scholarly journals Distinct functions for Rho1 in maintaining adherens junctions and apical tension in remodeling epithelia

2009 ◽  
Vol 185 (6) ◽  
pp. 1111-1125 ◽  
Author(s):  
Stephen J. Warner ◽  
Gregory D. Longmore
Keyword(s):  
Cancer Progression ◽  
Cell Shape ◽  
Adherens Junctions ◽  
Single Cells ◽  
Apical Cell ◽  
Clonal Analysis ◽  
Dependent Manner ◽  
Epithelial Cadherin ◽  
Rho Effectors

Maintenance and remodeling of adherens junctions (AJs) and cell shape in epithelia are necessary for the development of functional epithelia and are commonly altered during cancer progression/metastasis. Although formation of nascent AJs has received much attention, whether shared mechanisms are responsible for the maintenance and remodeling of AJs in dynamic epithelia, particularly in vivo, is not clear. Using clonal analysis in the postmitotic Drosophila melanogaster pupal eye epithelium, we demonstrate that Rho1 is required to maintain AJ integrity independent of its role in sustaining apical cell tension. Rho1 depletion in a remodeling postmitotic epithelium disrupts AJs but only when depleted in adjacent cells. Surprisingly, neither of the Rho effectors, Rok or Dia, is necessary downstream of Rho1 to maintain AJs; instead, Rho1 maintains AJs by inhibiting Drosophila epithelial cadherin endocytosis in a Cdc42/Par6-dependent manner. In contrast, depletion of Rho1 in single cells decreases apical tension, and Rok and myosin are necessary, while Dia function also contributes, downstream of Rho1 to sustain apical cell tension.

scholarly journals Myosin-dependent remodeling of adherens junctions protects junctions from Snail-dependent disassembly

2016 ◽  
Vol 212 (2) ◽  
pp. 219-229 ◽  
Author(s):  
Mo Weng ◽  
Eric Wieschaus
Keyword(s):  
Cell Shape ◽  
Adherens Junctions ◽  
Myosin Ii ◽  
Cell Junctions ◽  
Snail Expression ◽  
Quantitative Image ◽  
Early Expression ◽  
Temporally Correlated ◽  
Shape Changes

Although Snail is essential for disassembly of adherens junctions during epithelial–mesenchymal transitions (EMTs), loss of adherens junctions in Drosophila melanogaster gastrula is delayed until mesoderm is internalized, despite the early expression of Snail in that primordium. By combining live imaging and quantitative image analysis, we track the behavior of E-cadherin–rich junction clusters, demonstrating that in the early stages of gastrulation most subapical clusters in mesoderm not only persist, but move apically and enhance in density and total intensity. All three phenomena depend on myosin II and are temporally correlated with the pulses of actomyosin accumulation that drive initial cell shape changes during gastrulation. When contractile myosin is absent, the normal Snail expression in mesoderm, or ectopic Snail expression in ectoderm, is sufficient to drive early disassembly of junctions. In both cases, junctional disassembly can be blocked by simultaneous induction of myosin contractility. Our findings provide in vivo evidence for mechanosensitivity of cell–cell junctions and imply that myosin-mediated tension can prevent Snail-driven EMT.

scholarly journals LncRNA CASC11 Promotes Hepatocellular Carcinoma Progression via Upregulation of UBE2T in a m6A-Dependent Manner

2021 ◽  
Vol 11 ◽  
Author(s):  
Fei Chen ◽  
Meijun Li ◽  
Liang Wang
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cancer Progression ◽  
Cancer Susceptibility ◽  
Underlying Mechanism ◽  
Epigenetic Mechanism ◽  
Migration And Invasion ◽  
Dependent Manner ◽  
Tumor Growth And Metastasis

Hepatocellular carcinoma (HCC) is one of the most frequent malignancies and the third leading cause of cancer-related deaths worldwide. Besides, it has been revealed that long non-coding RNA (LncRNA) cancer susceptibility candidate 11 (CASC11) is involved in cancer progression. However, the functional role and underlying mechanism of CASC11 in HCC remains largely unknown. In this context, here, it was found that CASC11 was upregulated in HCC tissues and associated with tumor grades, metastasis, and prognosis of HCC patients. Functionally, CASC11 facilitated HCC cell proliferation, migration, and invasion in vitro, and enhanced tumor growth and metastasis in vivo. Mechanistically, CASC11 associated with and stabilized Ubiquitin-conjugating enzyme E2T (UBE2T) mRNA. To be specific, it decreased UBE2T N6-methyladenosine (m6A) level via recruiting ALKBH5. Moreover, CASC11 inhibited the association between UBE2T mRNA and m6A reader protein YTHDF2. Taken together, our findings demonstrate the epigenetic mechanism of CASC11 in the regulation of UBE2T expression and possibly provide a novel therapeutic target for HCC treatment.

scholarly journals Overexpression of the transcribed ultraconserved region Uc.138 accelerates colon cancer progression

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yuki Kuwano ◽  
Kensei Nishida ◽  
Kazuhito Rokutan
Keyword(s):  
Colon Cancer ◽  
Cancer Progression ◽  
Colon Adenocarcinoma ◽  
Dependent Manner ◽  
Cell Cycle Regulators ◽  
Nuclear Retention ◽  
Exon 2 ◽  
Potential Biomarker ◽  
Colon Cancer Progression

AbstractUltraconserved regions (UCRs) are 481 genomic sequences with 100% identity across humans, rats, and mice. Increasing evidence suggests that non-coding RNAs transcribed from UCRs are involved in various diseases, especially cancers. The human transformer 2β gene (TRA2B) encodes a UCR (uc.138) that spans exon 2 and its neighboring introns. TRA2B4 RNA is the only transcript that contains the whole exon 2 among five spliced TRA2B RNA variants (TRA2B1-5). TRA2B4 is upregulated in colon cancer cell lines, although it is not translated to Tra2β protein because of its nuclear retention. Nevertheless, the clinical significance and biological functions of uc.138 in colon cancer cells remain unclear. In this study, RNA in situ hybridization showed that TRA2B4 was predominantly overexpressed in the nucleus of colon adenocarcinoma and adenoma. Overexpression of TRA2B4 in colon cancer HCT116 cells promoted cell proliferation by changing the expression of G2/M-related cell cycle regulators. Moreover, TRA2B4 increased migration and cell viability in a uc.138 sequence-dependent manner. TRA2B4 significantly enhanced tumorigenesis in vivo. Taken together, uc.138 encoded in TRA2B4 plays an oncogenic role in tumor progression and may become a potential biomarker and therapeutic target in colon cancer.

An Additional Mechanism of Action of Abciximab: Dispersal of Newly Formed Platelet Aggregates

2002 ◽  
Vol 87 (06) ◽  
pp. 1020-1025 ◽  
Author(s):  
Stanley Marciniak ◽  
Mark Furman ◽  
Alan Michelson ◽  
Joseph Jakubowski ◽  
Robert Jordan ◽  
...  
Keyword(s):  
Single Cells ◽  
Dense Granule ◽  
Light Transmittance ◽  
Dependent Manner ◽  
Aggregate Formation ◽  
Fibrinogen Binding ◽  
Platelet Disaggregation ◽  
Platelet Aggregates

SummaryThe ability of abciximab to prevent fibrinogen binding to activated platelets indicates it may also promote dissolution of platelet-rich thrombi. The present study examined the capacity of abciximab to reverse platelet aggregation in vitro. Experiments were performed on blood from healthy non-medicated donors. Platelet aggregate formation and disaggregation were monitored turbidimetrically. Platelet-bound fibrinogen was measured by flow cytometry. For disaggregation studies, platelets were first stimulated with either ADP or the 11-mer thrombin receptor activating peptide (TRAP), then varying amounts of abciximab were added at periodic intervals after agonist addition. Platelet disaggregation was detected by comparing the extent of light transmittance at 4 min after addition of either abciximab or saline to PRP. ATP release was simultaneously monitored by chemi-luminescence. When added 1 min after low concentrations of ADP, abciximab rapidly (<1 min) dispersed platelet aggregates in a dose-dependent manner, with complete disaggregation observed with 6.25 µg/mL of the β3 antagonist. In contrast, equivalent concentrations of abciximab did not induce appreciable disaggregation to platelets stimulated with TRAP (10 µM). Platelet counts of samples that had undergone complete disaggregation, as assessed by aggregometry, were equivalent to baseline, indicating dispersal of aggregates to single cells. Concentrations of abciximab that produced complete disaggregation induced partial displacement of platelet-bound fibrinogen (52 ± 8% inhibition of fibrinogen binding at 12.5 µg/ml abciximab). The disaggregation effectiveness of abciximab decreased as the time between ADP and subsequent abciximab addition widened, and as the amount of both dense granule release and agonist stimulation increased. However, pre-treatment of platelets with acetylsalicylic acid (ASA) did not potentiate platelet disaggregation induced by abciximab.These data indicate that abciximab facilitates the dispersal of newly formed platelet aggregates in vitro, by partially displacing fibrinogen from activated GPIIb/IIIa receptors. In vivo, abciximab may destabilize coronary thrombi by preventing aggregate formation and dispersing mural thrombi.

scholarly journals MINDY1 promotes bladder cancer progression by stabilizing YAP

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yongwen Luo ◽  
Jun Zhou ◽  
Jianing Tang ◽  
Fengfang Zhou ◽  
Zhiwen He ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Cancer Progression ◽  
Target Genes ◽  
Hippo Pathway ◽  
Tumor Model ◽  
Dependent Manner ◽  
Interaction Domain ◽  
Bona Fide ◽  
The Hippo Pathway

Abstract Background Bladder cancer is one of the most commonly diagnosed urological malignant tumor. The Hippo tumor suppressor pathway is highly conserved in mammals and plays an important role in carcinogenesis. YAP is one of major key effectors of the Hippo pathway. However, the mechanism supporting abnormal YAP expression in bladder cancer remains to be characterized. Methods Western blot was used to measure the expression of MINDY1 and YAP, while the YAP target genes were measured by real-time PCR. CCK8 assay was used to detect the cell viability. The xeno-graft tumor model was used for in vivo study. Protein stability assay was used to detect YAP protein degradation. Immuno-precipitation assay was used to detect the interaction domain between MINDY1 and YAP. The ubiquitin-based Immuno-precipitation assays were used to detect the specific ubiquitination manner happened on YAP. Results In the present study, we identified MINDY1, a DUB enzyme in the motif interacting with ubiquitin-containing novel DUB family, as a bona fide deubiquitylase of YAP in bladder cancer. MINDY1 was shown to interact with, deubiquitylate, and stabilize YAP in a deubiquitylation activity-dependent manner. MINDY1 depletion significantly decreased bladder cancer cell proliferation. The effects induced by MINDY1 depletion could be rescued by further YAP overexpression. Depletion of MINDY1 decreased the YAP protein level and the expression of YAP/TEAD target genes in bladder cancer, including CTGF, ANKRD1 and CYR61. Conclusion In general, our findings establish a previously undocumented catalytic role for MINDY1 as a deubiquitinating enzyme of YAP and provides a possible target for the therapy of bladder cancer.

scholarly journals SYT8 promotes pancreatic cancer progression via the TNNI2/ERRα/SIRT1 signaling pathway

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Zhiping Fu ◽  
Xing Liang ◽  
Ligang Shi ◽  
Liang Tang ◽  
Danlei Chen ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Proliferation ◽  
Cancer Progression ◽  
Tumor Metastasis ◽  
Molecular Mechanisms ◽  
Hormone Secretion ◽  
Migration And Invasion ◽  
Dependent Manner ◽  
Orphan Nuclear Receptor

AbstractPancreatic cancer is a highly lethal malignancy due to failures of early detection and high metastasis in patients. While certain genetic mutations in tumors are associated with severity, the molecular mechanisms responsible for cancer progression are still poorly understood. Synaptotagmin-8 (SYT8) is a membrane protein that regulates hormone secretion and neurotransmission, and its expression is positively regulated by the promoter of the insulin gene in pancreatic islet cells. In this study, we identified a previously unknown role of SYT8 in altering tumor characteristics in pancreatic cancer. SYT8 levels were upregulated in patient tumors and contributed towards increased cell proliferation, migration, and invasion in vitro and in vivo. Increased SYT8 expression also promoted tumor metastasis in an in vivo tumor metastasis model. Furthermore, we showed that SYT8-mediated increase in tumorigenicity was regulated by SIRT1, a protein deacetylase previously known to alter cell metabolism in pancreatic lesions. SIRT1 expression was altered by orphan nuclear receptor ERRα and troponin-1 (TNNI2), resulting in cell proliferation and migration in an SYT8-dependent manner. Together, we identified SYT8 to be a central regulator of tumor progression involving signaling via the SIRT1, ERRα, and TNNI2 axis. This knowledge may provide the basis for the development of therapeutic strategies to restrict tumor metastasis in pancreatic cancer.

scholarly journals Spatiotemporal Dynamics of Intra-tumoral Dependence on NEK2-EZH2 Signaling in Glioblastoma Cancer Progression

2020 ◽  
Author(s):  
Jia Wang ◽  
Marat S Pavliukov ◽  
Daisuke Yamashita ◽  
Peng Cheng ◽  
Zhuo Zhang ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Kinase Inhibitor ◽  
Molecular Profile ◽  
Dependent Manner ◽  
Dynamic Changes ◽  
Molecule Inhibitor ◽  
Signaling Axis ◽  
Therapeutic Development ◽  
Worse Prognosis

AbstractThe highly lethal brain cancer glioblastoma undergoes dynamic changes in molecular profile and cellular phenotype throughout tumor core establishment and in primary-to-recurrent tumor progression. These dynamic changes allow glioblastoma tumors to escape from multimodal therapies, resulting in patient lethality. Here, we identified the emergence of dependence on NEK2-mediated EZH2 signaling, specifically in therapy-resistant tumor core-located glioblastoma cells. In patient-derived glioblastoma core models, NEK2 was required for in vivo tumor initiation, propagation, and radio-resistance. Mechanistically, in glioblastoma core cells, NEK2 binds with EZH2 to prevent its proteasome-mediated degradation in a kinase-dependent manner. Clinically, NEK2 expression is elevated in recurrent tumors after therapeutic failure as opposed to their matched primary untreated cases, and its high expression is indicative of worse prognosis. For therapeutic development, we designed a novel NEK2 kinase inhibitor CMP3a, which effectively attenuated growth of murine glioblastoma models and exhibited a synergistic effect with radiation therapy. Collectively, the emerging NEK2-EZH2 signaling axis is critical in glioblastoma, particularly within the tumor core, and the small molecule inhibitor CMP3a for NEK2 is a potential novel therapeutic agent for glioblastoma.

CircMETTL3, Upregulated in a m6A-dependent Manner, Promotes Breast Cancer Progression through circMETTL3/miR-31-5p/CDK1 axis

2020 ◽  
Author(s):  
Zhi Li ◽  
HaiYan Yang ◽  
XinYuan Dai ◽  
Xu Zhang ◽  
YuZhou Huang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Biological Function ◽  
Breast Cancer Progression ◽  
Host Gene ◽  
Luciferase Reporter ◽  
Dependent Manner ◽  
Repressive Effect ◽  
Rna Immunoprecipitation

Abstract Background: Growing evidence indicates N6-methyladenosine (m6A) has biological function in oncogenesis. METTL3, the catalytic component, is the most important part of methyltransferase complex and plays a crucial role in cancers. However, the biological function of circRNAs derived from METTL3 and the underlying molecular mechanism remains unclear.Methods: Quantitative real-time PCR was used to determine the circMETTL3 expression in breast cancer tissues and cell lines. Then, functional experiments in vitro and in vivo were performed to investigate the effects of circMETTL3 on tumor growth and metastasis in breast cancer. Mechanistically, fluorescent in situ hybridization, dual luciferase reporter assay, RNA pull-down and RNA immunoprecipitation experiments were performed to confirm the interaction between circMETTL3 and miR-31-5p in breast cancer. Furthermore, we explored regulatory effects of m6A modification on circMETTL3 expression with m6A RNA immunoprecipitation.Results: We found that circMETTL3 was significantly upregulated in breast cancer. The results indicated that circMETTL3 could promote breast cancer cell proliferation, migration and invasion as well as tumorigenesis in vivo. Mechanistic analysis showed that circMETTL3 might act as a ceRNA (competing endogenous RNA) of miR-31-5p to relieve the repressive effect of miR-31-5p on its target cyclin-dependent kinases (CDK1). Moreover, m6A modification of circMETTL3 might affect its expression.Conclusion: Our findings suggest that circMETTL3 promotes breast cancer progression through circMETTL3/miR-31-5p/CDK1 axis. Moreover, METTL3, the host gene of circMETTL3, may regulates circMETTL3 expression in a m6A-dependent manner, while circMETTL3 has no effect on METTL3 expression, providing a new relationship between the circRNA and the corresponding host gene. Thus, it may serve as a new diagnostic marker or therapeutic target for breast cancer patients.

The Identification and Characterization of Zebrafish Mast Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2405-2405
Author(s):  
Jason N. Berman ◽  
Jake Seibert ◽  
Tristan Dobson ◽  
Eve Teh ◽  
Olga Hrytsenko ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Mast Cells ◽  
Cancer Progression ◽  
Fluorescent Protein ◽  
Human Mast Cell ◽  
Blood Levels ◽  
Transgenic Zebrafish ◽  
Dependent Manner ◽  
Efficient System

Abstract Mast cells (MCs), tissue counterparts to mammalian basophils, are known for their role in allergic reactions, inflammation and cancer progression, yet their developmental origin remains controversial due to limitations studying these cells in traditional animal models. The zebrafish provides a highly efficient system for studying vertebrate MC development. All other major hematopoietic lineages have zebrafish counterparts and the fundamental genetic mechanisms controlling hematopoiesis are well conserved. We are the first to identify zebrafish MCs in the gill and intestine. These cells demonstrate classic MC phenotypes including prominent metachromatic granules following staining with toluidine blue and positive immunohistochemical reactions to antibodies against human tryptase and C-KIT. Electron microscopy demonstrates a striking morphologic resemblance to mammalian MCs. Functional studies using the stimulating agent, Compound 48/80 or formalin-killed Aeromonas result in MC degranulation and increased blood levels of key mediators, such as tryptase. These cells also express carboxypeptidase A5 (cpa5), a zebrafish homologue of the human mast cell-specific CPA enzymes. Cpa5 expression in zebrafish embryonic blood cells begins at 24 hours post fertilization and co-localizes with a number of established granulocytic and monocytic markers suggesting that MCs arise from a common granulocyte/monocyte progenitor. Morpholino knockdown studies have demonstrated that the transcription factors gata-2 and pu.1, but not gata-1 are necessary for early MC development. Interestingly, friend of gata-1 (fog-1) may also be required, but in a gata-1 dependent manner. Ongoing morpholino and mutant rescue studies will further establish in vivo the contribution that these transcription factors make to vertebrate MC development. Finally, we have cloned a cpa5 promoter element and shown it can drive expression of the green fluorescent protein in early zebrafish MCs providing a means for generating transgenic zebrafish lines to model human MC diseases for use in high throughput small molecule modifier screens.

scholarly journals Collective cancer cell invasion requires RNA accumulation at the invasive front

2020 ◽  
Vol 117 (44) ◽  
pp. 27423-27434 ◽  
Author(s):  
George Chrisafis ◽  
Tianhong Wang ◽  
Konstadinos Moissoglu ◽  
Alexander N. Gasparski ◽  
Yeap Ng ◽  
...  
Keyword(s):  
Cancer Cell ◽  
Cancer Progression ◽  
Cell Invasion ◽  
Single Cells ◽  
Three Dimensional ◽  
Nucleotide Exchange ◽  
Cancer Cell Invasion ◽  
Invasive Front ◽  
Rna Accumulation

Localization of RNAs at protrusive regions of cells is important for single-cell migration on two-dimensional surfaces. Protrusion-enriched RNAs encode factors linked to cancer progression, such as the RAB13 GTPase and the NET1 guanine nucleotide exchange factor, and are regulated by the tumor-suppressor protein APC. However, tumor cells in vivo often do not move as single cells but rather utilize collective modes of invasion and dissemination. Here, we developed an inducible system of three-dimensional (3D) collective invasion to study the behavior and importance of protrusion-enriched RNAs. We find that, strikingly, both theRAB13andNET1RNAs are enriched specifically at the invasive front of leader cells in invasive cell strands. This localization requires microtubules and coincides with sites of high laminin concentration. Indeed, laminin association and integrin engagement are required for RNA accumulation at the invasive front. Importantly, perturbing RNA accumulation reduces collective 3D invasion. Examination of in vivo tumors reveals a similar localization of theRAB13andNET1RNAs at potential invasive sites, suggesting that this mechanism could provide a targeting opportunity for interfering with collective cancer cell invasion.

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