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 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 Linc00426 accelerates lung adenocarcinoma progression by regulating miR-455-5p as a molecular sponge

2020 ◽  
Vol 11 (12) ◽  
Author(s):  
Hongli Li ◽  
Qingjie Mu ◽  
Guoxin Zhang ◽  
Zhixin Shen ◽  
Yuanyuan Zhang ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Ectopic Expression ◽  
Tumor Development ◽  
Biological Significance ◽  
Mesenchymal Transition

AbstractIncreasing lines of evidence indicate the role of long non-coding RNAs (LncRNAs) in gene regulation and tumor development. Hence, it is important to elucidate the mechanisms of LncRNAs underlying the proliferation, metastasis, and invasion of lung adenocarcinoma (LUAD). We employed microarrays to screen LncRNAs in LUAD tissues with and without lymph node metastasis and revealed their effects on LUAD. Among them, Linc00426 was selected for further exploration in its expression, the biological significance, and the underlying molecular mechanisms. Linc00426 exhibits ectopic expression in LUAD tissues and cells. The ectopic expression has been clinically linked to tumor size, lymphatic metastasis, and tumor differentiation of patients with LUAD. The deregulation of Linc00426 contributes to a notable impairment in proliferation, invasion, metastasis, and epithelial–mesenchymal transition (EMT) in vitro and in vivo. Mechanistically, the deregulation of Linc00426 could reduce cytoskeleton rearrangement and matrix metalloproteinase expression. Meanwhile, decreasing the level of Linc00426 or increasing miR-455-5p could down-regulate the level of UBE2V1. Thus, Linc00426 may act as a competing endogenous RNA (ceRNA) to abate miR-455-5p-dependent UBE2V1 reduction. We conclude that Linc00426 accelerates LUAD progression by acting as a molecular sponge to regulate miR-455-5p, and may be a potential novel tumor marker for LUAD.

Retinoic Acid Inducible Gene-I like Receptors Activate Snail to Limit RNA Viral Infections

2021 ◽  
Author(s):  
Dhiviya Vedagiri ◽  
Divya Gupta ◽  
Anurag Mishra ◽  
Gayathri Krishna ◽  
Meenakshi Bhaskar ◽  
...  
Keyword(s):  
Viral Infections ◽  
Epithelial Mesenchymal Transition ◽  
Ectopic Expression ◽  
Antiviral Response ◽  
Poly I:C ◽  
Type I ◽  
Type I Ifn ◽  
Mesenchymal Transition ◽  
Type I Ifns ◽  
General Response

RLRs are important cytosolic PRRs that sense viral RNA before mounting a response leading to the activation of Type-I IFNs. Several viral infections induce epithelial-mesenchymal transition (EMT), even as its significance remains unclear. Here, we describe that EMT or EMT like process is a general response to viral infections. Our studies identify a previously unknown mechanism of regulation of an important EMT-TF Snail during RNA viral infections, and describe its possible implication. RNA viral infections, poly (I:C) transfection, and ectopic expression of RLR components induced Snail levels, indicating that RLR pathway could regulate its expression. Detailed examination using MAVS-KO cells established that MAVS is essential in this regulation. We identified two ISREs in SNAI1 promoter region and demonstrated that they are important in its transcriptional activation by phosphorylated IRF3. Increasing the levels of Snail activated RLR pathway and dramatically limited replication of RNA viruses DENV, JEV and VSV, pointing to their antiviral functions. Knock-down of Snail resulted in considerable increase in JEV titer, validating its antiviral functions. Finally, TGF-β mediated IFNB activation was dependent on Snail levels, confirming its important role in Type-I IFN activation. Thus, EMT-TF Snail is transcriptionally co-regulated with Type-I IFN by RLRs and in turn promotes RLR pathway, further strengthening the antiviral state in the cell. Our work identified an interesting mechanism of regulation of Snail that demonstrates potential co-regulation of multiple innate antiviral pathways triggered by RLRs. Identification of antiviral functions of Snail also provides an opportunity to expand the sphere of RLR signaling. IMPORTANCE RLRs sense viral genomic RNA or the dsRNA intermediates and trigger the activation of Type I IFNs. Snail transcription factor, commonly associated with epithelial-mesenchymal transition, has been reported to facilitate EMT in several viral infections. Much of these reports come from oncoviruses, leading to the speculation that EMT induced during infection is an important factor in the oncogenesis triggered by these infections. However, our studies reveal that EMT or EMT like processes during viral infections have important functions in antiviral response. We have characterized a new mechanism of transcriptional regulation of Snail by IRF3 through ISRE in their promoters and this finding could have importance in non-viral contexts as well. We also identify that EMT-TF Snail promotes antiviral status of the infected cells through RLR pathway. This work characterizes a new regulatory mechanism of activation of Snail and establishes its unidentified function in antiviral response.

Up-regulation of miR-125b reverses epithelial-mesenchymal transition in paclitaxel-resistant lung cancer cells

2015 ◽  
Vol 0 (0) ◽  
Author(s):  
Yu Zhang ◽  
Shaoxiang Huang
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Chemotherapy Resistance ◽  
Ectopic Expression ◽  
Lung Cancer Cells ◽  
Tumor Xenograft ◽  
Mesenchymal Transition ◽  
Immunodeficient Mice

Abstract Recent studies have demonstrated that acquisition of epithelial-mesenchymal transition (EMT) is associated with drug resistance in lung cancer cells. However, the underlying mechanisms are not fully elucidated. Emerging evidence suggests that microRNAs play a crucial role in controlling EMT. The aim of this study was to explore the potential role of miR-125b in governing EMT in paclitaxel-resistant (PR) lung cancer cells. To achieve this goal, we explored the role of miR-125b in regulation of EMT in stable PR lung cancer cells, namely A549-PR and H460-PR. We found that miR-125b was significantly downregulated in A549-PR and H460-PR cells. Notably, ectopic expression of miR-125b led to the reversal of EMT phenotype. Moreover, we found that miR-125b governed PR-induced EMT partly due to down-regulation of its target Sema4C. More importantly, overexpression of miR-125b or depletion of Sema4C sensitized PR cells to paclitaxel. Furthermore, stable overexpression miR-125b in A549-PR cells inhibited tumor xenograft growth in immunodeficient mice. Our study implied that up-regulation of miR-125b could be a novel approach to reverse chemotherapy resistance in lung cancers.

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 The Cancer Microbiota: EMT and Inflammation as Shared Molecular Mechanisms Associated with Plasticity and Progression

2019 ◽  
Vol 2019 ◽  
pp. 1-16 ◽  
Author(s):  
Daniele Vergara ◽  
Pasquale Simeone ◽  
Marina Damato ◽  
Michele Maffia ◽  
Paola Lanuti ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Common Ground ◽  
Epithelial Mesenchymal Transition ◽  
Human Cancer ◽  
Malignant Progression ◽  
Pathogenic Microorganisms ◽  
Mesenchymal Transition ◽  
Host Interactions

With the advent of novel molecular platforms for high-throughput/next-generation sequencing, the communities of commensal and pathogenic microorganisms that inhabit the human body have been defined in depth. In the last decade, the role of microbiota-host interactions in driving human cancer plasticity and malignant progression has been well documented. Germ-free preclinical models provided an invaluable tool to demonstrate that the human microbiota can confer susceptibility to various types of cancer and can also modulate the host response to therapeutic treatments. Of interest, besides the detrimental effects of dysbiosis on cancer etiopathogenesis, specific microorganisms have been shown to exert protective activities against cancer growth. This has strong clinical implications, as restoration of the physiologic microbiota is being rapidly implemented as a novel anticancer therapeutic strategy. Here, we reviewed past and recent literature depicting the role of microbiota-host interactions in modulating key molecular mechanisms that drive human cancer plasticity and lead to malignant progression. We analyzed microbiota-host interactions occurring in the gut as well as in other anatomic sites, such as oral and nasal cavities, lungs, breast, esophagus, stomach, reproductive tract, and skin. We revealed a common ground of biological alterations and pathways modulated by a dysbiotic microbiota and potentially involved in the control of cancer progression. The molecular mechanisms most frequently affected by the pathogenic microorganisms to induce malignant progression involve epithelial-mesenchymal transition- (EMT-) dependent barrier alterations and tumor-promoting inflammation. This evidence may pave the way to better stratify high-risk cancer patients based on unique microenvironmental/microbial signatures and to develop novel, personalized, biological therapies.

scholarly journals Exosomes-Mediated Transfer of Itga2 Promotes Migration and Invasion of Prostate Cancer Cells by Inducing Epithelial-Mesenchymal Transition

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2300
Author(s):  
Rofaida Gaballa ◽  
Hamdy E. A. Ali ◽  
Mohamed O. Mahmoud ◽  
Johng S. Rhim ◽  
Hamed I. Ali ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Ectopic Expression ◽  
Normal Subjects ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Aggressive Phenotype ◽  
Endogenous Expression

Although integrin alpha 2 subunit (ITGA2) mediates cancer progression and metastasis, its transfer by exosomes has not been investigated in prostate cancer (PCa). We aimed to determine the role of exosomal ITGA2 derived from castration-resistant PCa (CRPC) cells in promoting aggressive phenotypes in androgen receptor (AR)-positive cells. Exosomes were co-incubated with recipient cells and tested for different cellular assays. ITGA2 was enriched in exosomes derived from CRPC cells. Co-culture of AR-positive cells with CRPC-derived exosomes increased their proliferation, migration, and invasion by promoting epithelial-mesenchymal transition, which was reversed via ITGA2 knockdown or inhibition of exosomal uptake by methyl-β-cyclodextrin (MβCD). Ectopic expression of ITGA2 reproduced the effect of exosomal ITGA2 in PCa cells. ITGA2 transferred by exosomes exerted its effect within a shorter time compared to that triggered by its endogenous expression. The difference of ITGA2 protein expression in localized tumors and those with lymph node metastatic tissues was indistinguishable. Nevertheless, its abundance was higher in circulating exosomes collected from PCa patients when compared with normal subjects. Our findings indicate the possible role of the exosomal-ITGA2 transfer in altering the phenotype of AR-positive cells towards more aggressive phenotype. Thus, interfering with exosomal cargo transfer may inhibit the development of aggressive phenotype in PCa cells.

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.

Magnesium Chloride is an Effective Therapeutic Agent for Prostate Cancer

2018 ◽  
Vol 8 (1) ◽  
pp. 62 ◽  
Author(s):  
Julianna Maria Santos ◽  
Fazle Hussain
Keyword(s):  
Prostate Cancer ◽  
Magnesium Chloride ◽  
Epithelial Mesenchymal Transition ◽  
Chromatin Condensation ◽  
Myosin Ii ◽  
In Vivo Studies ◽  
Migration Speed ◽  
Mesenchymal Transition

Background: Reduced levels of magnesium can cause several diseases and increase cancer risk. Motivated by magnesium chloride’s (MgCl2) non-toxicity, physiological importance, and beneficial clinical applications, we studied its action mechanism and possible mechanical, molecular, and physiological effects in prostate cancer with different metastatic potentials.Methods: We examined the effects of MgCl2, after 24 and 48 hours, on apoptosis, cell migration, expression of epithelial mesenchymal transition (EMT) markers, and V-H+-ATPase, myosin II (NMII) and the transcription factor NF Kappa B (NFkB) expressions.Results: MgCl2 induces apoptosis, and significantly decreases migration speed in cancer cells with different metastatic potentials.  MgCl2 reduces the expression of V-H+-ATPase and myosin II that facilitates invasion and metastasis, suppresses the expression of vimentin and increases expression of E-cadherin, suggesting a role of MgCl2 in reversing the EMT. MgCl2 also significantly increases the chromatin condensation and decreases NFkB expression.Conclusions: These results suggest a promising preventive and therapeutic role of MgCl2 for prostate cancer. Further studies should explore extending MgCl2 therapy to in vivo studies and other cancer types.Keywords: Magnesium chloride, prostate cancer, migration speed, V-H+-ATPase, and EMT.

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