scholarly journals Altered translation initiation ofGja1limits gap junction formation during epithelial–mesenchymal transition

2018 ◽  
Vol 29 (7) ◽  
pp. 797-808 ◽  
Author(s):  
Carissa C. James ◽  
Michael J. Zeitz ◽  
Patrick J. Calhoun ◽  
Samy Lamouille ◽  
James W. Smyth
Keyword(s):  
Gap Junctions ◽  
Gap Junction ◽  
Translation Initiation ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Ectopic Expression ◽  
Dependent Manner ◽  
Mesenchymal Transition ◽  
Junction Protein ◽  
Junction Formation

Epithelial–mesenchymal transition (EMT) is activated during development, wound healing, and pathologies including fibrosis and cancer metastasis. Hallmarks of EMT are remodeling of intercellular junctions and adhesion proteins, including gap junctions. The GJA1 mRNA transcript encoding the gap junction protein connexin43 (Cx43) has been demonstrated to undergo internal translation initiation, yielding truncated isoforms that modulate gap junctions. The PI3K/Akt/mTOR pathway is central to translation regulation and is activated during EMT, leading us to hypothesize that altered translation initiation would contribute to gap junction loss. Using TGF-β–induced EMT as a model, we find reductions in Cx43 gap junctions despite increased transcription and stabilization of Cx43 protein. Biochemical experiments reveal suppression of the internally translated Cx43 isoform, GJA1-20k in a Smad3 and ERK-dependent manner. Ectopic expression of GJA1-20k does not halt EMT, but is sufficient to rescue gap junction formation. GJA1-20k localizes to the Golgi apparatus, and using superresolution localization microscopy we find retention of GJA1-43k at the Golgi in mesenchymal cells lacking GJA1-20k. NativePAGE demonstrates that levels of GJA1-20k regulate GJA1-43k hexamer oligomerization, a limiting step in Cx43 trafficking. These findings reveal alterations in translation initiation as an unexplored mechanism by which the cell regulates Cx43 gap junction formation during EMT.

scholarly journals SPNS2 Downregulation Induces EMT and Promotes Colorectal Cancer Metastasis via Activating AKT Signaling Pathway

2021 ◽  
Vol 11 ◽  
Author(s):  
Lei Lv ◽  
Qiyi Yi ◽  
Ying Yan ◽  
Fengmei Chao ◽  
Ming Li
Keyword(s):  
Colorectal Cancer ◽  
Molecular Mechanisms ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Ectopic Expression ◽  
Migration And Invasion ◽  
Akt Inhibitor ◽  
Colon Adenoma ◽  
Mesenchymal Transition

Spinster homologue 2 (SPNS2), a transporter of S1P (sphingosine-1-phosphate), has been reported to mediate immune response, vascular development, and pathologic processes of diseases such as cancer via S1P signaling pathways. However, its biological functions and expression profile in colorectal cancer (CRC) is elusive. In this study, we disclosed that SPNS2 expression, which was regulated by copy number variation and DNA methylation of its promoter, was dramatically upregulated in colon adenoma and CRC compared to normal tissues. However, its expression was lower in CRC than in colon adenoma, and low expression of SPN2 correlated with advanced T/M/N stage and poor prognosis in CRC. Ectopic expression of SPNS2 inhibited cell proliferation, migration, epithelial–mesenchymal transition (EMT), invasion, and metastasis in CRC cell lines, while silencing SPNS2 had the opposite effects. Meanwhile, measuring the intracellular and extracellular level of S1P after overexpression of SPNS2 pinpointed a S1P-independent model of SPNS2. Mechanically, SPNS2 led to PTEN upregulation and inactivation of Akt. Moreover, AKT inhibitor (MK2206) abrogated SPNS2 knockdown-induced promoting effects on the migration and invasion, while AKT activator (SC79) reversed the repression of migration and invasion by SPNS2 overexpression in CRC cells, confirming the pivotal role of AKT for SPNS2’s function. Collectively, our study demonstrated the suppressor role of SPNS2 during CRC metastasis, providing new insights into the pathology and molecular mechanisms of CRC progression.

scholarly journals Connexin 43 impacts the chick premigratory cranial neural crest cell population without affecting the neural crest cell epithelial-to-mesenchymal transition

2019 ◽  
Author(s):  
Karyn Jourdeuil ◽  
Lisa A. Taneyhill
Keyword(s):  
Gap Junctions ◽  
Neural Crest ◽  
Gap Junction ◽  
Neural Crest Cell ◽  
Neural Crest Cells ◽  
Cranial Neural Crest ◽  
Mesenchymal Transition ◽  
Junction Protein ◽  
Cranial Neural Crest Cells ◽  
Crest Cell

ABSTRACTGap junctions are intercellular channels that allow for the diffusion of small ions and solutes between coupled cells. Connexin 43 (Cx43), also known as Gap Junction Protein α1, is the most broadly expressed gap junction protein in vertebrate development. Cx43 is strongly expressed in premigratory cranial neural crest cells and is maintained throughout the neural crest cell epithelial-to-mesenchymal transition (EMT), but its function in these cells is not known. To this end, we have used a combination of in vivo and ex vivo live imaging with confocal microscopy, immunohistochemistry, and functional assays to assess gap junction formation, and Cx43 function, in chick premigratory cranial neural crest cells. Our results demonstrate that gap junctions exist between chick premigratory and migratory cranial neural crest cells, with Cx43 depletion inhibiting the function of gap junctions. While a reduction in Cx43 levels just prior to neural crest cell EMT did not affect EMT and subsequent emigration of neural crest cells from the neural tube, the size of the premigratory neural crest cell domain was decreased in the absence of any changes in cell proliferation or death. Collectively, these data identify a role for Cx43 within the chick premigratory cranial neural crest cell population prior to EMT and migration.

scholarly journals Anthocyanins fromVitis coignetiaePulliat Inhibit Cancer Invasion and Epithelial-Mesenchymal Transition, but These Effects Can Be Attenuated by Tumor Necrosis Factor in Human Uterine Cervical Cancer HeLa Cells

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Jing Nan Lu ◽  
Won Sup Lee ◽  
Jeong Won Yun ◽  
Min Jeong Kim ◽  
Hye Jung Kim ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Hela Cells ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Uterine Cervical Cancer ◽  
Dependent Manner ◽  
Mesenchymal Transition ◽  
Anticancer Effects ◽  
Dose Dependent ◽  
Necrosis Factor

Recently we have demonstrated that anthocyanins from fruits ofVitis coignetiaePulliat (AIMs) have anticancer effects. Here, we investigate the effects of AIMs on cell proliferation and invasion as well as epithelial-mesenchymal transition (EMT) which have been linked to cancer metastasis in human uterine cervical cancer HeLa cells. AIMs inhibited the invasion of HeLa cells in a dose-dependent manner. AIMs inhibited MMP-9 expression in a dose-dependent manner. AIMs inhibited the motility of HeLa cells in a wound healing test. AIMs still suppressed NF-κB activation induced by TNF. AIMs also inhibited EMT in HeLa cells. AIMs suppressed vimentin, N-cadherin, andβ-catenin expression and induced E-cadherin. AIMs also suppressed expression ofβ-catenin and Snail, which was regulated by GSK-3. These effects of AIMs were also limited in the HeLa cells treated with TNF. In conclusion, this study indicates that AIMs have anticancer effects by suppressing NF-κB-regulated genes and EMT, which relates to suppression of IκBαphosphorylation and GSK-3 activity, respectively. However, the effects of AIMs were attenuated in the TNF-high condition.

scholarly journals Epithelial Mesenchymal Transition and its transcription factors

2021 ◽  
Author(s):  
Pallabi Debnath ◽  
Rohit Singh Huirem ◽  
Paloma Dutta ◽  
Santanu Palchaudhuri
Keyword(s):  
Transcription Factors ◽  
Regulatory Network ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Transcriptional Regulatory Network ◽  
Tissue Type ◽  
Dependent Manner ◽  
Apoptosis Resistance ◽  
Mesenchymal Transition ◽  
Composition And Structure

Epithelial-mesenchymal transition or EMT is an extremely dynamic process involved in conversion of epithelial cells into mesenchymal cells, stimulated by an ensemble of signaling pathways, leading to change in cellular morphology, suppression of epithelial characters and acquisition of properties such as enhanced cell motility and invasiveness, reduced cell death by apoptosis, resistance to chemotherapeutic drugs etc. Significantly, EMT has been found to play a crucial role during embryonic development, tissue fibrosis and would healing, as well as during cancer metastasis. Over the years, work from various laboratories have identified a rather large number of transcription factors including the master regulators of EMT, with the ability to regulate the EMT process directly.  In this review, we put together these EMT transcription factors and discussed their role in the process. We have also tried to focus on their mechanism of action, their inter-dependency, and the large regulatory network they form. Subsequently, it has become clear that the composition and structure of the transcriptional regulatory network behind EMT probably varies based upon various physiological and pathological contexts, or even in a cell/tissue type dependent manner.

scholarly journals Hic-5 promotes invadopodia formation and invasion during TGF-β–induced epithelial–mesenchymal transition

2012 ◽  
Vol 197 (3) ◽  
pp. 421-437 ◽  
Author(s):  
Jeanine Pignatelli ◽  
David A. Tumbarello ◽  
Ronald P. Schmidt ◽  
Christopher E. Turner
Keyword(s):  
Cell Migration ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Ectopic Expression ◽  
Migration And Invasion ◽  
Dependent Manner ◽  
Matrix Degradation ◽  
Mesenchymal Transition ◽  
Cell Migration And Invasion ◽  
Invadopodia Formation

Transforming growth factor β (TGF-β)–stimulated epithelial–mesenchymal transition (EMT) is an important developmental process that has also been implicated in increased cell invasion and metastatic potential of cancer cells. Expression of the focal adhesion protein Hic-5 has been shown to be up-regulated in epithelial cells in response to TGF-β. Herein, we demonstrate that TGF-β–induced Hic-5 up-regulation or ectopic expression of Hic-5 in normal MCF10A cells promoted increased extracellular matrix degradation and invasion through the formation of invadopodia. Hic-5 was tyrosine phosphorylated in an Src-dependent manner after TGF-β stimulation, and inhibition of Src activity or overexpression of a Y38/60F nonphosphorylatable mutant of Hic-5 inhibited matrix degradation and invasion. RhoC, but not RhoA, was also required for TGF-β– and Hic-5–induced matrix degradation. Hic-5 also induced matrix degradation, cell migration, and invasion in the absence of TGF-β via Rac1 regulation of p38 MAPK. These data identify Hic-5 as a critical mediator of TGF-β–stimulated invadopodia formation, cell migration, and invasion.

scholarly journals The reciprocal interaction between tumor cells and activated fibroblasts mediated by TNF-α/IL-33/ST2L signaling promotes gastric cancer metastasis

Oncogene ◽  
2019 ◽  
Vol 39 (7) ◽  
pp. 1414-1428 ◽  
Author(s):  
Quan Zhou ◽  
Xiongyan Wu ◽  
Xiaofeng Wang ◽  
Zhenjia Yu ◽  
Tao Pan ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Critical Role ◽  
Tumor Stroma ◽  
Migration And Invasion ◽  
Dependent Manner ◽  
Aberrant Expression ◽  
Mesenchymal Transition ◽  
Tnf Α

Abstract Gastric cancer (GC) is characterized by extensive local invasion, distant metastasis and poor prognosis. In most cases, GC progression is associated with aberrant expression of cytokines or activation of signaling cascades mediated by tumor–stroma interactions. However, the mechanisms by which these interactions contribute to GC progression are poorly understood. In this study, we find that IL-33 and its receptor ST2L are upregulated in the human GC and served as prognostic markers for poor survival of GC patients. In a co-culture model with GC cells and cancer-associated fibroblasts (CAFs), we further demonstrate that CAFs-derived IL-33 enhances the migration and invasion of GC cells by inducing the epithelial–mesenchymal transition (EMT) through activation of the ERK1/2-SP1-ZEB2 pathway in a ST2L-dependent manner. Furthermore, the secretion of IL-33 by CAFs can be induced by the proinflammatory cytokines TNF-α that is released by GC cells via TNFR2-NF-κB-IRF-1 pathway. Additionally, silencing of IL-33 expression in CAFs or ST2L expression in GC cells inhibits the peritoneal dissemination and metastatic potential of GC cells in nude mice. Taken together, these results characterize a critical role of the interaction between epithelial-stroma mediated by the TNF-α/IL-33/ST2L signaling in GC progression, and provide a rationale for targeting this pathway to treat GC metastasis.

scholarly journals Rotavirus Induces Epithelial–Mesenchymal Transition Markers by Transcriptional Suppression of miRNA-29b

2021 ◽  
Vol 12 ◽  
Author(s):  
Urbi Mukhopadhyay ◽  
Anwesha Banerjee ◽  
Mamta Chawla-Sarkar ◽  
Anupam Mukherjee
Keyword(s):  
Viral Infections ◽  
Epithelial Mesenchymal Transition ◽  
Ectopic Expression ◽  
Dependent Manner ◽  
Structural Protein ◽  
Mesenchymal Transition ◽  
Host Interactions ◽  
Cyclin E1 ◽  
Cellular Components

Acute gastroenteritis (AGE) is a serious global health problem and has been known to cause millions of infant deaths every year. Rotavirus (RV), a member of the Reoviridae family, still majorly accounts for the AGE in children below 5 years of age in India and worldwide. The involvement of miRNAs in the pathogenesis of RV has been suggested to be of the proviral as well as the anti-viral nature. miRNAs that promote the RV pathogenesis are capable of targeting the cellular components to evade the host anti-viral strategies. On the other hand, miRNAs with anti-rotaviral properties are themselves incapacitated during the progression of the infection. The exploitation of the epithelial–mesenchymal transition (EMT) as a pro-rotaviral strategy has already been identified. Thus, miRNAs that proficiently target the intermediates of the EMT pathway may serve as anti-viral counterparts in the RV–host interactions. The role of microRNA-29b (miR-29b) in the majority of human cancers has been well demonstrated, but its significance in viral infections is yet to be elaborated. In this study, we have assessed the role of miR-29b in RV-induced EMT and RV replication. Our study on miR-29b provides evidence for the recruitment of RV non-structural protein NSP1 to control the trans-repression of miR-29b in a p53-dependent manner. The trans-repression of miR-29b modulates the EMT pathway by targeting tripartite motif-containing protein 44 (TRIM44) and cyclin E1 (CCNE1). SLUG and SNAIL transcription repressors (downstream of TRIM44 and CCNE1) regulate the expression of E-cadherin, an important marker of the EMT. Also, it is established that ectopic expression of miR-29b not only constrains the EMT pathway but also restricts RV replication. Therefore, miR-29b repression is a crucial event in the RV pathogenesis. Ectopic expression of miR-29b displays potential anti-viral properties against RV propagation.

scholarly journals Oxidized Phospholipids in Tumor Microenvironment Stimulate Tumor Metastasis via Regulation of Autophagy

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 558
Author(s):  
Jin Kyung Seok ◽  
Eun-Hee Hong ◽  
Gabsik Yang ◽  
Hye Eun Lee ◽  
Sin-Eun Kim ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Autophagic Flux ◽  
Oxidized Phospholipids ◽  
Mcf7 Cells ◽  
Mesenchymal Transition ◽  
Tumor Tissues

Oxidized phospholipids are well known to play physiological and pathological roles in regulating cellular homeostasis and disease progression. However, their role in cancer metastasis has not been entirely understood. In this study, effects of oxidized phosphatidylcholines such as 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (POVPC) on epithelial-mesenchymal transition (EMT) and autophagy were determined in cancer cells by immunoblotting and confocal analysis. Metastasis was analyzed by a scratch wound assay and a transwell migration/invasion assay. The concentrations of POVPC and 1-palmitoyl-2-glutaroyl-sn-glycero-phosphocholine (PGPC) in tumor tissues obtained from patients were measured by LC-MS/MS analysis. POVPC induced EMT, resulting in increase of migration and invasion of human hepatocellular carcinoma cells (HepG2) and human breast cancer cells (MCF7). POVPC induced autophagic flux through AMPK-mTOR pathway. Pharmacological inhibition or siRNA knockdown of autophagy decreased migration and invasion of POVPC-treated HepG2 and MCF7 cells. POVPC and PGPC levels were greatly increased at stage II of patient-derived intrahepatic cholangiocarcinoma tissues. PGPC levels were higher in malignant breast tumor tissues than in adjacent nontumor tissues. The results show that oxidized phosphatidylcholines increase metastatic potential of cancer cells by promoting EMT, mediated through autophagy. These suggest the positive regulatory role of oxidized phospholipids accumulated in tumor microenvironment in the regulation of tumorigenesis and metastasis.

Galectin-3: A factotum in carcinogenesis bestowing an archery for prevention

Tumor Biology ◽  
2021 ◽  
Vol 43 (1) ◽  
pp. 77-96
Author(s):  
T. Jeethy Ram ◽  
Asha Lekshmi ◽  
Thara Somanathan ◽  
K. Sujathan
Keyword(s):  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Therapy Resistance ◽  
Cellular Level ◽  
Clinical Samples ◽  
Innovative Strategy ◽  
Mesenchymal Transition ◽  
Galectin 3

Cancer metastasis and therapy resistance are the foremost hurdles in oncology at the moment. This review aims to pinpoint the functional aspects of a unique multifaceted glycosylated molecule in both intracellular and extracellular compartments of a cell namely galectin-3 along with its metastatic potential in different types of cancer. All materials reviewed here were collected through the search engines PubMed, Scopus, and Google scholar. Among the 15 galectins identified, the chimeric gal-3 plays an indispensable role in the differentiation, transformation, and multi-step process of tumor metastasis. It has been implicated in the molecular mechanisms that allow the cancer cells to survive in the intravascular milieu and promote tumor cell extravasation, ultimately leading to metastasis. Gal-3 has also been found to have a pivotal role in immune surveillance and pro-angiogenesis and several studies have pointed out the importance of gal-3 in establishing a resistant phenotype, particularly through the epithelial-mesenchymal transition process. Additionally, some recent findings suggest the use of gal-3 inhibitors in overcoming therapeutic resistance. All these reports suggest that the deregulation of these specific lectins at the cellular level could inhibit cancer progression and metastasis. A more systematic study of glycosylation in clinical samples along with the development of selective gal-3 antagonists inhibiting the activity of these molecules at the cellular level offers an innovative strategy for primary cancer prevention.

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