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.

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 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.

Upregulation of Bromodomain PHD‑finger transcription factor in ovarian cancer and its critical role for cancer cell proliferation and survival

2020 ◽  
Author(s):  
Juan Miao ◽  
Min Zhang ◽  
Xiaohao Huang ◽  
Lei Xu ◽  
Ranran Tang ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Proliferation ◽  
Transcription Factor ◽  
Signaling Pathways ◽  
Cell Lines ◽  
Epithelial Mesenchymal Transition ◽  
Critical Role ◽  
Nucleosome Remodeling ◽  
Phd Finger ◽  
Mesenchymal Transition

Abstract: Bromodomain PHD finger transcription factor (BPTF) is a core subunit of nucleosome-remodeling factor (NURF) complex, which plays an important role in the development of several cancers. However, it is unknown whether BPTF regulates ovarian cancer (OC) progression. Relative expression of BPTF in cell lines and tissues of OC were measured by Western blot and immunohistochemistry respectively. Clinical significance of BPTF in OC was analyzed by Chisquare test. BPTF knockdown effects on the proliferation, migration, invasion and apoptosis of OC cells were examined. Mechanism studies revealed that these effects were achieved through simultaneous modulation of multiple signaling pathways. We found that BPTF was highly expressed in OC cell lines and tissues compared with normal human ovarian epithelial cell and non-cancerous tissues (p<0.05). These results are also supported by the public RNA-seq data. BPTF overexpression was correlated with poor ovarian cancer patient survival (p<0.05). Vitro experiments revealed that the down-regulation of BPTF inhibited OC cell proliferation, colony formation, migration, invasion and induced its apoptosis. BPTF knockdown also regulated the epithelial-mesenchymal transition (EMT) signaling pathways and induced the cleavage of apoptosis-related proteins. Consequently, BPTF plays a critical role in regulating OC cell survival and functions as a potential therapeutic target for OC.

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 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 Beyond N-Cadherin, Relevance of Cadherins 5, 6 and 17 in Cancer Progression and Metastasis

2019 ◽  
Vol 20 (13) ◽  
pp. 3373 ◽  
Author(s):  
J. Ignacio Casal ◽  
Rubén A. Bartolomé
Keyword(s):  
Cancer Progression ◽  
Cancer Metastasis ◽  
De Novo ◽  
Epithelial Mesenchymal Transition ◽  
Critical Role ◽  
Mesenchymal Transition ◽  
Rgd Motif ◽  
Metastatic Cells ◽  
Pathway Activation ◽  
Structural And Functional Properties

Cell-cell adhesion molecules (cadherins) and cell-extracellular matrix adhesion proteins (integrins) play a critical role in the regulation of cancer invasion and metastasis. Although significant progress has been made in the characterization of multiple members of the cadherin superfamily, most of the published work continues to focus in the switch E-/N-cadherin and its role in the epithelial–mesenchymal transition. Here, we will discuss the structural and functional properties of a subset of cadherins (cadherin 17, cadherin 5 and cadherin 6) that have an RGD motif in the extracellular domains. This RGD motif is critical for the interaction with α2β1 integrin and posterior integrin pathway activation in cancer metastatic cells. However, other signaling pathways seem to be affected by RGD cadherin interactions, as will be discussed. The range of solid tumors with overexpression or “de novo” expression of one or more of these three cadherins is very wide (gastrointestinal, gynaecological and melanoma, among others), underscoring the relevance of these cadherins in cancer metastasis. Finally, we will discuss different evidences that support the therapeutic use of these cadherins by blocking their capacity to work as integrin ligands in order to develop new cures for metastatic patients.

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

Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 5937
Author(s):  
Samriddhi Arora ◽  
Jyoti Tanwar ◽  
Nutan Sharma ◽  
Suman Saurav ◽  
Rajender K. Motiani
Keyword(s):  
Cell Lines ◽  
Cell Cycle Progression ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Critical Role ◽  
Bioinformatic Analysis ◽  
Mesenchymal Transition

Store operated Ca2+ entry (SOCE) mediated by Orai1/2/3 channels is a highly regulated and ubiquitous Ca2+ influx pathway. Although the role of Orai1 channels is well studied, the significance of Orai2/3 channels is still emerging in nature. 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 six PC cell lines and found that Orai3 forms a functional SOCE channel 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 overexpression leads to poor prognosis in PC patients, it appears to be a highly attractive therapeutic target.

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.

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