scholarly journals WDR5 modulates cell motility and morphology and controls nuclear changes induced by a 3D environment

2018 ◽  
Vol 115 (34) ◽  
pp. 8581-8586 ◽  
Author(s):  
Pengbo Wang ◽  
Marcel Dreger ◽  
Elena Madrazo ◽  
Craig J. Williams ◽  
Rafael Samaniego ◽  
...  
Keyword(s):  
Cell Migration ◽  
Cell Polarity ◽  
Underlying Mechanism ◽  
H3k4 Methylation ◽  
Nuclear Mechanics ◽  
3D Environment ◽  
3D Environments ◽  
And Migration

Cell migration through extracellular matrices requires nuclear deformation, which depends on nuclear stiffness. In turn, chromatin structure contributes to nuclear stiffness, but the mechanosensing pathways regulating chromatin during cell migration remain unclear. Here, we demonstrate that WD repeat domain 5 (WDR5), an essential component of H3K4 methyltransferase complexes, regulates cell polarity, nuclear deformability, and migration of lymphocytes in vitro and in vivo, independent of transcriptional activity, suggesting nongenomic functions for WDR5. Similarly, depletion of RbBP5 (another H3K4 methyltransferase subunit) promotes similar defects. We reveal that a 3D environment increases the H3K4 methylation dependent on WDR5 and results in a globally less compacted chromatin conformation. Further, using atomic force microscopy, nuclear particle tracking, and nuclear swelling experiments, we detect changes in nuclear mechanics that accompany the epigenetic changes induced in 3D conditions. Indeed, nuclei from cells in 3D environments were softer, and thereby more deformable, compared with cells in suspension or cultured in 2D conditions, again dependent on WDR5. Dissecting the underlying mechanism, we determined that actomyosin contractility, through the phosphorylation of myosin by MLCK (myosin light chain kinase), controls the interaction of WDR5 with other components of the methyltransferase complex, which in turn up-regulates H3K4 methylation activation in 3D conditions. Taken together, our findings reveal a nongenomic function for WDR5 in regulating H3K4 methylation induced by 3D environments, physical properties of the nucleus, cell polarity, and cell migratory capacity.

scholarly journals Glycocalyx-mediated Cell Adhesion and Migration

2020 ◽  
Author(s):  
Samuel Schmidt ◽  
Bettina Weigelin ◽  
Joost te Riet ◽  
Veronika te Boekhorst ◽  
Mariska te Lindert ◽  
...  
Keyword(s):  
Cell Attachment ◽  
Adaptive Process ◽  
Nanoscale Interactions ◽  
Cell Adhesion And Migration ◽  
3D Environments ◽  
And Migration ◽  
Force Range ◽  
Membrane Deformations

SummaryCell migration is a force-dependent adaptive process mediated by integrin-dependent adhesion as well as other yet poorly defined interactions to the extracellular matrix. Using enzymatic multi-targeted digestion of sugar moieties on the surface of mesenchymal cells and leukocytes after interference with integrin function, we demonstrate that the surface glycocalyx represents an independent adhesion system. The glycocalyx mediates cell attachment to ECM ligand in the 100-500 pN force range and amoeboid migration in 3D environments in vitro and in vivo. Glycan-based adhesions consist of actin-rich membrane deformations and appositions associated with bleb-like and other protrusions forming complex-shaped sub-micron contact sites to ECM fibrils. These data implicate the glycocalyx in mediating generic stickiness to support nanoscale interactions (nanogrips) between the cell surface and ECM, mechano-coupling, and migration.

scholarly journals MiRNA let-7b promotes the development of hypoxic pulmonary hypertension by targeting ACE2

2019 ◽  
Vol 316 (3) ◽  
pp. L547-L557 ◽  
Author(s):  
Ruifeng Zhang ◽  
Hua Su ◽  
Xiuqing Ma ◽  
Xiaoling Xu ◽  
Li Liang ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Hypoxia Inducible Factor ◽  
Underlying Mechanism ◽  
Pulmonary Vessel ◽  
Hypoxic Pulmonary Hypertension ◽  
And Migration ◽  
Ventricle Hypertrophy ◽  
Proliferation And Migration

Angiotensin-converting enzyme 2 (ACE2) protects against hypoxic pulmonary hypertension (HPH) by inhibiting the proliferation and migration of pulmonary artery smooth muscle cells (PASMCs). Under hypoxia, the hypoxia-inducible factor 1α (HIF-1α) inhibits ACE2 indirectly; however, the underlying mechanism is unclear. In the present study, we found that exposure to chronic hypoxia stimulated microRNA (miRNA) let-7b expression in rat lung via a HIF-1α-dependent pathway. Let-7b downregulated ACE2 expression by directly targeting the coding sequence of ACE2. Our in vitro and in vivo results revealed that let-7b contributed to the pathogenesis of HPH by inducing PASMCs proliferation and migration. Let-7b knockout mitigated right ventricle hypertrophy and pulmonary vessel remodeling in HPH by restoring ACE2 expression. Overall, we demonstrated that HIF-1α inhibited ACE2 expression via the HIF-1α-let-7b-ACE2 axis, which contributed to the pathogenesis of HPH by stimulating PASMCs proliferation and migration. Since let-7b knockout alleviated the development of HPH, let-7b may serve as a potential clinical target for the treatment of HPH.

scholarly journals Synergistic antitumor effect of 5-fluorouracil with the novel LSD1 inhibitor ZY0511 in colorectal cancer

2020 ◽  
Vol 12 ◽  
pp. 175883592093742
Author(s):  
Wen Peng ◽  
Huaqing Zhang ◽  
Shisheng Tan ◽  
Yan Li ◽  
Yang Zhou ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Antitumor Effect ◽  
Underlying Mechanism ◽  
Synergistic Antitumor Effect ◽  
Anticancer Effects ◽  
Potential Marker ◽  
And Migration ◽  
Induced Apoptosis

Background: Lysine-specific histone demethylase 1 (LSD1) is a potential target of cancer therapy. In the present study, we aimed to investigate the combined antitumor activity of a novel LSD1 inhibitor (ZY0511) with 5-fluorouracil (5-FU) and elucidate the underlying mechanism in colorectal cancer (CRC). Methods: We evaluated LSD1 expression in CRC tissues from patients who received 5-FU treatment. The synergistic antitumor effect of 5-FU with ZY0511 against human CRC cells was detected both in vitro and in vivo. The underlying mechanism was explored based on mRNA sequencing (mRNA-seq) technology. Results: Overexpression of LSD1 was observed in human CRC tissues, and correlated with CRC development and 5-FU resistance. ZY0511, a novel LSD1 inhibitor, effectively inhibited CRC cells proliferation, both in vitro and in vivo. Notably, the combination of ZY0511 and 5-FU synergistically reduced CRC cells viability and migration in vitro. It also suppressed Wnt/β-catenin signaling and DNA synthesis pathways, which finally induced apoptosis of CRC cells. In addition, the combination of ZY0511 with 5-FU significantly reduced CRC xenograft tumor growth, along with lung and liver metastases in vivo. Conclusions: Our findings identify LSD1 as a potential marker for 5-FU resistance in CRC. ZY0511 is a promising candidate for CRC therapy as it potentiates 5-FU anticancer effects, thereby providing a new combinatorial strategy for treating CRC.

scholarly journals LOXL1-AS1 contributes to the proliferation and migration of laryngocarcinoma cells through miR-589-5p/TRAF6 axis

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Guijun He ◽  
Wenfeng Yao ◽  
Liang Li ◽  
Yang Wu ◽  
Guojian Feng ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Underlying Mechanism ◽  
Luciferase Reporter ◽  
Non Coding Rna ◽  
Reporter Assays ◽  
And Migration ◽  
Long Non Coding Rna ◽  
Proliferation And Migration

Abstract Background LOXL1-AS1 is a long non-coding RNA (lncRNA) that plays crucial roles in various cancers. However, the functional role of LOXL1-AS1 in laryngocarcinoma remains unclear. Thus we planned to probe into the function and underlying mechanism of LOXL1-AS1 in laryngocarcinoma. Methods Gene expression was evaluated in laryngocarcinoma cells using RT-qPCR. The ability of cell proliferation and migration was assessed by CCK8, colony formation, wound healing and transwell assays. The interaction among LOXL1-AS1, miR-589-5p and TRAF6 was detected by Ago2-RIP, RNA pull down and luciferase reporter assays. Results LOXL1-AS1 was overexpressed in laryngocarcinoma cells. Silencing of LOXL1-AS1 suppressed cell proliferation, migration and EMT in laryngocarcinoma. Moreover, miR-589-5p, the downstream of LOXL1-AS1, directly targeted TRAF6 in laryngocarcinoma. Importantly, LOXL1-AS1 augmented TRAF6 expression in laryngocarcinoma cells by sequestering miR-589-5p. Besides, miR-589-5p worked as a tumor-inhibitor while TRAF6 functioned as a tumor-facilitator in laryngocarcinoma. Of note, rescue experiments both in vitro and in vivo validated that LOXL1-AS1 aggravated the malignancy in laryngocarcinoma by targeting miR-589-5p/TRAF6 pathway. Conclusions LOXL1-AS1 promotes the proliferation and migration of laryngocarcinoma cells through absorbing miR-589-5p to upregulate TRAF6 expression.

scholarly journals Abi2-Deficient Mice Exhibit Defective Cell Migration, Aberrant Dendritic Spine Morphogenesis, and Deficits in Learning and Memory

2004 ◽  
Vol 24 (24) ◽  
pp. 10905-10922 ◽  
Author(s):  
Matthew Grove ◽  
Galina Demyanenko ◽  
Asier Echarri ◽  
Patricia A. Zipfel ◽  
Marisol E. Quiroz ◽  
...  
Keyword(s):  
Cell Migration ◽  
Dendritic Spine ◽  
Actin Polymerization ◽  
Adherens Junctions ◽  
Actin Dynamics ◽  
Long Term Memory ◽  
Cell Morphogenesis ◽  
And Migration

ABSTRACT The Abl-interactor (Abi) family of adaptor proteins has been linked to signaling pathways involving the Abl tyrosine kinases and the Rac GTPase. Abi proteins localize to sites of actin polymerization in protrusive membrane structures and regulate actin dynamics in vitro. Here we demonstrate that Abi2 modulates cell morphogenesis and migration in vivo. Homozygous deletion of murine abi2 produced abnormal phenotypes in the eye and brain, the tissues with the highest Abi2 expression. In the absence of Abi2, secondary lens fiber orientation and migration were defective in the eye, without detectable defects in proliferation, differentiation, or apoptosis. These phenotypes were consistent with the localization of Abi2 at adherens junctions in the developing lens and at nascent epithelial cell adherens junctions in vitro. Downregulation of Abi expression by RNA interference impaired adherens junction formation and correlated with downregulation of the Wave actin-nucleation promoting factor. Loss of Abi2 also resulted in cell migration defects in the neocortex and hippocampus, abnormal dendritic spine morphology and density, and severe deficits in short- and long-term memory. These findings support a role for Abi2 in the regulation of cytoskeletal dynamics at adherens junctions and dendritic spines, which is critical for intercellular connectivity, cell morphogenesis, and cognitive functions.

scholarly journals Myo1g is required for efficient adhesion and migration of activated B lymphocytes to inguinal lymph nodes

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
D. Cruz-Zárate ◽  
O. López-Ortega ◽  
D. A. Girón-Pérez ◽  
A. M. Gonzalez-Suarez ◽  
J. L. García-Cordero ◽  
...  
Keyword(s):  
Cell Migration ◽  
Lymph Node ◽  
B Lymphocytes ◽  
Dynamic Process ◽  
Inguinal Lymph Node ◽  
Cytoskeletal Remodeling ◽  
And Migration

AbstractCell migration is a dynamic process that involves adhesion molecules and the deformation of the moving cell that depends on cytoskeletal remodeling and actin-modulating proteins such as myosins. In this work, we analyzed the role of the class I Myosin-1 g (Myo1g) in migratory processes of LPS + IL-4 activated B lymphocytes in vivo and in vitro. In vivo, the absence of Myo1g reduced homing of activated B lymphocytes into the inguinal lymph node. Using microchannel chambers and morphology analysis, we found that the lack of Myo1g caused adhesion and chemotaxis defects. Additionally, deficiency in Myo1g causes flaws in adopting a migratory morphology. Our results highlight the importance of Myo1g during B cell migration.

scholarly journals IRF2 Destabilizes Oncogenic KPNA2 to Modulate the Tumorigenesis of Osteosarcoma via Regulating NF-κB/p65

2021 ◽  
Author(s):  
Shuchi Xia ◽  
Yiqun Ma
Keyword(s):  
Tumor Growth ◽  
Western Blot ◽  
Underlying Mechanism ◽  
Normal Human ◽  
And Migration ◽  
Oncogenic Function ◽  
Opposing Effect ◽  
Proliferation And Migration

Abstract Background: Osteosarcomas (OS) are the most frequent primary malignant bone tumor. Emerging evidence revealed that karyopherin alpha 2 (KPNA2) was strongly associated with the tumorigenesis and development of numerous human cancers. The aim of the present study was to investigate the expression pattern, biological functions and underlying mechanism of KPNA2 in OS. Methods: Bioinformatics TFBIND online was applied to forecast the transcription factor (TF) binding sites in the promoter region of KPNA2. The expression profile of KPNA2 in OS tissues were firstly assessed using TARGET dataset. The expression of KPNA2 in clinical OS samples and normal human adjacent samples were analyzed by RT-qPCR and western blot. CCK8, colony formation, wound-healing, and Transwell assays were used to assess cell viability, proliferation and migration in vitro, and in vivo experiments were performed to explore the effects of KPNA2 and interferon regulatory factor-2 (IRF2) on tumor growth. In addition, the correlation between IRF2 and KPNA2, and their roles on the NF-κB/p65 was investigated using chromatin immunoprecipitation (ChIP), RT-qPCR, western blot and dual-luciferase assays. Results: KPNA2 was obviously upregulated while IRF2 was significantly decreased in OS tissues and cell lines, as well as they were negatively correlated with each other. KPNA2 knockdown remarkably suppressed OS cell growth, migration, invasion in vitro and tumor growth in vivo, while IRF2 knockdown exerts an opposing effect. IRF2 binds to KPNA2 promoter to modulate the tumorigenic malignant phenotypes of OS via regulating NF-κB/p65 signaling. Conclusion: The present study demonstrated that KPNA2 performed the oncogenic function, possibly regulating tumorigenesis through NF-κB/p65 signaling pathway. Importantly, IRF2 was confirmed to serve a potential upstream TF of KPNA2 involving in the regulation of NF-κB/p65 pathway in OS.

scholarly journals CtBP modulates Snail-mediated tumor invasion in Drosophila

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Chenxi Wu ◽  
Xiang Ding ◽  
Zhuojie Li ◽  
Yuanyuan Huang ◽  
Qian Xu ◽  
...  
Keyword(s):  
Cell Migration ◽  
Tumor Invasion ◽  
Epithelial To Mesenchymal Transition ◽  
Model Organism ◽  
Underlying Mechanism ◽  
Primary Tumors ◽  
Mesenchymal Transition ◽  
Invasive Cell

AbstractCancer is one of the most fatal diseases that threaten human health, whereas more than 90% mortality of cancer patients is caused by tumor metastasis, rather than the growth of primary tumors. Thus, how to effectively control or even reverse the migration of tumor cells is of great significance for cancer therapy. CtBP, a transcriptional cofactor displaying high expression in a variety of human cancers, has become one of the main targets for cancer prediction, diagnosis, and treatment. The roles of CtBP in promoting tumorigenesis have been well studied in vitro, mostly based on gain-of-function, while its physiological functions in tumor invasion and the underlying mechanism remain largely elusive. Snail (Sna) is a well-known transcription factor involved in epithelial-to-mesenchymal transition (EMT) and tumor invasion, yet the mechanism that regulates Sna activity has not been fully understood. Using Drosophila as a model organism, we found that depletion of CtBP or snail (sna) suppressed RasV12/lgl-/--triggered tumor growth and invasion, and disrupted cell polarity-induced invasive cell migration. In addition, loss of CtBP inhibits RasV12/Sna-induced tumor invasion and Sna-mediated invasive cell migration. Furthermore, both CtBP and Sna are physiologically required for developmental cell migration during thorax closure. Finally, Sna activates the JNK signaling and promotes JNK-dependent cell invasion. Given that CtBP physically interacts with Sna, our data suggest that CtBP and Sna may form a transcriptional complex that regulates JNK-dependent tumor invasion and cell migration in vivo.

scholarly journals Vimentin fibers orient traction stress

2017 ◽  
Vol 114 (20) ◽  
pp. 5195-5200 ◽  
Author(s):  
Nancy Costigliola ◽  
Liya Ding ◽  
Christoph J. Burckhardt ◽  
Sangyoon J. Han ◽  
Edgar Gutierrez ◽  
...  
Keyword(s):  
Cell Migration ◽  
Single Cell ◽  
Graph Matching ◽  
Single Cells ◽  
Mechanical Strain ◽  
Migration Direction ◽  
Human Foreskin Fibroblasts ◽  
And Migration

The intermediate filament vimentin is required for cells to transition from the epithelial state to the mesenchymal state and migrate as single cells; however, little is known about the specific role of vimentin in the regulation of mesenchymal migration. Vimentin is known to have a significantly greater ability to resist stress without breaking in vitro compared with actin or microtubules, and also to increase cell elasticity in vivo. Therefore, we hypothesized that the presence of vimentin could support the anisotropic mechanical strain of single-cell migration. To study this, we fluorescently labeled vimentin with an mEmerald tag using TALEN genome editing. We observed vimentin architecture in migrating human foreskin fibroblasts and found that network organization varied from long, linear bundles, or “fibers,” to shorter fragments with a mesh-like organization. We developed image analysis tools employing steerable filtering and iterative graph matching to characterize the fibers embedded in the surrounding mesh. Vimentin fibers were aligned with fibroblast branching and migration direction. The presence of the vimentin network was correlated with 10-fold slower local actin retrograde flow rates, as well as spatial homogenization of actin-based forces transmitted to the substrate. Vimentin fibers coaligned with and were required for the anisotropic orientation of traction stresses. These results indicate that the vimentin network acts as a load-bearing superstructure capable of integrating and reorienting actin-based forces. We propose that vimentin's role in cell motility is to govern the alignment of traction stresses that permit single-cell migration.

scholarly journals Eupatilin Inhibits Renal Cancer Growth by Downregulating MicroRNA-21 through the Activation of YAP1

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Weifeng Zhong ◽  
Zhiming Wu ◽  
Nanhui Chen ◽  
Kaihua Zhong ◽  
Yifeng Lin ◽  
...  
Keyword(s):  
Renal Cancer ◽  
Nude Mice ◽  
Underlying Mechanism ◽  
Renal Tumors ◽  
Anticancer Effects ◽  
Tumor Tissues ◽  
And Migration ◽  
Lower Expression

Renal cell carcinoma (RCC) is the second most common human urinary tumor. Eupatilin is the main active ingredient of the traditional Chinese medicineArtemisia asiatica. The effect of Eupatilin on RCC and the underlying mechanism remain unknown. Here, we investigated the anticancer effects and mechanisms of Eupatilin in RCCin vivoandin vitro, laying an experimental foundation for the clinical application of Eupatilin in the treatment of RCC. The results showed that Eupatilin significantly inhibited 786-O cell viability and migration and promoted apoptosis. Eupatilin inhibited the expression of miR-21 in 786-O cells, and overexpression of miR-21 suppressed the effect of Eupatilin on viability, apoptosis, and migration in 786-O cells. Eupatilin inhibited the growth of renal tumors in nude mice by downregulating miR-21. YAP1, which was identified as a target of miR-21, showed significantly lower expression in RCC tissues than in healthy tissues. miR-21 significantly inhibited YAP1 protein expression in 786-O cells and tumor tissues isolated from nude mice, and YAP1 attenuated the effect of miR-21 on the viability, apoptosis, and migration of 786-O cells. In conclusion, Eupatilin inhibited the expression of miR-21, which mediated the proapoptotic and antimigratory effects of Eupatilin by suppressing YAP1 in renal cancer cells. These results suggested that Eupatilin could be a potent agent for the treatment of RCC.

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