted in embryonic (Tie2-Cre) and perinatal (Vav-icre) lethality due to severe cephalic hemorrhaging and decreased levels of angiopoietin-1 and, subsequently, improper pericyte coverage of the cephalic vasculature. These results reveal essential roles for Zeb2 in embryonic hematopoiesis and are suggestive of a role for Zeb2 in hematopoietic-related pathologies in the adult.

scholarly journals Intermittent Hypoxia Mediates Paraspeckle Protein-1 Upregulation in Sleep Apnea

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3888
Author(s):  
Elena Díaz-García ◽  
Sara García-Tovar ◽  
Raquel Casitas ◽  
Ana Jaureguizar ◽  
Ester Zamarrón ◽  
...  
Keyword(s):  
Sleep Apnea ◽  
Intracellular Signaling ◽  
Intermittent Hypoxia ◽  
Epithelial To Mesenchymal Transition ◽  
Hypoxia Inducible Factor ◽  
Matrix Metalloproteinase 2 ◽  
Mesenchymal Transition ◽  
Expression Of Genes ◽  
Obstructive Sleep ◽  
Cancer Aggressiveness

As some evidence suggests that hypoxia might be an inducer of nuclear paraspeckle formation, we explore whether intermittent hypoxia (IH)-mediated paraspeckle protein-1 (PSPC1) overexpression might contribute to the activation of tumor growth factor (TGF)β-SMAD pathway in patients with obstructive sleep apnea (OSA). This activation would promote changes in intracellular signaling that would explain the increased cancer aggressiveness reported in these patients. Here, we show that patients with OSA exhibit elevated PSPC1 levels both in plasma and in monocytes. Our data suggest that PSPC1 is ultimately delivered to the plasma through its cleavage from OSA monocytes by matrix metalloproteinase-2 (MMP2). In addition, IH promotes PSPC1, TGFβ, and MMP2 expression in monocytes through the hypoxia-inducible factor. Lastly, both PSPC1 and TGFβ induce increased expression of genes that drive the epithelial-to-mesenchymal transition. Our study details the mechanism by which hypoxemia upmodulates the extracellular release of PSPC1 by means of MMP2, such that plasma PSPC1 together with TGFβ activation signaling further promotes tumor metastasis and supports cancer aggressiveness in patients with OSA.

scholarly journals Resolving the heterogeneity of diaphragmatic mesenchyme: a novel mouse model of congenital diaphragmatic hernia

2021 ◽  
Vol 14 (1) ◽  
pp. dmm046797
Author(s):  
Louise Cleal ◽  
Sophie L. McHaffie ◽  
Martin Lee ◽  
Nick Hastie ◽  
Ofelia M. Martínez-Estrada ◽  
...  
Keyword(s):  
Congenital Diaphragmatic Hernia ◽  
Diaphragmatic Hernia ◽  
Epithelial To Mesenchymal Transition ◽  
Wilms Tumor ◽  
Cell Types ◽  
Lineage Tracing ◽  
Developmental Defect ◽  
Mortality And Morbidity ◽  
Mesenchymal Transition ◽  
Expression Of Genes

ABSTRACTCongenital diaphragmatic hernia (CDH) is a relatively common developmental defect with considerable mortality and morbidity. Formation of the diaphragm is a complex process that involves several cell types, each with different developmental origins. Owing to this complexity, the aetiology of CDH is not well understood. The pleuroperitoneal folds (PPFs) and the posthepatic mesenchymal plate (PHMP) are transient structures that are essential during diaphragm development. Using several mouse models, including lineage tracing, we demonstrate the heterogeneous nature of the cells that make up the PPFs. The conditional deletion of Wilms tumor 1 homolog (Wt1) in the non-muscle mesenchyme of the PPFs results in CDH. We show that the fusion of the PPFs and the PHMP to form a continuous band of tissue involves movements of cells from both sources. The PPFs of mutant mice fail to fuse with the PHMP and exhibit increased RALDH2 (also known as ALDH1A2) expression. However, no changes in the expression of genes (including Snai1, Snai2, Cdh1 and Vim) implicated in epithelial-to-mesenchymal transition are observed. Additionally, the mutant PPFs lack migrating myoblasts and muscle connective tissue fibroblasts (TCF4+/GATA4+), suggesting possible interactions between these cell types. Our study demonstrates the importance of the non-muscle mesenchyme in development of the diaphragm.

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