scholarly journals A possible role for epigenetic feedback regulation in the dynamics of the Epithelial-Mesenchymal Transition (EMT)

2019 ◽  
Author(s):  
Wen Jia ◽  
Abhijeet Deshmukh ◽  
Sendurai A. Mani ◽  
Mohit Kumar Jolly ◽  
Herbert Levine
Keyword(s):  
Epigenetic Regulation ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Critical Role ◽  
Feedback Regulation ◽  
Inhibitory Effect ◽  
Mesenchymal Transition ◽  
Proposed Model ◽  
Preliminary Experimental Data

The epithelial-mesenchymal transition (EMT) often plays a critical role in cancer metastasis and chemoresistance, and decoding its dynamics is crucial to design effective therapeutics. EMT is regulated at multiple levels transcriptional, translational, protein stability, and epigenetics; the mechanisms by which epigenetic regulation can alter the dynamics of EMT remain elusive. Here, to identify the possible effects of epigenetic regulation in EMT, we incorporate a feedback term in our previously proposed model of EMT regulation of the miR 200/ZEB/miR 34/SNAIL circuit. This epigenetic feedback that stabilizes long-term transcriptional activity can alter the relative stability and distribution of states in a given cell population, particularly when incorporated in the inhibitory effect on miR 200 from ZEB. This feedback can stabilize the mesenchymal state, thus making transitions out of that state difficult. Conversely, epigenetic regulation of the self activation of ZEB has only minor effects. Our model predicts that this effect could be seen in experiments, when epithelial cells are treated with an external EMT inducing signal for a sufficiently long period of time and then allowed to recover. Our preliminary experimental data indeed shows that a prolonged TGF beta; exposure gives rise to increasing difficult reversion back to the epithelial state. Thus, this integrated theoretical experimental approach yields insights into how an epigenetic feedback may alter the dynamics of EMT.

The Role of Calcium Signaling in Regulation of Epithelial-Mesenchymal Transition

2020 ◽  
pp. 1-23
Author(s):  
Divya Adiga ◽  
Raghu Radhakrishnan ◽  
Sanjiban Chakrabarty ◽  
Prashant Kumar ◽  
Shama Prasada Kabekkodu
Keyword(s):  
Cancer Metastasis ◽  
Epithelial To Mesenchymal Transition ◽  
Epithelial Mesenchymal Transition ◽  
Critical Role ◽  
Cancer Therapeutics ◽  
Growth And Survival ◽  
Mesenchymal Transition ◽  
Microenvironmental Factors ◽  
Favorable Clinical Outcome

Despite substantial advances in the field of cancer therapeutics, metastasis is a significant challenge for a favorable clinical outcome. Epithelial to mesenchymal transition (EMT) is a process of acquiring increased motility, invasiveness, and therapeutic resistance by cancer cells for their sustained growth and survival. A plethora of intrinsic mechanisms and extrinsic microenvironmental factors drive the process of cancer metastasis. Calcium (Ca<sup>2+</sup>) signaling plays a critical role in dictating the adaptive metastatic cell behavior comprising of cell migration, invasion, angiogenesis, and intravasation. By modulating EMT, Ca<sup>2+</sup> signaling can regulate the complexity and dynamics of events leading to metastasis. This review summarizes the role of Ca<sup>2+</sup> signal remodeling in the regulation of EMT and metastasis in cancer.

scholarly journals Relationship between Expression of EMT Transcription Factor of ZEB1 and CXCR4 Chemokine Receptor

2017 ◽  
Vol 3 ◽  
pp. 55
Author(s):  
Naghmeh Ahmadiankia
Keyword(s):  
Transcription Factor ◽  
Cause Of Death ◽  
Chemokine Receptor ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Critical Role ◽  
Cxcr4 Expression ◽  
Mesenchymal Transition

Metastasis is one the most leading cause of death from cancer and the chemokine receptor of CXCR4 has a critical role in cancer metastasis. Moreover, metastasis is always correlated with epithelial-mesenchymal transition (EMT). In this study, the correlation between expression of EMT-TF of ZEB1 and CXCR4 has been examined. The results revealed that in ZEB1 knocked out cells, the expression of CXCR4 decreased significantly. This indicated that ZEB1 might be one of the regulators of CXCR4 expression.

scholarly journals NRF2-dependent epigenetic regulation can promote the hybrid epithelial/mesenchymal phenotype

2021 ◽  
Author(s):  
Wen Jia ◽  
Mohit Kumar Jolly ◽  
Herbert Levine
Keyword(s):  
Epigenetic Regulation ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Critical Factor ◽  
Epigenetic Inheritance ◽  
Stability Factor ◽  
Mesenchymal Phenotype ◽  
Mesenchymal Transition ◽  
Hybrid State ◽  
Regulation Model

AbstractThe epithelial-mesenchymal transition (EMT) is a cellular process critical for wound healing, cancer metastasis and embryonic development. Recent efforts have identified the role of hybrid epithelial/mesenchymal states, having both epithelial and mesehncymal traits, in enabling cancer metastasis and resistance to various therapies. Also, previous work has suggested that NRF2 can act as phenotypic stability factor to help stablize such hybrid states. Here, we incorporate a phenomenological epigenetic feedback effect into our previous computational model for EMT signaling. We show that this type of feedback can stabilize the hybrid state as compared to the fully mesenchymal phenotype if NRF2 can influence SNAIL at an epigenetic level, as this link makes transitions out of hybrid state more difficult. However, epigenetic regulation on other NRF2-related links do not significantly change the EMT dynamics. Finally, we considered possible cell division effects in our epigenetic regulation model, and our results indicate that the degree of epigenetic inheritance does not appear to be a critical factor for the hybrid E/M state stabilizing behavior of NRF2.

scholarly journals Extracellular HSP90α-LRP1 Signaling Promote Pancreatic Cancer Metastasis and Chemoresistance Via Regulating Epithelial-To-Mesenchymal Transition

2021 ◽  
Author(s):  
Nina Xue ◽  
Tingting Du ◽  
Fangfang Lai ◽  
Jing Jin ◽  
Ming Ji ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Metastasis ◽  
Epithelial To Mesenchymal Transition ◽  
Epithelial Mesenchymal Transition ◽  
Critical Role ◽  
Density Lipoprotein ◽  
Underlying Mechanism ◽  
Migration And Invasion ◽  
Mesenchymal Transition

Abstract Extracellular heat shock protein 90α (HSP90α) has been reported to promote cancer cell invasion and migration. However, whether pancreatic cancer (PC) cells expressed membrane-bound or secreted HSP90α and its underlying mechanism for PC progression were still unclear. Our study pointed out that highly invasive Capan2 cells has a higher level of secreted HSP90α, rather than membrane HSP90α, compared with those of less invasive PL45 cells. The conditioned medium of Capan2 cells or recombinant HSP90α protein was able to stimulate the migration and invasion of PL45 or capan2 cells, which could be prevented by a neutralizing anti-HSP90α antibody. Furthermore, secreted HSP90α promoted elements of epithelial-mesenchymal transition (EMT) in PL45 cells, including increases in vimentin and snail expressions, decreases in E-cadherin expression and changes in cell shape towards a mesenchymal phenotype, but these phenomena were reversed by anti-HSP90α antibody in Capan2 cells. In addition, high levels of low-density lipoprotein receptor-related protein 1 (LRP1) mRNA were associated with worsened patient survival in pancreatic adenocarcinoma. LRP1 as a receptor of eHSP90α for its stimulatory role of PC cells EMT and metastasis by activating AKT signaling. Down-regulation of LRP1 could promote chemosensitivity to gemcitabine and doxorubicin, but not to topotecan and paclitaxel in Capan2 cells. Therefore, our study reveals a critical role of secreted HSP90α on EMT events and suggests blocking secreted HSP90α underlies an aspect of metastasis and chemoresistance.

scholarly journals Orai3 Regulates Pancreatic Cancer Metastasis by Encoding a Functional Store Operated Calcium Entry Channel

2021 ◽  
Author(s):  
Samriddhi Arora ◽  
Jyoti Tanwar ◽  
Nutan Sharma ◽  
Suman Saurav ◽  
Rajender K. Motiani
Keyword(s):  
Pancreatic Cancer ◽  
Survival Time ◽  
Cell Lines ◽  
Cancer Progression ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Critical Role ◽  
Mesenchymal Transition

Pancreatic cancer (PC) is one of the most lethal forms of cancers with 5-year mean survival rate of less than 10%. Most of the PC associated deaths are due to metastasis to secondary sites. Calcium (Ca2+) signaling plays a critical role in regulating hallmarks of cancer progression including cell proliferation, migration and apoptotic resistance. Store operated Ca2+ entry (SOCE) mediated by Orai1/2/3 channels is a highly regulated and ubiquitous pathway responsible for Ca2+ influx into non-excitable cells. In this study, we performed extensive bioinformatic analysis of publicly available datasets and observed that Orai3 expression is inversely associated with the mean survival time of PC patients. Orai3 expression analysis in a battery of PC cell lines corroborated its differential expression profile. We then carried out thorough Ca2+ imaging experiments in 6 PC cell lines and found that Orai3 forms a functional SOCE in PC cells. Our in vitro functional assays show that Orai3 regulates PC cell cycle progression, apoptosis and migration. Most importantly, our in vivo xenograft studies demonstrate a critical role of Orai3 in PC tumor growth and secondary metastasis. Mechanistically, Orai3 controls G1 phase progression, matrix metalloproteinase expression and epithelial-mesenchymal transition in PC cells. Taken together, this study for the first time reports that Orai3 drives aggressive phenotypes of PC cells i.e. migration in vitro and metastasis in vivo. Considering that Orai3 expression is inversely associated with the PC patients survival time, it appears to be a highly attractive therapeutic target.

scholarly journals Epigenetic Regulation of Epithelial to Mesenchymal Transition in the Cancer Metastatic Cascade: Implications for Cancer Therapy

2021 ◽  
Vol 11 ◽  
Author(s):  
Qiu-Luo Liu ◽  
Maochao Luo ◽  
Canhua Huang ◽  
Hai-Ning Chen ◽  
Zong-Guang Zhou
Keyword(s):  
Cancer Cells ◽  
Cancer Progression ◽  
Epigenetic Regulation ◽  
Cancer Metastasis ◽  
Epithelial To Mesenchymal Transition ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Metastatic Cascade ◽  
Subsequent Transformation ◽  
Metastatic Cells

Metastasis is the end stage of cancer progression and the direct cause of most cancer-related deaths. The spreading of cancer cells from the primary site to distant organs is a multistep process known as the metastatic cascade, including local invasion, intravasation, survival in the circulation, extravasation, and colonization. Each of these steps is driven by the acquisition of genetic and/or epigenetic alterations within cancer cells, leading to subsequent transformation of metastatic cells. Epithelial–mesenchymal transition (EMT), a cellular process mediating the conversion of cell from epithelial to mesenchymal phenotype, and its reverse transformation, termed mesenchymal–epithelial transition (MET), together endow metastatic cells with traits needed to generate overt metastases in different scenarios. The dynamic shift between these two phenotypes and their transitional state, termed partial EMT, emphasizes the plasticity of EMT. Recent advances attributed this plasticity to epigenetic regulation, which has implications for the therapeutic targeting of cancer metastasis. In this review, we will discuss the association between epigenetic events and the multifaceted nature of EMT, which may provide insights into the steps of the cancer metastatic cascade.

scholarly journals Protein Expression Profile in Rat Silicosis Model Reveals Upregulation of PTPN2 and Its Inhibitory Effect on Epithelial-Mesenchymal Transition by Dephosphorylation of STAT3

2020 ◽  
Vol 21 (4) ◽  
pp. 1189
Author(s):  
Ying Zhu ◽  
Jingxin Yao ◽  
Yuxia Duan ◽  
Hong Xu ◽  
Qiyun Cheng ◽  
...  
Keyword(s):  
Epithelial Mesenchymal Transition ◽  
Tyrosine Phosphatase ◽  
Inhibitory Effect ◽  
Differentially Expressed ◽  
Absolute Quantitation ◽  
Opposite Pattern ◽  
Mesenchymal Transition ◽  
Enhanced Expression ◽  
Isobaric Tags

Silicosis is a chronic occupational lung disease caused by long-term inhalation of crystalline silica particulates. We created a rat model that closely approximates the exposure and development of silicosis in humans. Isobaric tags for relative and absolute quantitation (iTRAQ) technologies we used to identify proteins differentially expressed in activated rat lung tissue. We constructed three lentiviral knockdown vectors and an overexpression vector for the protein tyrosine phosphatase non-receptor type 2 (PTPN2) gene to achieve stable long-term expression. A total of 471 proteins were differentially expressed in the silicosis group compared with controls. Twenty upregulated, and eight downregulated proteins exhibited a ≥1.5-fold change relative to controls. We next found that the PTPN2, Factor B, and VRK1 concentrations in silicotic rats silicosis and SiO2-stimulated MLE-12 cells were significantly higher than control groups. More importantly, we found that overexpression of PTPN2 simultaneously decreased the expression of phospho–signal transducer and activator of transcription 3 (p-STAT3) and Vimentin, while increasing E-cadherin expression. The opposite pattern was observed for PTPN2-gene silencing. We identified three proteins with substantially enhanced expression in silicosis. Our study also showed that PTPN2 can inhibit epithelial-mesenchymal transition by dephosphorylating STAT3 in silicosis fibrosis.

scholarly journals A Cancer Cell Cluster Marked by LincRNA MEG3 Leads Pancreatic Ductal Adenocarcinoma Metastasis

2021 ◽  
Vol 11 ◽  
Author(s):  
Hong Pan ◽  
Huanrong Diao ◽  
Wen Zhong ◽  
Taifang Wang ◽  
Ping Wen ◽  
...  
Keyword(s):  
Single Cell ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Critical Role ◽  
Marker Gene ◽  
Differentially Expressed Gene ◽  
Ductal Adenocarcinoma ◽  
Multiple Cancer ◽  
Mesenchymal Transition

Pancreatic ductal adenocarcinoma (PDAC) is a highly devastating disease with poor prognosis and rising incidence worldwide. Late detection and particularly aggressive characteristics are the major challenges that lead to therapeutic failure of this disease. A well described gene program and core regulators are yet to be discovered to drive the metastasis of the PDAC cells. As the development of single cell omics technologies including single cell RNA-sequencing (scRNA-seq), detailed characterization of the cellular composition of solid tumors and their microenvironments are well elaborated. In the current study, we accessed a recently published scRNA-seq dataset on primary and metastatic PDAC tissues and subset the tumor cells. By comparative analysis, we profiled the differentially expressed gene programs of primary and metastatic PDAC and found several long intergenic non-coding RNAs (LincRNAs) in top genes. The PDAC cancer cells showed some heterogeneity and were divided into four major subclusters based on gene profiles, one of which was mostly contributed by metastatic PDAC. Interestingly, this subcluster was remarkably marked by one of the above LincRNAs, MEG3, and exhibited significantly increased Epithelial–Mesenchymal-Transition (EMT) signatures. Ingenuity Pathway Analysis (IPA) on the signature genes of this subcluster gave multiple cancer metastasis associated and EMT signaling pathways, suggesting a critical role of this cluster in leading tumor cell metastasis. Taken together, this study displayed a PDAC cancer subcluster and its marker gene, biologically targeting of which might significantly attenuate the metastasis of tumor and might be a potential strategy for the therapeutic treatment of cancer.

scholarly journals Epigenetic Regulation and Post-Translational Modifications of SNAI1 in Cancer Metastasis

2021 ◽  
Vol 22 (20) ◽  
pp. 11062
Author(s):  
Bo Dong ◽  
Yadi Wu
Keyword(s):  
Cancer Progression ◽  
Epigenetic Regulation ◽  
Tumor Metastasis ◽  
Metabolic Regulation ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Post Translational Modifications ◽  
Mesenchymal Transition ◽  
Novel Therapeutic Strategies

SNAI1, a zinc finger transcription factor, not only acts as the master regulator of epithelial-mesenchymal transition (EMT) but also functions as a driver of cancer progression, including cell invasion, survival, immune regulation, stem cell properties, and metabolic regulation. The regulation of SNAI1 occurs at the transcriptional, translational, and predominant post-translational levels including phosphorylation, acetylation, and ubiquitination. Here, we discuss the regulation and role of SNAI1 in cancer metastasis, with a particular emphasis on epigenetic regulation and post-translational modifications. Understanding how signaling networks integrate with SNAI1 in cancer progression will shed new light on the mechanism of tumor metastasis and help develop novel therapeutic strategies against cancer metastasis.

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.

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