scholarly journals Mutant p53 amplifies a dynamin-1/APPL1 endosome feedback loop that regulates recycling and migration

2019 ◽  
Vol 218 (6) ◽  
pp. 1928-1942 ◽  
Author(s):  
Ashley M. Lakoduk ◽  
Philippe Roudot ◽  
Marcel Mettlen ◽  
Heather M. Grossman ◽  
Sandra L. Schmid ◽  
...  
Keyword(s):  
Feedback Loop ◽  
Migration And Invasion ◽  
Mutant P53 ◽  
Surface Receptors ◽  
Protein Levels ◽  
Early Endosomes ◽  
Cell Progression ◽  
Metastatic Activity ◽  
Focal Adhesion Turnover ◽  
And Migration

Multiple mechanisms contribute to cancer cell progression and metastatic activity, including changes in endocytic trafficking and signaling of cell surface receptors downstream of gain-of-function (GOF) mutant p53. We report that dynamin-1 (Dyn1) is up-regulated at both the mRNA and protein levels in a manner dependent on expression of GOF mutant p53. Dyn1 is required for the recruitment and accumulation of the signaling scaffold, APPL1, to a spatially localized subpopulation of endosomes at the cell perimeter. We developed new tools to quantify peripherally localized early endosomes and measure the rapid recycling of integrins. We report that these perimeter APPL1 endosomes modulate Akt signaling and activate Dyn1 to create a positive feedback loop required for rapid recycling of EGFR and β1 integrins, increased focal adhesion turnover, and cell migration. Thus, Dyn1- and Akt-dependent perimeter APPL1 endosomes function as a nexus that integrates signaling and receptor trafficking, which can be co-opted and amplified in mutant p53–driven cancer cells to increase migration and invasion.

scholarly journals Mutant p53 triggers a dynamin-1/APPL1 endosome feedback loop that regulates β1 integrin recycling and migration

2018 ◽  
Author(s):  
Ashley M. Lakoduk ◽  
Philippe Roudot ◽  
Marcel Mettlen ◽  
Heather M. Grossman ◽  
Sandra L. Schmid ◽  
...  
Keyword(s):  
Cell Migration ◽  
Positive Feedback ◽  
Feedback Loop ◽  
Egf Receptor ◽  
Migration And Invasion ◽  
Mutant P53 ◽  
Positive Feedback Loop ◽  
P53 Expression ◽  
Surface Receptors ◽  
Protein Levels

ABSTRACTMultiple mechanisms contribute to cancer cell progression and metastatic activity, including changes in endocytic trafficking and signaling of cell surface receptors. We report that gain-of-function (GOF) mutant p53 expression enhances β integrin and EGF receptor recycling and increases cell migration by triggering a positive feedback loop involving the activation of dynamin-1 (Dyn1) and accumulation of a spatially-restricted subpopulation of APPL1-positive ‘perimeter’ endosomes. DNM1 is upregulated at both the mRNA and protein levels in a manner dependent on expression of GOF mutant p53. Perimeter APPL1 endosomes are required for rapid recycling of EGFR and β1 integrins and modulate Akt signaling and Dyn1 activation to create the positive feedback loop that culminates in increased focal adhesion turnover and cell migration. Thus, Dyn1- and Akt-dependent perimeter APPL1 endosomes function as a nexus, integrating signaling and receptor trafficking, that can be co-opted by cancer cells for mutant p53-driven migration and invasion.

scholarly journals Long Non-Coding RNA-DUXAP8 Regulates TOP2A in the Growth and Metastasis of Osteosarcoma via MicroRNA-635

2020 ◽  
Author(s):  
Ting Yang ◽  
Jian Ping Quo ◽  
Fan Li ◽  
Chao Xiu ◽  
Hua Wang ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Human Cancer ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
High Morbidity ◽  
Real Time Quantitative Pcr ◽  
Diagnosis And Prognosis ◽  
Non Coding Rna ◽  
Cell Progression ◽  
And Migration

Abstract Purpose: Osteosarcoma (OS) is a malignant tumor disease with high morbidity and mortality in children and adolescents. Evidence indicates that long non-coding RNAs (lncRNAs) may be important players in human cancer progression, including OS. In this study, we identified the role of lnc-DUXAP8 in the development of OS.Materials and Methods: Expression of lncRNA DUXAP8 was determined by real-time quantitative PCR and Western blotting in OS tissues. Cell proliferation was evaluated using CCK8 and colony formation assay; Transwell assay was conducted to measure cell invasion. Cell migration was evaluated using Wound Healing assay. The binding site between the lnc-DUXAP8 and miR-635 RNAs was evaluated using a luciferase reporter assay. Results: The expression of the lnc-DUXAP8 was significantly upregulated in OS samples and OS cell lines compared to normal tissue. High expression of lncRNA DUXAP8 was associated with shorter overall survival. Knockdown of lncRNA DUXAP8 inhibited proliferation and migration, and invasion in OS cells. More importantly, mechanism investigation revealed that lncRNA DUXAP8 was predominantly acted as a competing endogenous RNA (ceRNA) in OS by regulating miR-635/ TOP2A axis. Conclusion: LncRNA DUXAP8 is upregulated in OS, and LncRNA DUXAP8 knockdown plays a vital anti-tumor role in OS cell progression through a miR-635/ TOP2A axis. Our study suggests that LncRNA DUXAP8 may be a novel, promising biomarker for diagnosis and prognosis of OS.

scholarly journals Annexin A2 Coordinates STAT3 to Regulate the Invasion and Migration of Colorectal Cancer CellsIn Vitro

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Dianhui Xiu ◽  
Lin Liu ◽  
Fengli Qiao ◽  
Haishan Yang ◽  
Lu Cui ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Annexin A2 ◽  
Migration And Invasion ◽  
Invasion And Migration ◽  
Protein Levels ◽  
And Migration

The present study aimed to reveal the expression of STAT3 and Anxa 2 in CRC specimens and to investigate the effects of STAT3 and Anxa 2 signaling on the proliferation, invasion, and migration in CRC Caco-2 cells. Results demonstrated that both Anxa 2 and STAT3 were highly expressed in CRC specimens in both mRNA and protein levels, with or without phosphorylation (Tyrosine 23 in Anxa 2 and Tyrosine 705 in STAT3). And the upregulated Anxa 2 promoted the phosphorylation of STAT3 (Tyrosine 705) in CRC Caco-2 cells. The upregulated Anxa 2 promoted the proliferation, migration, and invasion of Caco-2 cells in vitro. Moreover, the STAT3 knockdown also repressed the proliferation, migration, and invasion of Caco-2 cells. In conclusion, the overexpressed Annexin A2 regulated the proliferation, invasion, and migration in CRC cells in an association with STAT3.

Knockdown of TPPP3 to inhibit cell proliferation and invasion in human colorectal cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e23006-e23006 ◽  
Author(s):  
Yintao Li ◽  
Jinming Yu
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Protein Family ◽  
Migration And Invasion ◽  
Clinicopathologic Characteristics ◽  
Invasion And Migration ◽  
Protein Levels ◽  
Angiogenesis Assay ◽  
And Migration

e23006 Background: Tubulin Polymerization Promoting Protein Family Member 3, TPPP3, a member of the TPPP protein family, has been reported to play important roles in initiation and progression of human cancers, such as lung cancer. However, the expression and underlying function of TPPP3 in colorectal cancer (CRC) have not yet been fully clarified. Methods: In this study, the mRNA and protein levels of TPPP3 in 96 clinical CRC specimens were determined by RT-PCR and immunohistochemistry. The relation between TPPP3 expression and clinicopathologic characteristics and overall survival (OS) were evaluated. TPPP3 was stably knockdowned by shRNA. In addition, CCK-8、Colony formation、Flow cytometric、Transwell and Angiogenesis assay were to examine the biological function of TPPP3 in CRC cells in vitro. Results: We show that TPPP3 was significantly increased in CRC tissues and associated with aggressive factors and poor patient survival. Further experiments showed that knockdown of TPPP3 inhibited cell proliferation, migration and invasion and induced cell apoptosis in vitro. In addition, TPPP3 silencing resulted in a decrease of angiogenesis and S phase fraction. And TPPP3 significantly affected the invasion and migration of CRC cells via the expression of MMP-9, Rac-1 and E-cadherin. Conclusions: Our results suggested that TPPP3 played an important role in CRC progress and might serve as novel therapeutic targets for CRC treatment.

scholarly journals The Suppressing Effects of Dkk3 Expression on Aggressiveness and Tumorigenesis of Colorectal Cancer

2020 ◽  
Vol 10 ◽  
Author(s):  
Shuang Zhao ◽  
Chang-lai Hao ◽  
En-hong Zhao ◽  
Hua-mao Jiang ◽  
Hua-chuan Zheng
Keyword(s):  
Colorectal Cancer ◽  
Cellular Adhesion ◽  
Migration And Invasion ◽  
Signal Pathways ◽  
Protein Levels ◽  
Cancer Aggressiveness ◽  
Pattern Differentiation ◽  
And Migration ◽  
Patient Prognosis ◽  
Epithelial Lesions

Dkk3 has been discovered during comparison of immortalized and parental cells. Its expression has been shown to reduce colony formation and induce apoptosis of cancer cells, acting as a tumor suppressor. Herein, we demonstrate that Dkk3 overexpression or protein treatment may inhibit colorectal cancer cell proliferation, migration, and invasion and that they may promote apoptosis and G2 phase arrest with hypoexpression of Bcl-2, cdc25B, cdc25c, N-cadherin, slug, and twist and hyperexpression of Bax and E-cadherin. This effect is consistent with that of recombinant Dkk3 exposure and blocked with anti-Dkk3 antibody. Dkk3 deletion in intestinal cells was not associated with the emergence of epithelial lesions; however, adenoma emerged after sodium desoxycholate treatment. At both mRNA and protein levels, Dkk3 expression was higher in normal than in cancer tissues (p<0.05). Dkk3 mRNA expression was negatively associated with its promoter methylation, growth pattern, differentiation, and favorable prognosis in the patients with colorectal cancer (p<0.05). Dkk3-related signal pathways in colorectal cancer included those of cellular adhesion and migration, melanogenesis, chemokine, Hedgehog, JAK-STAT, TOLL-like receptor, TGF-β, MAPK, and calcium signaling (p<0.05). These findings indicate that Dkk3 expression levels can help assess cancer aggressiveness and patient prognosis. It might also suppress aggressive phenotypes and tumorigenesis as a molecular target in gene therapy.

scholarly journals CSIG-10. GENOTYPE – KINOME GUIDED DEVELOPMENT OF PRECISION EGFR-TARGETED THERAPEUTICS FOR GLIOBLASTOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii29-ii29
Author(s):  
Erin Smithberger ◽  
Abigail Shelton ◽  
Madison Butler ◽  
Allie Stamper ◽  
Ryan Bash ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Treatment Options ◽  
Growth Factor Receptor ◽  
Primary Brain Tumor ◽  
Genetically Engineered ◽  
Migration And Invasion ◽  
Matrix Remodeling ◽  
Protein Levels ◽  
And Migration

Abstract Glioblastoma (GBM) is an aggressive primary brain tumor with poor survival and limited treatment options. However, it is an attractive candidate for precision therapeutic approaches due to the frequency of amplification and/or activating mutations in the epidermal growth factor receptor (EGFR) gene and the availability of several brain penetrant second- and third-generation EGFR tyrosine kinase inhibitors (TKI). We used comprehensive molecular profiling of a panel of genetically engineered mouse astrocyte models to examine whether mutational profiles, particularly EGFR and PTEN status, could be used to identify kinases upregulated in specific mutational backgrounds. Using RNA-seq and multiplex inhibitor bead/mass spectrometry (MIB-MS) to analyze the kinase transcriptomes and proteomes, respectively, we have identified several potential targets for combination therapy. Overexpression of wild type EGFR in immortalized, Cdkn2a-/- astrocytes resulted in mild rewiring of the GBM kinome. Only 5 kinases aside from EGFR itself were overexpressed on either the transcript or protein levels. One overexpressed kinase, Hck, has been shown to be involved in cell survival, proliferation, adhesion, and migration. In contrast, overexpression of EGFRvIII, a constitutively active, extracellular domain truncation mutant of EGFR, resulted in significant alteration of the GBM kinome – 81 kinases showed differential expression, with 27 upregulated. One potentially attractive target among these was Cdk6, a drug-targetable, prognostically significant cyclin-dependent kinase implicated in proliferation, migration, and invasion. Finally, overexpression of EGFRvIII in cells lacking Pten dysregulated 46 kinases, including 15 upregulated. One particularly interesting target in these cells was Ddr2, a tyrosine kinase involved in migration, invasion, and extracellular matrix remodeling. We conclude that Hck, Cdk6, and Ddr2 represent attractive targets for therapeutic intervention in their relevant genetic contexts. These findings also suggest that molecular diagnostics for EGFR and PTEN status may be useful in guiding development of rational, EGFR TKI-centric drug combinations.

scholarly journals Tumor Cell-Derived Exosomal hsa_circ_0017252 Suppresses the Tumorigenesis of Gastric Cancer Through Suppressing M2 Polarization of Macrophage

2021 ◽  
Author(s):  
Jin Song ◽  
Xiaolong Xu ◽  
Shasha He ◽  
Ning Wang ◽  
Yunjing Bai ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Migration And Invasion ◽  
Nanoparticle Tracking Analysis ◽  
Transwell Assay ◽  
Gene Expressions ◽  
Protein Levels ◽  
M2 Polarization ◽  
Transmission Electron ◽  
And Migration

Abstract Background: Gastric cancer (GC) is a source of global cancer death. MiR-17-5p is reported to regulate the tumorigenesis of GC. Meanwhile, hsa_circ_0017252 is known to be upregulated in GC. However, the relation between hsa_circ_0017252 and miR-17-5p in GC remains unclear. Methods: Cell viability, migration and invasion were tested by CCK-8 and transwell assay, respectively. Gene expressions were detected by RT-qPCR, and the protein levels in cells or exosomes were tested by western blot. The efficiency of exosomes isolation was investigated by transmission electron microscope (TEM) and nanoparticle tracking analysis (NTA). Meanwhile, cell apoptosis was tested by flow cytometry. In vivo model was constructed to assess the function of MKN45 cells-derived exosomal hsa_circ_0017252 in GC. Results: Hsa_circ_0017252 was verified to be significantly downregulated in GC tissues. Hsa_circ_0017252 upregulation significantly decreased the viability and migration of GC cells, and hsa_circ_0017252 could bind with miR-17-5p. Additionally, exosomal hsa_circ_0017252 reversed the polarization of M2 macrophages, and the polarized macrophages decreased the GC cell invasion. Furthermore, exosomes with upregulated hsa_circ_0017252 suppressed the tumor growth of GC. Conclusion: Delivery of hsa_circ_0017252 by GC cells-derived exosomes inhibits the tumorigenesis of GC through reversing M2 polarization of macrophages. Thus, our finding might provide a new method for GC treatment.

scholarly journals Exogenous Hydrogen Sulfide Regulates the Growth of Human Thyroid Carcinoma Cells

2019 ◽  
Vol 2019 ◽  
pp. 1-18 ◽  
Author(s):  
Dongdong Wu ◽  
Jianmei Li ◽  
Qianqian Zhang ◽  
Wenke Tian ◽  
Peiyu Zhong ◽  
...  
Keyword(s):  
Hydrogen Sulfide ◽  
Thyroid Carcinoma ◽  
Tumor Growth ◽  
Carcinoma Cells ◽  
Human Thyroid ◽  
Migration And Invasion ◽  
Thyroid Cells ◽  
Protein Levels ◽  
And Migration ◽  
Carcinoma Xenograft

Hydrogen sulfide (H2S) is involved in the development and progression of many types of cancer. However, the effect and mechanism of H2S on the growth of human thyroid carcinoma cells remain unknown. In the present study, we found that the proliferation, viability, migration, and invasion of human thyroid carcinoma cells were enhanced by 25–50 μM NaHS (an H2S donor) and inhibited by 200 μM NaHS. However, H2S showed no obvious effects on the proliferation, viability, and migration of human normal thyroid cells. Administration of 50 μM NaHS increased the expression levels of CBS, SQR, and TST, while 200 μM NaHS showed reverse effects in human thyroid carcinoma cells. After treatment with 25-50 μM NaHS, the ROS levels were decreased and the protein levels of p-PI3K, p-AKT, p-mTOR, H-RAS, p-RAF, p-MEK1/2, and p-ERK1/2 were increased, whereas 200 μM NaHS exerted opposite effects in human thyroid carcinoma cells. Furthermore, 1.4-2.8 mg/kg/day NaHS promoted the tumor growth and blood vessel formation in human thyroid carcinoma xenograft tumors, while 11.2 mg/kg/day NaHS inhibited the tumor growth and angiogenesis. In conclusion, our results demonstrate that exogenous H2S regulates the growth of human thyroid carcinoma cells through ROS/PI3K/Akt/mTOR and RAS/RAF/MEK/ERK signaling pathways. Novel H2S-releasing donors/drugs can be designed and applied for the treatment of thyroid cancer.

scholarly journals IL-33 Induces ADAMTS5 Expression and Cell Migration in Glioblastoma Multiforme

2021 ◽  
Author(s):  
Dilara Akcora Yildiz ◽  
Yunus Yukselten ◽  
Merve Sunguroglu ◽  
Hasan Caglar Ugur ◽  
Asuman SUNGUROGLU
Keyword(s):  
Glioblastoma Multiforme ◽  
High Rate ◽  
Migration And Invasion ◽  
Low Grade ◽  
Dependent Manner ◽  
Interleukin 33 ◽  
Protein Levels ◽  
And Migration ◽  
Migration Capacity ◽  
The Impact

Abstract Glioblastoma multiforme (GBM), characterized by a high rate of proliferation and migration capacity, is an incurable brain tumor in adults. Interleukin-33 (IL-33), a member of the IL-1 cytokine superfamily and a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5), a family of zinc dependent metalloproteinases are known to have an essential roles in GBM migration and invasion. Previous studies have separately revealed elevated expressions of IL-33 and ADAMTS5 in GBM; however, the interaction between IL-33 and ADAMTS5 in GBM pathogenesis has remained unclear. Here, using publically available GlioVis and GEPIA programs, we showed that mRNA expression of IL-33 and ADAMTS5 is significantly high in GBM cells, and a positive correlation between IL-33 and ADAMTS5 was also determined in these cells. In parallel with the mRNA data of IL-33 and ADAMTS5, by Western blot analysis, protein levels were found to be elevated in GBM tissues and increased gradually with the disease progression. Primary GBM cells and low-grade glioma cells were then treated with IL-33 to examine its stimulating effect on ADAMTS5 expression. Exposure to IL-33 raised ADAMTS5 protein levels in a dose-dependent manner. Finally, the wound healing method was performed to confirm the impact of IL-33 on migration in primary GBM cells. IL-33 promoted migration of primary GBM cells three-times higher than untreated GBM cells. Thus, the current study suggests for the first time that IL-33 might have a role in play a part in GBM progression through induction of ADAMTS5 expression and promotion of migration in GBM cells.

scholarly journals LncRNA SNHG3 Promotes Gastric Cancer Cells Proliferation, Migration, and Invasion by Targeting miR-326

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Jun Rao ◽  
Jinjin Fu ◽  
Chuchen Meng ◽  
Jin Huang ◽  
Xiangrong Qin ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Lines ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Luciferase Reporter Gene ◽  
Gastric Cancer Cells ◽  
Invasion And Migration ◽  
Protein Levels ◽  
Rna Immunoprecipitation ◽  
And Migration

The function and possible mechanism of lncRNA Small Nucleolar RNA Host Gene 3 (SNHG3) in GC have not been fully studied. The aim of our study was to investigate the role of SNHG3 in the proliferation, migration, and invasion of GC cell lines. The expressions of SNHG3, miR-326, and TWIST in GC9811-P GC cell lines were detected by RT-qPCR. Western blotting was performed to detect the protein levels of TWIST and EMT-related genes. Luciferase reporter gene analysis and RNA immunoprecipitation (RIP) analysis confirmed the interaction between lncRNA SNHG3, miR-326, and TWIST. CCK-8 and Transwell assays were performed to detect cell proliferation, invasion, and migration abilities. The results showed that lncRNA SNHG3 and TWIST were highly expressed in GC cell lines, while miR-326 was expressed to a low degree. Moreover, lncRNA SNHG3 knockdown or miR-326 overexpression significantly inhibited cell proliferation, migration, and invasion of GC cell lines. In addition, TWIST overexpression can reverse the inhibition of lncRNA SNHG3 knockdown or miR-326 overexpression on cell proliferation, migration, and invasion. In conclusion, lncRNA SNHG3 may promote GC progression through the miR-326/TWIST axis, which may provide a new diagnostic and prognostic biomarker for GC.

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