A Multiscale computational model of YAP signaling in epithelial fingering behaviour

Model Simulation ◽

Multiscale Model ◽

Cellular Potts Model ◽

Mesenchymal Transition ◽

In epithelial-mesenchymal transition (EMT), cells organized into sheets break away and become motile mesenchymal cells. EMT plays a crucial role in wound healing, embryonic development, and cancer metastasis. Intracellular signaling in response to mechanical, topographic, or chemical stimuli can promote EMT. We present a multiscale model for EMT downstream of the protein YAP, which suppresses the cell-cell adhesion protein E-cadherin and activates the GTPase Rac1 that enhances cell migration. We first propose an ODE model for YAP/Rac1/E-cadherin interactions. The model dynamics are bistable, accounting for motile loose cells as for adherent slower cells. We implement this model in a cellular Potts model simulation of 2D wound-healing using the open source platform Morpheus. We show that, under suitable stimuli (depicting topographic cues) the sheet exhibits finger-like projections and EMT. Morphological, as well as quantitative differences in YAP levels as well as cell speed across the sheet are consistent with preexisting experimental observations of epithelial sheets grown on topographic features in vitro. The simulation is also consistent with experiments that knockdown or over-express YAP, inhibit Rac1, or block E-cadherin.

Inhibitor of DNA-Binding Protein 4 Suppresses Cancer Metastasis through the Regulation of Epithelial Mesenchymal Transition in Lung Adenocarcinoma

Cancers ◽

10.3390/cancers11122021 ◽

2019 ◽

Vol 11 (12) ◽

pp. 2021 ◽

Cited By ~ 1

Author(s):

Chi-Chung Wang ◽

Yuan-Ling Hsu ◽

Chi-Jen Chang ◽

Chia-Jen Wang ◽

Tzu-Hung Hsiao ◽

...

Keyword(s):

Lung Cancer ◽

Dna Binding ◽

Lung Adenocarcinoma ◽

Cancer Metastasis ◽

Migration And Invasion ◽

Mesenchymal Transition ◽

Inhibitor Of Dna Binding ◽

Metastasis is a predominant cause of cancer death and the major challenge in treating lung adenocarcinoma (LADC). Therefore, exploring new metastasis-related genes and their action mechanisms may provide new insights for developing a new combative approach to treat lung cancer. Previously, our research team discovered that the expression of the inhibitor of DNA binding 4 (Id4) was inversely related to cell invasiveness in LADC cells by cDNA microarray screening. However, the functional role of Id4 and its mechanism of action in lung cancer metastasis remain unclear. In this study, we report that the expression of Id4 could attenuate cell migration and invasion in vitro and cancer metastasis in vivo. Detailed analyses indicated that Id4 could promote E-cadherin expression through the binding of Slug, cause the occurrence of mesenchymal-epithelial transition (MET), and inhibit cancer metastasis. Moreover, the examination of the gene expression database (GSE31210) also revealed that high-level expression of Id4/E-cadherin and low-level expression of Slug were associated with a better clinical outcome in LADC patients. In summary, Id4 may act as a metastatic suppressor, which could not only be used as an independent predictor but also serve as a potential therapeutic for LADC treatment.

NRF2 activates a partial epithelial-mesenchymal transition and is maximally present in a hybrid epithelial/mesenchymal phenotype

Integrative Biology ◽

10.1093/intbio/zyz021 ◽

2019 ◽

Vol 11 (6) ◽

pp. 251-263 ◽

Cited By ~ 28

Author(s):

Federico Bocci ◽

Satyendra C Tripathi ◽

Samuel A Vilchez Mercedes ◽

Jason T George ◽

Julian P Casabar ◽

...

Keyword(s):

Cancer Cells ◽

Cancer Metastasis ◽

Therapy Resistance ◽

Collective Cell Migration ◽

Mesenchymal Transition ◽

Regulatory Circuit ◽

Clinical Records ◽

Abstract The epithelial-mesenchymal transition (EMT) is a key process implicated in cancer metastasis and therapy resistance. Recent studies have emphasized that cells can undergo partial EMT to attain a hybrid epithelial/mesenchymal (E/M) phenotype – a cornerstone of tumour aggressiveness and poor prognosis. These cells can have enhanced tumour-initiation potential as compared to purely epithelial or mesenchymal ones and can integrate the properties of cell-cell adhesion and motility that facilitates collective cell migration leading to clusters of circulating tumour cells (CTCs) – the prevalent mode of metastasis. Thus, identifying the molecular players that can enable cells to maintain a hybrid E/M phenotype is crucial to curb the metastatic load. Using an integrated computational-experimental approach, we show that the transcription factor NRF2 can prevent a complete EMT and instead stabilize a hybrid E/M phenotype. Knockdown of NRF2 in hybrid E/M non-small cell lung cancer cells H1975 and bladder cancer cells RT4 destabilized a hybrid E/M phenotype and compromised the ability to collectively migrate to close a wound in vitro. Notably, while NRF2 knockout simultaneously downregulated E-cadherin and ZEB-1, overexpression of NRF2 enriched for a hybrid E/M phenotype by simultaneously upregulating both E-cadherin and ZEB-1 in individual RT4 cells. Further, we predict that NRF2 is maximally expressed in hybrid E/M phenotype(s) and demonstrate that this biphasic dynamic arises from the interconnections among NRF2 and the EMT regulatory circuit. Finally, clinical records from multiple datasets suggest a correlation between a hybrid E/M phenotype, high levels of NRF2 and its targets and poor survival, further strengthening the emerging notion that hybrid E/M phenotype(s) may occupy the ‘metastatic sweet spot’.

NRF2 activates a partial Epithelial-Mesenchymal Transition and is maximally present in a hybrid Epithelial/Mesenchymal phenotype

10.1101/390237 ◽

2018 ◽

Cited By ~ 6

Author(s):

Federico Bocci ◽

Satyendra C Tripathi ◽

Samuel A Vilchez Mercedes ◽

Jason T George ◽

Julian P Casabar ◽

...

Keyword(s):

Cancer Cells ◽

Cancer Metastasis ◽

Therapy Resistance ◽

Collective Cell Migration ◽

Mesenchymal Transition ◽

Regulatory Circuit ◽

Clinical Records ◽

AbstractThe Epithelial-Mesenchymal Transition (EMT) is a key process implicated in cancer metastasis and therapy resistance. Recent studies have emphasized that cells can undergo partial EMT to attain a hybrid epithelial/mesenchymal (E/M) phenotype - a cornerstone of tumour aggressiveness and poor prognosis. These cells can have enhanced tumour-initiation potential as compared to purely epithelial or mesenchymal ones and can integrate the properties of cell-cell adhesion and motility that facilitates collective cell migration leading to clusters of Circulating Tumour Cells (CTCs) - the prevalent mode of metastasis. Thus, identifying the molecular players that can enable cells to maintain a hybrid E/M phenotype is crucial to curb the metastatic load. Here, using an integrated computational-experimental approach, we show that the transcription factor NRF2 can prevent a complete EMT and instead stabilize a hybrid E/M phenotype. Knockdown of NRF2 in hybrid E/M non-small cell lung cancer cells H1975 and bladder cancer cells RT4 destabilised a hybrid E/M phenotype and compromised the ability to collectively migrate to close a wound in vitro. Notably, while NRF2 knockout simultaneously downregulated E-cadherin and ZEB-1, overexpression of NRF2 enriched for a hybrid E/M phenotype by simultaneously upregulating both E-cadherin and ZEB-1 in individual RT4 cells. Further, we predict that NRF2 is maximally expressed in hybrid E/M phenotype(s) and demonstrate that this biphasic dynamic arises from the interconnections among NRF2 and the EMT regulatory circuit. Finally, clinical records from multiple datasets suggest a correlation between a hybrid E/M phenotype, high levels of NRF2 and its targets and poor survival, further strengthening the emerging notion that hybrid E/M phenotype(s) may occupy the ‘metastatic sweet spot’.

Upregulation of FBXW7 Suppresses Renal Cancer Metastasis and Epithelial Mesenchymal Transition

Disease Markers ◽

10.1155/2017/8276939 ◽

2017 ◽

Vol 2017 ◽

pp. 1-7 ◽

Cited By ~ 6

Author(s):

Yangke Cai ◽

Meng Zhang ◽

Xiaofu Qiu ◽

Bingwei Wang ◽

Yu Fu ◽

...

Keyword(s):

Cell Lines ◽

Renal Cell ◽

Cancer Metastasis ◽

Migration And Invasion ◽

Coding Region ◽

Mesenchymal Transition ◽

Renal Cell Line ◽

Emt Markers

Background and Objective. FBXW7, known as a general tumor suppressor, is commonly lowly expressed in metastatic malignancies. We aim to investigate the potential influence of FBXW7 overexpression on renal cell carcinoma (RCC) metastasis. Methods. We employed quantitative real-time PCR (qRT-PCR) and Western blotting (WB) to quantify the FBXW7 expression in RCC cell lines. Upregulation of FBXW7 was performed in vitro on RCC cells using the lentivirus covering coding region FBXW7 cDNA sequence, and functional tests were performed to verify FBXW7 overexpression on migration and invasion of RCC cells. Moreover, WB was employed to determine the expressions of MMP-2, MMP-9, and MMP-13, as well as EMT markers in the transfected RCC cells. Results. FBXW7 was significantly downregulated in RCC cell lines, dominated by 786-O and ACHN, when compared to normal renal cell line HK-2. Moreover, upregulation of FBXW7 in 786-O and ACHN cell lines significantly inhibited cell migration and invasion, as well as EMT. Present study also showed that FBXW7 was involved in the migration and invasion of RCC cells via regulating the expressions of MMP-2, MMP-9, and MMP-13. Conclusion. Our findings demonstrate that upregulation of FBXW7 inhibits RCC metastasis and EMT. FBXW7 is a potential therapeutic target for RCC patients.

Knockdown of ARK5 Expression Suppresses Invasion and Metastasis of Gastric Cancer

Cellular Physiology and Biochemistry ◽

10.1159/000478685 ◽

2017 ◽

Vol 42 (3) ◽

pp. 1025-1036 ◽

Cited By ~ 12

Author(s):

Dehu Chen ◽

Guiyuan Liu ◽

Ning Xu ◽

Xiaolan You ◽

Haihua Zhou ◽

...

Keyword(s):

Gastric Cancer ◽

Western Blot ◽

Cancer Metastasis ◽

Migration And Invasion ◽

Invasion And Metastasis ◽

Ags Cells ◽

Mesenchymal Transition

Background/Aims: Gastric cancer (GC) is a common and lethal malignancy, and AMP-activated protein kinase-related kinase 5 (ARK5) has been discovered to promote cancer metastasis in certain types of cancer. In this study, we explored the role of ARK5 in GC invasion and metastasis. Methods: ARK5 and epithelial-mesenchymal transition (EMT)-related markers were determined by immunohistochemistry and western blot in GC specimens. Other methods including stably transfected against ARK5 into SGC7901 and AGS cells, western blot, migration and invasion assays in vitro and nude mice tumorigenicity in vivo were also employed. Results: The results demonstrated that ARK5 expression was increased and positively correlated with metastasis, EMT-related markers and poor prognosis in patients with GC. Knockdown of ARK5 expression remarkably suppressed GC cells invasion and metastasis via regulating EMT, rather than proliferation in vitro and in vivo. And knockdown of ARK5 expression in GC cells resulted in the down-regulation of the mTOR/p70S6k signals, Slug and SIP1. Conclusion: The elevated ARK5 expression was closely associated with cancer metastasis and patient survival, and it seemed to function in GC cells migration and invasion via EMT alteration, together with the alteration of the mTOR/p70S6k signals, Slug and SIP1, thus providing a potential therapeutic target for GC.

The role of protein kinase PAK1 in the regulation of estrogen-independent growth of breast cancer

Biomeditsinskaya Khimiya ◽

10.18097/pbmc20146003322 ◽

2014 ◽

Vol 60 (3) ◽

pp. 322-331 ◽

Cited By ~ 2

Author(s):

E.A. Avilova ◽

O.E. Andreeva ◽

V.A. Shatskaya ◽

M.A. Krasilnikov

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Intracellular Signaling ◽

Breast Cancer Cells ◽

Breast Cancer Cell Lines ◽

Hormone Resistance ◽

Mesenchymal Transition

The main goal of this work was to study the intracellular signaling pathways responsible for the development of hormone resistance and maintaining the autonomous growth of breast cancer cells. In particular, the role of PAK1 (p21-activated kinase 1), the key mitogenic signaling protein, in the development of cell resistance to estrogens was analyzed. In vitro studies were performed on cultured breast cancer cell lines: estrogen-dependent estrogen receptor (ER)-positive MCF-7 cells and estrogen-resistant ER-negative HBL-100 cells. We found that the resistant HBL-100 cells were characterized by a higher level of PAK1 and demonstrated PAK1 involvement in the maintaining of estrogen-independent cell growth. We have also shown PAK1 ability to up-regulate Snail1, one of the epithelial-mesenchymal transition proteins, and obtained experimental evidence for Snail1 importance in the regulation of cell proliferation. In general, the results obtained in this study demonstrate involvement of PAK1 and Snail1 in the formation of estrogen-independent phenotype of breast cancer cells showing the potential role of both proteins as markers of hormone resistance of breast tumors.

Value of Biomarkers in Liver Cancer EMT model under different interventions：A meta-analysis

10.21203/rs.3.rs-892562/v2 ◽

2021 ◽

Author(s):

Jing Yan ◽

Shuli Zou ◽

Bei Xie ◽

Ye Tian ◽

Zhiheng Peng ◽

...

Keyword(s):

Liver Cancer ◽

Gene Knockout ◽

Meta Analysis ◽

China National Knowledge Infrastructure ◽

Mesenchymal Transition ◽

Tumor Microenvironments ◽

Genetic Intervention ◽

Abstract Background There are various interventions to establish the Liver cancer epithelial-mesenchymal transition (EMT) models. However, the ideal biomarkers for unique model are not well established. Further studies are necessary to evaluation of effective EMT biomarkers under different interventions in vitro studies. A meta-analysis was performed to evaluate the performance of different biomarkers in HepG2 cells during EMT under multiple interventions. Methods PubMed, Web of Science, Embase, the China National Knowledge Infrastructure (CNKI), the China Biology Medicine disc (CBM), Wan Fang Data, and VIP databases were systematically searched from inception to June 14, 2020 by two independent reviewers. Results A total of 58 studies were included in the meta-analysis. Our study showed that E-cadherin responds well to the intervention of medication, genetic intervention, gene knockout/knockdown, hypoxia, and other tumor microenvironments, as well as non-coding RNA (ncRNA) overexpression and silencing. N-cadherin can effectively evaluate the intervention effect of medication, genetic intervention, hypoxia and other tumor microenvironments, as well as ncRNA overexpression. Vimentin reflects the effects of medication, pro-EMT genetic intervention and gene knockout/knockdown, anti-EMT ncRNA overexpression and anti-EMT ncRNA silencing and hypoxia. Snail only responds to the intervention of anti-EMT genetic intervention and gene knockout/knockdown, tumor microenvironments other than hypoxia, anti-EMT ncRNA overexpression and ncRNA silencing. Conclusions Our results shows that some medicine, some gene, microenvironment and some ncRNA can effectively induce/inhibit EMT process. E-cadherin, N-cadherin, Vimentin and Snail are effective biomarkers during this process. They respond differently to different intervention. Therefore, different biomarkers should be chosen under different intervention based on their performance.

CD36 promotes the epithelial–mesenchymal transition and metastasis in cervical cancer by interacting with TGF-β

Journal of Translational Medicine ◽

10.1186/s12967-019-2098-6 ◽

2019 ◽

Vol 17 (1) ◽

Cited By ~ 8

Author(s):

Min Deng ◽

Xiaodong Cai ◽

Ling Long ◽

Linying Xie ◽

Hongmei Ma ◽

...

Keyword(s):

Cervical Cancer ◽

Cancer Cells ◽

Cancer Metastasis ◽

Mesenchymal Transition ◽

Expression Levels ◽

Cd36 Expression ◽

Cervical Cancer Cells

Abstract Background Accumulating evidence indicates that CD36 initiates metastasis and correlates with an unfavorable prognosis in cancers. However, there are few reports regarding the roles of CD36 in initiation and metastasis of cervical cancer. Methods Using immunohistochemistry, we analyzed 133 cervical cancer samples for CD36 protein expression levels, and then investigated the correlation between changes in its expression and clinicopathologic parameters. The effect of CD36 expression on the epithelial–mesenchymal transition (EMT) in cervical cancer cells was evaluated by Western immunoblotting analysis. In vitro invasion and in vivo metastasis assays were also used to evaluate the role of CD36 in cervical cancer metastasis. Results In the present study, we confirmed that CD36 was highly expressed in cervical cancer samples relative to normal cervical tissues. Moreover, overexpression of CD36 promoted invasiveness and metastasis of cervical cancer cells in vitro and in vivo, while CD36 knockdown suppressed proliferation, migration, and invasiveness. We demonstrated that TGF-β treatment attenuated E-cadherin expression and enhanced the expression levels of CD36, vimentin, slug, snail, and twist in si-SiHa, si-HeLa, and C33a–CD36 cells, suggesting that TGF-β synergized with CD36 on EMT via active CD36 expression. We also observed that the expression levels of TGF-β in si-SiHa cells and si-HeLa cells were down-regulated, whereas the expression levels of TGF-β were up-regulated in C33a–CD36 cells. These results imply that CD36 and TGF-β interact with each other to promote the EMT in cervical cancer. Conclusions Our findings suggest that CD36 is likely to be an effective target for guiding individualized clinical therapy of cervical cancer.

BTBD7 Downregulates E-Cadherin and Promotes Epithelial-Mesenchymal Transition in Lung Cancer

BioMed Research International ◽

10.1155/2019/5937635 ◽

2019 ◽

Vol 2019 ◽

pp. 1-11 ◽

Cited By ~ 3

Author(s):

Jie Shu ◽

Lin Wang ◽

Fei Han ◽

Yubin Chen ◽

Shunjun Wang ◽

...

Keyword(s):

Lung Cancer ◽

Western Blotting ◽

Nude Mice ◽

Cancer Metastasis ◽

A549 Cells ◽

Migration Ability ◽

Mesenchymal Transition ◽

Qrt Pcr ◽

Metastasis is the leading cause of lung cancer-associated death. Downregulated expression of E-cadherin followed by epithelial-mesenchymal transition (EMT) is critical for metastasis initiation in lung cancer. BTBD7 plays essential roles in lung cancer metastasis, but the mechanisms remain unknown. This study aimed to investigate the relationship between BTBD7 and E-cadherin in lung cancer and explore the role of BTBD7 in EMT. Fresh lung cancer and paracancer tissue specimens were collected from 30 patients, and the expression of BTBD7, E-cadherin, N-cadherin, fibronectin, and vimentin was analyzed by qRT-PCR, western blotting, and immunohistochemistry. A549 and HBE cells were cultured and treated with TGF-β1 for 72 h to induce EMT. Western blotting and qRT-PCR were performed to evaluate the expression of BTBD7, E-cadherin, N-cadherin, fibronectin, and vimentin. Then, A549 cells were treated separately with the BTBD7-ENTER plasmid, BTBD7-siRNA, and paclitaxel. After TGF-β1-induced EMT, the abovementioned markers were analyzed by western blotting and qRT-PCR. Wound healing assays were applied to assess the migration ability of cells in different groups. For animal experiments, A549 cells transfected with the BTBD7-ENTER plasmid were transplanted into BALB/c nude mice. After 4 weeks, all nude mice were sacrificed, and tumor tissues were harvested for qRT-PCR, western blot, and immunohistochemical analyses of the abovementioned markers. All experimental results showed that the levels of BTBD7, N-cadherin, fibronectin, and vimentin were increased in lung cancer tissues and cells, while the E-cadherin level was decreased. Transfection experiments showed that BTBD7 inhibited E-cadherin expression and enhanced EMT. Moreover, the migration capacity of lung cancer cells was increased by the high level of BTBD7. We concluded that BTBD7 is highly expressed during lung cancer development and metastasis and can inhibit the expression of E-cadherin and promote EMT in lung cancer. BTBD7 may thus be a therapeutic target for lung cancer.

MicroRNA-26a and -26b inhibit lens fibrosis and cataract by negatively regulating Jagged-1/Notch signaling pathway

Cell Death and Differentiation ◽

10.1038/cdd.2016.152 ◽

2017 ◽

Vol 24 (8) ◽

pp. 1431-1442 ◽

Cited By ~ 20

Author(s):

Xiaoyun Chen ◽

Wei Xiao ◽

Weirong Chen ◽

Xialin Liu ◽

Mingxing Wu ◽

...

Keyword(s):

Epithelial Cells ◽

Notch Signaling ◽

Cancer Metastasis ◽

Notch Pathway ◽

Lens Epithelial Cells ◽

Mesenchymal Transition ◽

Fibrotic Diseases

Abstract Fibrosis is a chronic process involving development and progression of multiple diseases in various organs and is responsible for almost half of all known deaths. Epithelial–mesenchymal transition (EMT) is the vital process in organ fibrosis. Lens is an elegant biological tool to investigate the fibrosis process because of its unique biological properties. Using gain- and loss-of-function assays, and different lens fibrosis models, here we demonstrated that microRNA (miR)-26a and miR-26b, members of the miR-26 family have key roles in EMT and fibrosis. They can significantly inhibit proliferation, migration, EMT of lens epithelial cells and lens fibrosis in vitro and in vivo. Interestingly, we revealed that the mechanisms of anti-EMT effects of miR-26a and -26b are via directly targeting Jagged-1 and suppressing Jagged-1/Notch signaling. Furthermore, we provided in vitro and in vivo evidence that Jagged-1/Notch signaling is activated in TGFβ2-stimulated EMT, and blockade of Notch signaling can reverse lens epithelial cells (LECs) EMT and lens fibrosis. Given the general involvement of EMT in most fibrotic diseases, cancer metastasis and recurrence, miR-26 family and Notch pathway may have therapeutic uses in treating fibrotic diseases and cancers.