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Epithelial-Mesenchymal Transition (EMT) 2021
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Epithelial-Mesenchymal Transition (EMT) 2021

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (30 November 2021) | Viewed by 32960

Special Issue Editors

Prof. Dr. Monica Fedele

E-Mail Website
Guest Editor
CNR—Institute of Experimental Endocrinology and Oncology, 80131 Naples, Italy
Interests: molecular mechanisms of cancer cell transformation; PATZ1 in development and cancer; animal models; tumor biology
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Manfioletti Guidalberto

E-Mail Website
Guest Editor
Department of Life Sciences, University of Trieste, 34127 Trieste, Italy
Interests: high mobility group A (HMGA) proteins; chromatin; regulation of gene expression; protein–protein interactions; post-translational modifications (PTMs); epithelial–mesenchymal transition; proteomics; tumor microenvironment; breast cancer; metastasis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The epithelial–mesenchymal transition (EMT), a biological process that allows an epithelial cell to assume a mesenchymal phenotype, including enhanced migratory capacity, invasiveness, elevated resistance to apoptosis, stem-like features, and increased production of ECM components, occurs during specific steps of embryogenesis and organ development leading to final differentiation. Due to its plasticity and reversibility, terminally differentiated epithelium can transdifferentiate and change its phenotype through EMT. This process can also be activated in a pathological situation, such as tissue injury and repair or neoplastic transformation. Indeed, it is now well recognized that EMT constitutes the first step for the invasiveness and metastatic dissemination of epithelial cancer cells. Moreover, acquisition of mesenchymal features in non-epithelial cancers, such as glioblastomas, has been associated with invasiveness and aggressiveness of the tumor, together with a worse prognosis of the patients.

The EMT program is initiated by different molecular processes, including activation of transcriptional factors, expression of specific cell-surface proteins, reorganization and expression of cytoskeletal proteins, production of ECM-degrading enzymes, and changes in the expression of microRNAs. There are both endogenous cell autonomous and exogenous noncell autonomous signals occurring in the process, including pathways orchestrated by TGF-b, Notch, Wnt, Hedgehog, and receptor tyrosine kinases, as well as the urokinase plasminogen activator system, the secretome of associated fibroblasts, macrophages, cancer stem cells and cancer cells, and exosomes with their cargo of microRNAs.

However, despite intense investigation in recent years, relatively little is known about how all these components are integrated and participate in the same process, and how the mesenchymal state is maintained. Deep knowledge of these aspects will help to design potential therapeutic approaches that could exploit the plasticity of this process to reverse the metastatic phenotype of many cancers. Papers related to any aspect of EMT will be considered for this Special Issue.

Prof. Dr. Monica Fedele
Prof. Dr. Manfioletti Guidalberto
Guest Editors

Manuscript Submission Information

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Keywords

  • EMT
  • Cancer progression
  • Embryogenesis
  • Tissue injury
  • Cell motility
  • Invasion
  • Metastasis
  • Stemness

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Published Papers (8 papers)

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Editorial

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4 pages, 201 KiB  
Editorial
Epithelial–Mesenchymal Transition (EMT) 2021
by Guidalberto Manfioletti and Monica Fedele
Int. J. Mol. Sci. 2022, 23(10), 5848; https://doi.org/10.3390/ijms23105848 - 23 May 2022
Cited by 58 | Viewed by 4125
Abstract
Epithelial–mesenchymal transition (EMT) is a transdifferentiation process wherein epithelial cells acquire characteristics typical of mesenchymal cells [...] Full article
(This article belongs to the Special Issue Epithelial-Mesenchymal Transition (EMT) 2021)

Research

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16 pages, 24720 KiB  
Article
SYNCRIP Modulates the Epithelial-Mesenchymal Transition in Hepatocytes and HCC Cells
by Veronica Riccioni, Flavia Trionfetti, Claudia Montaldo, Sabrina Garbo, Francesco Marocco, Cecilia Battistelli, Alessandra Marchetti, Raffaele Strippoli, Laura Amicone, Carla Cicchini and Marco Tripodi
Int. J. Mol. Sci. 2022, 23(2), 913; https://doi.org/10.3390/ijms23020913 - 14 Jan 2022
Cited by 8 | Viewed by 3063
Abstract
Heterogeneous nuclear ribonucleoproteins (hnRNPs) control gene expression by acting at multiple levels and are often deregulated in epithelial tumors; however, their roles in the fine regulation of cellular reprogramming, specifically in epithelial–mesenchymal transition (EMT), remain largely unknown. Here, we focused on the hnRNP-Q [...] Read more.
Heterogeneous nuclear ribonucleoproteins (hnRNPs) control gene expression by acting at multiple levels and are often deregulated in epithelial tumors; however, their roles in the fine regulation of cellular reprogramming, specifically in epithelial–mesenchymal transition (EMT), remain largely unknown. Here, we focused on the hnRNP-Q (also known as SYNCRIP), showing by molecular analysis that in hepatocytes it acts as a “mesenchymal” gene, being induced by TGFβ and modulating the EMT. SYNCRIP silencing limits the induction of the mesenchymal program and maintains the epithelial phenotype. Notably, in HCC invasive cells, SYNCRIP knockdown induces a mesenchymal–epithelial transition (MET), negatively regulating their mesenchymal phenotype and significantly impairing their migratory capacity. In exploring possible molecular mechanisms underlying these observations, we identified a set of miRNAs (i.e., miR-181-a1-3p, miR-181-b1-3p, miR-122-5p, miR-200a-5p, and miR-let7g-5p), previously shown to exert pro- or anti-EMT activities, significantly impacted by SYNCRIP interference during EMT/MET dynamics and gathered insights, suggesting the possible involvement of this RNA binding protein in their transcriptional regulation. Full article
(This article belongs to the Special Issue Epithelial-Mesenchymal Transition (EMT) 2021)
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15 pages, 6159 KiB  
Article
Investigation of the Epithelial to Mesenchymal Transition (EMT) Process in Equine Papillomavirus-2 (EcPV-2)-Positive Penile Squamous Cell Carcinomas
by Federico Armando, Samanta Mecocci, Virginia Orlandi, Ilaria Porcellato, Katia Cappelli, Luca Mechelli, Chiara Brachelente, Marco Pepe, Rodolfo Gialletti, Alessandro Ghelardi, Benedetta Passeri and Elisabetta Razzuoli
Int. J. Mol. Sci. 2021, 22(19), 10588; https://doi.org/10.3390/ijms221910588 - 30 Sep 2021
Cited by 12 | Viewed by 2743
Abstract
Equine penile squamous cell carcinoma (epSCC) is the most frequent tumor of the external male genitalia, representing 67.5% of equine genital cancers. epSCC is associated with papilloma virus (PV) infection and has been recently proposed as a model for human PV-induced squamous cell [...] Read more.
Equine penile squamous cell carcinoma (epSCC) is the most frequent tumor of the external male genitalia, representing 67.5% of equine genital cancers. epSCC is associated with papilloma virus (PV) infection and has been recently proposed as a model for human PV-induced squamous cell carcinomas. It has already been suggested that epSCC might undergo epithelial-to-mesenchymal transition (EMT). This work aims to investigate in detail this process and the possible role of PV oncoproteins in epSCC. For this purpose, 18 penile SCCs were retrospectively selected and tested for both EcPV2 presence and oncoproteins (EcPV2 E6 and EcPV2 E7) expression. Moreover, immunohistochemical EMT characterization was carried out by analyzing the main epithelial markers (E-cadherin, β-catenin, and pan-cytokeratin AE3/AE1), the main mesenchymal markers (N-cadherin and vimentin), and the main EMT-related transcription factors (TWIST-1, ZEB-1). PCR analysis was positive for EcPV2 in 16 out of 18 samples. EMT was investigated in epSCC positive for EcPV2. The immunohistochemistry results suggested the presence of EMT processes in the neoplastic cells at the tumor invasive front. Moreover, the significant upregulation of RANKL, together with BCATN1, LEF1, and FOSL1 genes, might suggest a canonical Wnt pathway activation, similarly to what is reported in human penile squamous cell carcinomas Full article
(This article belongs to the Special Issue Epithelial-Mesenchymal Transition (EMT) 2021)
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10 pages, 1839 KiB  
Communication
Expression of the E5 Oncoprotein of HPV16 Impacts on the Molecular Profiles of EMT-Related and Differentiation Genes in Ectocervical Low-Grade Lesions
by Danilo Ranieri, Deborah French, Salvatore Raffa, Luisa Guttieri, Maria Rosaria Torrisi and Francesca Belleudi
Int. J. Mol. Sci. 2021, 22(12), 6534; https://doi.org/10.3390/ijms22126534 - 18 Jun 2021
Cited by 7 | Viewed by 2142
Abstract
Infection with human papillomavirus type 16 (HPV16) is one of the major risk factors for the development of cervical cancer. Our previous studies have demonstrated the involvement of the early oncoprotein E5 of HPV16 (16E5) in the altered isoform switch of fibroblast growth [...] Read more.
Infection with human papillomavirus type 16 (HPV16) is one of the major risk factors for the development of cervical cancer. Our previous studies have demonstrated the involvement of the early oncoprotein E5 of HPV16 (16E5) in the altered isoform switch of fibroblast growth factor receptor 2 (FGFR2) and the consequent expression in human keratinocytes of the mesenchymal FGFR2c isoform, whose aberrant signaling leads to EMT, invasiveness, and dysregulated differentiation. Here, we aimed to establish the possible direct link between these pathological features or the appearance of FGFR2c and the expression of 16E5 in low-grade squamous intraepithelial lesions (LSILs). Molecular analysis showed that the FGFR2c expression displayed a statistically significant positive correlation with that of the viral oncoprotein, whereas the expression values of the epithelial FGR2b variant, as well as those of the differentiation markers keratin 10 (K10), loricrin (LOR) and involucrin (INV), were inversely linked to the 16E5 expression. In contrast, the expression of EMT-related transcription factors Snail1 and ZEB1 overlapped with that of 16E5, becoming a statistically significant positive correlation in the case of Snail2. Parallel analysis performed in human cervical LSIL-derived W12 cells, containing episomal HPV16, revealed that the depletion of 16E5 by siRNA was able to counteract these molecular events, proving to represent an effective strategy to identify the specific role of this viral oncoprotein in determining LSIL oncogenic and more aggressive profiles. Overall, coupling in vitro approaches to the molecular transcript analysis in ectocervical early lesions could significantly contribute to the characterization of specific gene expression profiles prognostic for those LSILs with a greater probability of direct neoplastic progression. Full article
(This article belongs to the Special Issue Epithelial-Mesenchymal Transition (EMT) 2021)
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18 pages, 3861 KiB  
Article
BMAL1 Knockdown Leans Epithelial–Mesenchymal Balance toward Epithelial Properties and Decreases the Chemoresistance of Colon Carcinoma Cells
by Yuan Zhang, Aurore Devocelle, Christophe Desterke, Lucas Eduardo Botelho de Souza, Éva Hadadi, Hervé Acloque, Adlen Foudi, Yao Xiang, Annabelle Ballesta, Yunhua Chang and Julien Giron-Michel
Int. J. Mol. Sci. 2021, 22(10), 5247; https://doi.org/10.3390/ijms22105247 - 16 May 2021
Cited by 28 | Viewed by 3682
Abstract
The circadian clock coordinates biological and physiological functions to day/night cycles. The perturbation of the circadian clock increases cancer risk and affects cancer progression. Here, we studied how BMAL1 knockdown (BMAL1-KD) by shRNA affects the epithelial–mesenchymal transition (EMT), a critical early event in [...] Read more.
The circadian clock coordinates biological and physiological functions to day/night cycles. The perturbation of the circadian clock increases cancer risk and affects cancer progression. Here, we studied how BMAL1 knockdown (BMAL1-KD) by shRNA affects the epithelial–mesenchymal transition (EMT), a critical early event in the invasion and metastasis of colorectal carcinoma (CRC). In corresponding to a gene set enrichment analysis, which showed a significant enrichment of EMT and invasive signatures in BMAL1_high CRC patients as compared to BMAL1_low CRC patients, our results revealed that BMAL1 is implicated in keeping the epithelial–mesenchymal equilibrium of CRC cells and influences their capacity of adhesion, migration, invasion, and chemoresistance. Firstly, BMAL1-KD increased the expression of epithelial markers (E-cadherin, CK-20, and EpCAM) but decreased the expression of Twist and mesenchymal markers (N-cadherin and vimentin) in CRC cell lines. Finally, the molecular alterations after BMAL1-KD promoted mesenchymal-to-epithelial transition-like changes mostly appeared in two primary CRC cell lines (i.e., HCT116 and SW480) compared to the metastatic cell line SW620. As a consequence, migration/invasion and drug resistance capacities decreased in HCT116 and SW480 BMAL1-KD cells. Together, BMAL1-KD alerts the delicate equilibrium between epithelial and mesenchymal properties of CRC cell lines, which revealed the crucial role of BMAL1 in EMT-related CRC metastasis and chemoresistance. Full article
(This article belongs to the Special Issue Epithelial-Mesenchymal Transition (EMT) 2021)
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18 pages, 3382 KiB  
Article
Suppression of PGC-1α Drives Metabolic Dysfunction in TGFβ2-Induced EMT of Retinal Pigment Epithelial Cells
by Daisy Y. Shu, Erik R. Butcher and Magali Saint-Geniez
Int. J. Mol. Sci. 2021, 22(9), 4701; https://doi.org/10.3390/ijms22094701 - 29 Apr 2021
Cited by 28 | Viewed by 4590
Abstract
PGC-1α, a key orchestrator of mitochondrial metabolism, plays a crucial role in governing the energetically demanding needs of retinal pigment epithelial cells (RPE). We previously showed that silencing PGC-1α induced RPE to undergo an epithelial-mesenchymal-transition (EMT). Here, we show that induction of EMT [...] Read more.
PGC-1α, a key orchestrator of mitochondrial metabolism, plays a crucial role in governing the energetically demanding needs of retinal pigment epithelial cells (RPE). We previously showed that silencing PGC-1α induced RPE to undergo an epithelial-mesenchymal-transition (EMT). Here, we show that induction of EMT in RPE using transforming growth factor-beta 2 (TGFβ2) suppressed PGC-1α expression. Correspondingly, TGFβ2 induced defects in mitochondrial network integrity with increased sphericity and fragmentation. TGFβ2 reduced expression of genes regulating mitochondrial dynamics, reduced citrate synthase activity and intracellular ATP content. High-resolution respirometry showed that TGFβ2 reduced mitochondrial OXPHOS levels consistent with reduced expression of NDUFB5. The reduced mitochondrial respiration was associated with a compensatory increase in glycolytic reserve, glucose uptake and gene expression of glycolytic enzymes (PFKFB3, PKM2, LDHA). Treatment with ZLN005, a selective small molecule activator of PGC-1α, blocked TGFβ2-induced upregulation of mesenchymal genes (αSMA, Snai1, CTGF, COL1A1) and TGFβ2-induced migration using the scratch wound assay. Our data show that EMT is accompanied by mitochondrial dysfunction and a metabolic shift towards reduced OXPHOS and increased glycolysis that may be driven by PGC-1α suppression. ZLN005 effectively blocks EMT in RPE and thus serves as a novel therapeutic avenue for treatment of subretinal fibrosis. Full article
(This article belongs to the Special Issue Epithelial-Mesenchymal Transition (EMT) 2021)
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Review

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30 pages, 3920 KiB  
Review
FRA-1 as a Regulator of EMT and Metastasis in Breast Cancer
by Laura Casalino, Francesco Talotta, Ilenia Matino and Pasquale Verde
Int. J. Mol. Sci. 2023, 24(9), 8307; https://doi.org/10.3390/ijms24098307 - 5 May 2023
Cited by 8 | Viewed by 3807
Abstract
Among FOS-related components of the dimeric AP-1 transcription factor, the oncoprotein FRA-1 (encoded by FOSL1) is a key regulator of invasion and metastasis. The well-established FRA-1 pro-invasive activity in breast cancer, in which FOSL1 is overexpressed in the TNBC (Triple Negative Breast [...] Read more.
Among FOS-related components of the dimeric AP-1 transcription factor, the oncoprotein FRA-1 (encoded by FOSL1) is a key regulator of invasion and metastasis. The well-established FRA-1 pro-invasive activity in breast cancer, in which FOSL1 is overexpressed in the TNBC (Triple Negative Breast Cancer)/basal subtypes, correlates with the FRA-1-dependent transcriptional regulation of EMT (Epithelial-to-Mesenchymal Transition). After summarizing the major findings on FRA-1 in breast cancer invasiveness, we discuss the FRA-1 mechanistic links with EMT and cancer cell stemness, mediated by transcriptional and posttranscriptional interactions between FOSL1/FRA-1 and EMT-regulating transcription factors, miRNAs, RNA binding proteins and cytokines, along with other target genes involved in EMT. In addition to the FRA-1/AP-1 effects on the architecture of target promoters, we discuss the diagnostic and prognostic significance of the EMT-related FRA-1 transcriptome, along with therapeutic implications. Finally, we consider several novel perspectives regarding the less explored roles of FRA-1 in the tumor microenvironment and in control of the recently characterized hybrid EMT correlated with cancer cell plasticity, stemness, and metastatic potential. We will also examine the application of emerging technologies, such as single-cell analyses, along with animal models of TNBC and tumor-derived CTCs and PDXs (Circulating Tumor Cells and Patient-Derived Xenografts) for studying the FRA-1-mediated mechanisms in in vivo systems of EMT and metastasis. Full article
(This article belongs to the Special Issue Epithelial-Mesenchymal Transition (EMT) 2021)
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34 pages, 3457 KiB  
Review
The Epithelial–Mesenchymal Transition at the Crossroads between Metabolism and Tumor Progression
by Monica Fedele, Riccardo Sgarra, Sabrina Battista, Laura Cerchia and Guidalberto Manfioletti
Int. J. Mol. Sci. 2022, 23(2), 800; https://doi.org/10.3390/ijms23020800 - 12 Jan 2022
Cited by 83 | Viewed by 6985
Abstract
The transition between epithelial and mesenchymal phenotype is emerging as a key determinant of tumor cell invasion and metastasis. It is a plastic process in which epithelial cells first acquire the ability to invade the extracellular matrix and migrate into the bloodstream via [...] Read more.
The transition between epithelial and mesenchymal phenotype is emerging as a key determinant of tumor cell invasion and metastasis. It is a plastic process in which epithelial cells first acquire the ability to invade the extracellular matrix and migrate into the bloodstream via transdifferentiation into mesenchymal cells, a phenomenon known as epithelial–mesenchymal transition (EMT), and then reacquire the epithelial phenotype, the reverse process called mesenchymal–epithelial transition (MET), to colonize a new organ. During all metastatic stages, metabolic changes, which give cancer cells the ability to adapt to increased energy demand and to withstand a hostile new environment, are also important determinants of successful cancer progression. In this review, we describe the complex interaction between EMT and metabolism during tumor progression. First, we outline the main connections between the two processes, with particular emphasis on the role of cancer stem cells and LncRNAs. Then, we focus on some specific cancers, such as breast, lung, and thyroid cancer. Full article
(This article belongs to the Special Issue Epithelial-Mesenchymal Transition (EMT) 2021)
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