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15 pages, 3465 KiB

Open AccessArticle

Targeting Src-Hic-5 Signal Cascade for Preventing Migration of Cholangiocarcinoma Cell HuCCT1

by Wen-Sheng Wu, Chin-Hsien Ling, Ming-Che Lee, Chuan-Chu Cheng, Rui-Fang Chen, Chen-Fang Lin, Ren-In You and Yen-Cheng Chen

Biomedicines 2022, 10(5), 1022; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10051022 - 28 Apr 2022

Cited by 3 | Viewed by 1918

Abstract

Cholangiocarcinoma (CCA) is the second most common primary liver cancer with poor prognosis. The deregulation of a lot of oncogenic signaling molecules, such as receptor tyrosine kinases (RTKs), has been found to be associated with CCA progression. However, RTKs-based target therapy showed limited [...] Read more.

Cholangiocarcinoma (CCA) is the second most common primary liver cancer with poor prognosis. The deregulation of a lot of oncogenic signaling molecules, such as receptor tyrosine kinases (RTKs), has been found to be associated with CCA progression. However, RTKs-based target therapy showed limited improvement suggesting a need to search for alternative targets for preventing CCA progression. To address this issue, we screened the oncogenic signal molecules upregulated in surgical tissues of CCAs. Interestingly, over-expression of hydrogen peroxide inducible clone-5 (Hic-5) coupled with over-activation of Src, AKT, JNK were observed in 50% of the cholangiocarcinoma with metastatic potential. To investigate whether these molecules may work together to trigger metastatic signaling, their up-and-down relationship was examined in a well-established cholangiocarcinoma cell line, HuCCT1. Src inhibitors PP1 (IC50, 13.4 μM) and dasatinib (IC50, 0.1 μM) significantly decreased both phosphorylated AKT (phosphor-AKT Thr450) and Hic-5 in HuCCT1. In addition, a knockdown of Hic-5 effectively suppressed activation of Src, JNK, and AKT. These implicated a positive cross-talk occurred between Hic-5 and Src for triggering AKT activation. Further, depletion of Hic-5 and inhibition of Src suppressed HuccT1 cell migration in a dose-dependent manner. Remarkably, prior transfection of Hic-5 siRNA for 24 h followed by treatment with PP1 or dasatinib for 24 h resulted in additive suppression of HuCCT1 migration. This suggested that a promising combinatory efficacy can be achieved by depletion of Hic-5 coupled with inhibition of Src. In the future, target therapy against CCA progression by co-targeting Hic-5 and Src may be successfully developed in vivo. Full article

(This article belongs to the Special Issue Advanced Research in Cell Motility)

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19 pages, 4731 KiB

Open AccessArticle

Prolonged Cadmium Exposure Alters Migration Dynamics and Increases Heterogeneity of Human Uterine Fibroid Cells—Insights from Time Lapse Analysis

by Yitang Yan, Min Shi, Rick Fannin, Linda Yu, Jingli Liu, Lysandra Castro and Darlene Dixon

Biomedicines 2022, 10(4), 917; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10040917 - 16 Apr 2022

Cited by 1 | Viewed by 2059

Abstract

Cadmium (Cd) is one of the most prevalent environmental heavy metal contaminants and is considered an endocrine disruptor and carcinogen. In women with uterine fibroids, there is a correlation between blood Cd levels and fibroid tumor size. In this study, fibroid cells were [...] Read more.

Cadmium (Cd) is one of the most prevalent environmental heavy metal contaminants and is considered an endocrine disruptor and carcinogen. In women with uterine fibroids, there is a correlation between blood Cd levels and fibroid tumor size. In this study, fibroid cells were exposed to 10 µM CdCl₂ for 6 months and a fast-growing Cd-Resistant Leiomyoma culture, termed CR-LM6, was recovered. To characterize the morphological and mechanodynamic features of uterine fibroid cells associated with prolonged Cd exposure, we conducted time lapse imaging using a Zeiss confocal microscope and analyzed data by Imaris and RStudio. Our experiments recorded more than 64,000 trackable nuclear surface objects, with each having multiple parameters such as nuclear size and shape, speed, location, orientation, track length, and track straightness. Quantitative analysis revealed that prolonged Cd exposure significantly altered cell migration behavior, such as increased track length and reduced track straightness. Cd exposure also significantly increased the heterogeneity in nuclear size. Additionally, Cd significantly increased the median and variance of instantaneous speed, indicating that Cd exposure results in higher speed and greater variation in motility. Profiling of mRNA by NanoString analysis and Ingenuity Pathway Analysis (IPA) strongly suggested that the direction of gene expression changes due to Cd exposure enhanced cell movement and invasion. The altered expression of extracellular matrix (ECM) genes such as collagens, matrix metallopeptidases (MMPs), secreted phosphoprotein 1 (SPP1), which are important for migration contact guidance, may be responsible for the greater heterogeneity. The significantly increased heterogeneity of nuclear size, speed, and altered migration patterns may be a prerequisite for fibroid cells to attain characteristics favorable for cancer progression, invasion, and metastasis. Full article

(This article belongs to the Special Issue Advanced Research in Cell Motility)

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14 pages, 3753 KiB

Open AccessArticle

Yes-Associated Protein Is Required for ZO-1-Mediated Tight-Junction Integrity and Cell Migration in E-Cadherin-Restored AGS Gastric Cancer Cells

by Seon-Young Kim, Song-Yi Park, Hwan-Seok Jang, Yong-Doo Park and Sun-Ho Kee

Biomedicines 2021, 9(9), 1264; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9091264 - 18 Sep 2021

Cited by 8 | Viewed by 3247

Abstract

Yes-associated protein (YAP) regulates numerous cellular homeostasis processes and malignant transformation. We found that YAP influences ZO-1-mediated cell migration using E-cadherin-restored EC96 cells derived from gastric malignant AGS cells. Ectopic expression of E-cadherin enhanced straightforward migration of cells, in comparison to the meandering [...] Read more.

Yes-associated protein (YAP) regulates numerous cellular homeostasis processes and malignant transformation. We found that YAP influences ZO-1-mediated cell migration using E-cadherin-restored EC96 cells derived from gastric malignant AGS cells. Ectopic expression of E-cadherin enhanced straightforward migration of cells, in comparison to the meandering movement of parental AGS cells. In EC96 cells, YAP and ZO-1 expression increased but nuclear YAP levels and activity were reduced. Nuclear factor-κB (NF-κB) mediated the increase in ZO-1 expression, possibly stabilizing cytoplasmic YAP post-translationally. Downregulation of YAP expression using siYAP RNA or stable knock-down inhibited straightforward cell migration by fragmenting ZO-1 containing tight junctions (TJs) but not adherens junctions, implying involvement of YAP in ZO-1-mediated cell migration. The association of YAP with ZO-1 was mediated by angiomotin (AMOT) because downregulation of AMOT dissociated YAP from ZO-1 and reduced cell migration. E-cadherin restoration in malignant cancer cells induced NF-κB signaling to enhance ZO-1 expression and subsequently stabilize YAP. At high expression levels, YAP associates with ZO-1 via AMOT at TJs, influencing ZO-1-mediated cell migration and maintaining TJ integrity. Full article

(This article belongs to the Special Issue Advanced Research in Cell Motility)

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18 pages, 1926 KiB

Open AccessArticle

Organization of the Cytoskeleton in Ectopic Foci of the Endometrium with Rare Localization

by Konstantin A. Toniyan, Victoria V. Povorova, Elena Yu. Gorbacheva, Valery V. Boyarintsev and Irina V. Ogneva

Biomedicines 2021, 9(8), 998; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9080998 - 11 Aug 2021

Cited by 4 | Viewed by 2236

Abstract

(1) Background: Endometriosis is a common pathology of the female reproductive system, often accompanied by pain and decreased fertility. However, its pathogenesis has not been sufficiently studied regarding the role of the cytoskeleton. In this study, we describe two clinical cases involving rare [...] Read more.

(1) Background: Endometriosis is a common pathology of the female reproductive system, often accompanied by pain and decreased fertility. However, its pathogenesis has not been sufficiently studied regarding the role of the cytoskeleton. In this study, we describe two clinical cases involving rare localization of extragenital endometriosis (umbilicus) and compare them with genital endometriosis of different localization (ovaries and uterus), as well as eutopic endometrium obtained with separate diagnostic curettage without confirmed pathology. (2) Methods: The relative content of actin and tubulin cytoskeleton proteins was determined by Western blotting, and the expression of genes encoding these proteins was determined by RT-PCR in the obtained intraoperative biopsies. The content of 5hmC was estimated by dot blot experiments, and the methylase/demethylase and acetylase/deacetylase contents were determined. (3) Results: The obtained results indicate that the content of the actin-binding protein alpha-actinin1 significantly increased (p < 0.05) in the groups with endometriosis, and this increase was most pronounced in patients with umbilical endometriosis. In addition, both the mRNA content of the ACTN1 gene and 5hmC content increased. It can be assumed that the increase in 5hmC is associated with a decrease in the TET3 demethylase content. Moreover, in the groups with extragenital endometriosis, alpha- and beta-tubulin content was decreased (p < 0.05) compared to the control levels. (4) Conclusions: In analyzing the results, further distance of ectopic endometrial foci from the eutopic localization may be associated with an increase in the content of alpha-actinin1, probably due to an increase in the expression of its gene and an increase in migration potential. In this case, a favorable prognosis can be explained by a decrease in tubulin content and, consequently, a decrease in the rate of cell division. Full article

(This article belongs to the Special Issue Advanced Research in Cell Motility)

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21 pages, 12740 KiB

Open AccessArticle

Matrix Stiffness Modulates Mechanical Interactions and Promotes Contact between Motile Cells

by Subhaya Bose, Kinjal Dasbiswas and Arvind Gopinath

Biomedicines 2021, 9(4), 428; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9040428 - 15 Apr 2021

Cited by 6 | Viewed by 3207

Abstract

The mechanical micro-environment of cells and tissues influences key aspects of cell structure and function, including cell motility. For proper tissue development, cells need to migrate, interact, and form contacts. Cells are known to exert contractile forces on underlying soft substrates and sense [...] Read more.

The mechanical micro-environment of cells and tissues influences key aspects of cell structure and function, including cell motility. For proper tissue development, cells need to migrate, interact, and form contacts. Cells are known to exert contractile forces on underlying soft substrates and sense deformations in them. Here, we propose and analyze a minimal biophysical model for cell migration and long-range cell–cell interactions through mutual mechanical deformations of the substrate. We compute key metrics of cell motile behavior, such as the number of cell-cell contacts over a given time, the dispersion of cell trajectories, and the probability of permanent cell contact, and analyze how these depend on a cell motility parameter and substrate stiffness. Our results elucidate how cells may sense each other mechanically and generate coordinated movements and provide an extensible framework to further address both mechanical and short-range biophysical interactions. Full article

(This article belongs to the Special Issue Advanced Research in Cell Motility)

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22 pages, 6273 KiB

Open AccessArticle

Ex Vivo Generation and Characterization of Human Hyaline and Elastic Cartilaginous Microtissues for Tissue Engineering Applications

by David Sánchez-Porras, Daniel Durand-Herrera, Ana B. Paes, Jesús Chato-Astrain, Rik Verplancke, Jan Vanfleteren, José Darío Sánchez-López, Óscar Darío García-García, Fernando Campos and Víctor Carriel

Biomedicines 2021, 9(3), 292; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9030292 - 12 Mar 2021

Cited by 6 | Viewed by 2069

Abstract

Considering the high prevalence of cartilage-associated pathologies, low self-repair capacity and limitations of current repair techniques, tissue engineering (TE) strategies have emerged as a promising alternative in this field. Three-dimensional culture techniques have gained attention in recent years, showing their ability to provide [...] Read more.

Considering the high prevalence of cartilage-associated pathologies, low self-repair capacity and limitations of current repair techniques, tissue engineering (TE) strategies have emerged as a promising alternative in this field. Three-dimensional culture techniques have gained attention in recent years, showing their ability to provide the most biomimetic environment for the cells under culture conditions, enabling the cells to fabricate natural, 3D functional microtissues (MTs). In this sense, the aim of this study was to generate, characterize and compare scaffold-free human hyaline and elastic cartilage-derived MTs (HC-MTs and EC-MTs, respectively) under expansion (EM) and chondrogenic media (CM). MTs were generated by using agarose microchips and evaluated ex vivo for 28 days. The MTs generated were subjected to morphometric assessment and cell viability, metabolic activity and histological analyses. Results suggest that the use of CM improves the biomimicry of the MTs obtained in terms of morphology, viability and extracellular matrix (ECM) synthesis with respect to the use of EM. Moreover, the overall results indicate a faster and more sensitive response of the EC-derived cells to the use of CM as compared to HC chondrocytes. Finally, future preclinical in vivo studies are still needed to determine the potential clinical usefulness of these novel advanced therapy products. Full article

(This article belongs to the Special Issue Advanced Research in Cell Motility)

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16 pages, 2825 KiB

Open AccessArticle

Regulation of Fibroblast Cell Polarity by Src Tyrosine Kinase

by Kazuo Katoh

Biomedicines 2021, 9(2), 135; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9020135 - 01 Feb 2021

Cited by 6 | Viewed by 2182

Abstract

Src protein tyrosine kinases (SFKs) are a family of nonreceptor tyrosine kinases that are localized beneath the plasma membrane and are activated during cell adhesion, migration, and elongation. Due to their involvement in the activation of signal transduction cascades, SFKs have been suggested [...] Read more.

Src protein tyrosine kinases (SFKs) are a family of nonreceptor tyrosine kinases that are localized beneath the plasma membrane and are activated during cell adhesion, migration, and elongation. Due to their involvement in the activation of signal transduction cascades, SFKs have been suggested to play important roles in the determination of cell polarity during cell extension and elongation. However, the mechanism underlying Src-mediated polarity formation remains unclear. The present study was performed to investigate the mechanisms underlying Src-induced cell polarity formation and cell elongation using Src knockout fibroblasts (SYFs) together with an inhibitor of Src. Normal and Src knockout fibroblasts were also transfected with a wild-type c-Src, dominant negative c-Src, or constitutively active c-Src gene to analyze the changes in cell morphology. SYF cells cultured on a glass substrate elongated symmetrically into spindle-shaped cells, with the formation of focal adhesions at both ends of the cells. When normal fibroblasts were treated with Src Inhibitor No. 5, a selective inhibitor of Src tyrosine kinases, they elongated into symmetrical spindle-shaped cells, similar to SYF cells. These results suggest that cell polarity during extension and elongation may be regulated by SFKs and that the expression and regulation of Src are important for the formation of polarity during cell elongation. Full article

(This article belongs to the Special Issue Advanced Research in Cell Motility)

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Review

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29 pages, 8235 KiB

Open AccessReview

Targeting Pin1 for Modulation of Cell Motility and Cancer Therapy

by Hsiang-Hao Chuang, Yen-Yi Zhen, Yu-Chen Tsai, Cheng-Hao Chuang, Ming-Shyan Huang, Michael Hsiao and Chih-Jen Yang

Biomedicines 2021, 9(4), 359; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9040359 - 31 Mar 2021

Cited by 17 | Viewed by 4925

Abstract

Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1) specifically binds and isomerizes the phosphorylated serine/threonine-proline (pSer/Thr-Pro) motif, which leads to changes in protein conformation and function. Pin1 is widely overexpressed in cancers and plays an important role in tumorigenesis. Mounting evidence has revealed that targeting [...] Read more.

Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1) specifically binds and isomerizes the phosphorylated serine/threonine-proline (pSer/Thr-Pro) motif, which leads to changes in protein conformation and function. Pin1 is widely overexpressed in cancers and plays an important role in tumorigenesis. Mounting evidence has revealed that targeting Pin1 is a potential therapeutic approach for various cancers by inhibiting cell proliferation, reducing metastasis, and maintaining genome stability. In this review, we summarize the underlying mechanisms of Pin1-mediated upregulation of oncogenes and downregulation of tumor suppressors in cancer development. Furthermore, we also discuss the multiple roles of Pin1 in cancer hallmarks and examine Pin1 as a desirable pharmaceutical target for cancer therapy. We also summarize the recent progress of Pin1-targeted small-molecule compounds for anticancer activity. Full article

(This article belongs to the Special Issue Advanced Research in Cell Motility)

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