scholarly journals Aspirin Inhibition of Group VI Phospholipase A2 Induces Synthetic Lethality in AAM Pathway Down-Regulated Gingivobuccal Squamous Carcinoma

Cells ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 123
Author(s):  
Kshama Pansare ◽  
Bhabani Mohanty ◽  
Ranjeeta Dhotre ◽  
Aafrin M. Pettiwala ◽  
Saili Parab ◽  
...  
Keyword(s):  
Acid Metabolism ◽  
Synthetic Lethality ◽  
Squamous Carcinoma ◽  
Immunohistochemical Analysis ◽  
Arachidonic Acid Metabolism ◽  
Rna Seq ◽  
Group Vi

Background: To elucidate the role of iPLA2/PLA2G6 in gingivobuccal squamous cell carcinoma (GB-SCC) and to ascertain the synthetic lethality-based chemoprevention role of aspirin in arachidonic acid metabolism (AAM) pathway down-regulated GB-SCC. Methods: The in vitro efficacy of aspirin on GB-SCC cells (ITOC-03 and ITOC-04) was assessed by cell proliferation, colony formation, apoptosis, cell migration, cell cycle assay and RNA-seq, while inhibition of PLA2G6 and AAM pathway components was affirmed by qPCR, Western blot and immunofluorescence staining. The in vivo effect of aspirin was evaluated using NOD-SCID mice xenografts and immunohistochemical analysis. Results: We found that aspirin, which has been reported to act through the COX pathway, is inhibiting PLA2G6, and thereby the COX and LOX components of the AAM pathway. The findings were validated using PLA2G6 siRNA and immunohistochemical marker panel. Moreover, a pronounced effect in ITOC-04 cells and xenografts implied aspirin-induced synthetic lethality in the AAM pathway down-regulated GB-SCC. Conclusions: This study reveals that aspirin induces the anti-tumor effect by a previously unrecognized mechanism of PLA2G6 inhibition. In addition, the effect of aspirin is influenced by the baseline AAM pathway status and could guide precision prevention clinical trials of AAM pathway inhibitors.

scholarly journals Low Intensity Shockwave Treatment Modulates Macrophage Functions Beneficial to Healing Chronic Wounds

2021 ◽  
Vol 22 (15) ◽  
pp. 7844
Author(s):  
Jason S. Holsapple ◽  
Ben Cooper ◽  
Susan H. Berry ◽  
Aleksandra Staniszewska ◽  
Bruce M. Dickson ◽  
...  
Keyword(s):  
Macrophage Activation ◽  
Molecular Mechanisms ◽  
Chronic Wounds ◽  
Immunohistochemical Analysis ◽  
Therapeutic Effects ◽  
Gene Expressions ◽  
Extracorporeal Shock Wave

Extracorporeal Shock Wave Therapy (ESWT) is used clinically in various disorders including chronic wounds for its pro-angiogenic, proliferative, and anti-inflammatory effects. However, the underlying cellular and molecular mechanisms driving therapeutic effects are not well characterized. Macrophages play a key role in all aspects of healing and their dysfunction results in failure to resolve chronic wounds. We investigated the role of ESWT on macrophage activity in chronic wound punch biopsies from patients with non-healing venous ulcers prior to, and two weeks post-ESWT, and in macrophage cultures treated with clinical shockwave intensities (150–500 impulses, 5 Hz, 0.1 mJ/mm2). Using wound area measurements and histological/immunohistochemical analysis of wound biopsies, we show ESWT enhanced healing of chronic ulcers associated with improved wound angiogenesis (CD31 staining), significantly decreased CD68-positive macrophages per biopsy area and generally increased macrophage activation. Shockwave treatment of macrophages in culture significantly boosted uptake of apoptotic cells, healing-associated cytokine and growth factor gene expressions and modulated macrophage morphology suggestive of macrophage activation, all of which contribute to wound resolution. Macrophage ERK activity was enhanced, suggesting one mechanotransduction pathway driving events. Collectively, these in vitro and in vivo findings reveal shockwaves as important regulators of macrophage functions linked with wound healing. This immunomodulation represents an underappreciated role of clinically applied shockwaves, which could be exploited for other macrophage-mediated disorders.

scholarly journals Molecular targeting of retinoic acid metabolism in neuroblastoma: the role of the CYP26 inhibitor R116010 in vitro and in vivo

2007 ◽  
Vol 96 (11) ◽  
pp. 1675-1683 ◽  
Author(s):  
J L Armstrong ◽  
G A Taylor ◽  
H D Thomas ◽  
A V Boddy ◽  
C P F Redfern ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Acid Metabolism ◽  
Molecular Targeting

The molecular biology of mammalian arachidonic acid metabolism

1991 ◽  
Vol 260 (2) ◽  
pp. L13-L28 ◽  
Author(s):  
E. Sigal
Keyword(s):  
Arachidonic Acid ◽  
Acid Metabolism ◽  
Recombinant Dna ◽  
Biological Activities ◽  
Biological Effects ◽  
Arachidonic Acid Metabolism ◽  
Bioactive Metabolites ◽  
Wide Range

The metabolism of arachidonic acid by cyclooxygenase and lipoxygenase enzymes results in a wide range of oxidized products with potent biological activities. These metabolites, which include the prostaglandins and leukotrienes, have been implicated in the pathogenesis of a variety of inflammatory diseases. Research over the last decade has focused primarily on the elucidation of the chemical structure of the metabolites and their biological effects in vitro and in vivo. Recently, research on the enzymes that produce these bioactive metabolites through oxidization of arachidonic acid has intensified. Recombinant DNA techniques have enabled investigators to determine the nucleotide sequences for several of the enzymes in the arachidonic acid cascade. The resulting cDNAs are now being used to further investigate the biochemical and biological features of arachidonic acid metabolism. The purpose of this paper is to review how the cDNAs for these enzymes were obtained, what information they convey, and how they are being applied in current research.

scholarly journals lncRNA H19 binds VGF and promotes pNEN progression via PI3K/AKT/CREB signaling

2019 ◽  
Vol 26 (7) ◽  
pp. 643-658 ◽  
Author(s):  
Meng Ji ◽  
Yanli Yao ◽  
Anan Liu ◽  
Ligang Shi ◽  
Danlei Chen ◽  
...  
Keyword(s):  
Migration And Invasion ◽  
Neuroendocrine Neoplasms ◽  
Endocrine Tumors ◽  
Rna Seq ◽  
Rna Immunoprecipitation ◽  
Poor Differentiation ◽  
Tumor Growth And Metastasis

Pancreatic neuroendocrine neoplasms (pNENs) are endocrine tumors arising in pancreas and is the most common neuroendocrine tumors. Mounting evidence indicates lncRNA H19 could be a determinant of tumor progression. However, the expression and mechanism of H19 and the relevant genes mediated by H19 in pNENs remain undefined. Microarray analysis was conducted to identify the differentially expressed lncRNAs in pNENs. H19 expression was analyzed in 39 paired pNEN tissues by qPCR. The biological role of H19 was determined by functional experiments. RNA pulldown, mass spectroscopy and RNA immunoprecipitation were performed to confirm the interaction between H19 and VGF. RNA-seq assays were performed after knockdown H19 or VGF. H19 was significantly upregulated in pNEN tissues with malignant behaviors, and the upregulation predicted poor prognosis in pNENs. In vitro and in vivo data showed that H19 overexpression promoted tumor growth and metastasis, whereas H19 knockdown led to the opposite phenotypes. H19 interacted with VGF, which was significantly upregulated in pNENs, and higher VGF expression was markedly related to poor differentiation and advanced stage. Furthermore, VGF was downregulated when H19 was knocked down, and VGF promoted cell proliferation, migration and invasion. Mechanistic investigations revealed that H19 activated PI3K/AKT/CREB signaling and promoted pNEN progression by interacting with VGF. These findings indicate that H19 is a promising prognostic factor in pNENs with malignant behaviors and functions as an oncogene via the VGF-mediated PI3K/AKT/CREB pathway. In addition, our study implies that VGF may also serve as a candidate prognostic biomarker and therapeutic target in pNENs.

scholarly journals Prognostic and Therapeutic Potential of The OIP5 Network in Papillary Renal Cell Carcinoma

2021 ◽  
Author(s):  
Mathilda Chow ◽  
Yan Gu ◽  
Lizhi He ◽  
Xiaozeng Lin ◽  
Ying Dong ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Therapeutic Potential ◽  
Synthetic Lethality ◽  
Papillary Renal Cell Carcinoma ◽  
Mrna Levels ◽  
Rna Seq

Abstract Background: Papillary renal cell carcinoma (pRCC) is an aggressive but minor type of RCC compared to the main RCC type, clear cell RCC. The current understanding and management of pRCC remain poor. OIP5 possesses oncogenic functions; its contributions to pRCC remain unknown.Methods: OIP5 expression in pRCC at both the protein and mRNA levels was determined using tissue microarray and TCGA dataset. OIP5 was ectopically expressed in metastatic ACHN pRCC cells; xenografts were performed with gene expression profiled by RNA-seq. Differentially expressed genes (DEGs) were analyzed for prognostic potential and impact on pRCC. The effect of PLK1, an OIP5-related DEG, on pRCC tumor growth in vivo was examined.Results: OIP5 expression is upregulated in pRCC. The upregulation associates with pRCC adverse features (T1P<T2P<CIMP, Stage1+2<Stage 3<Stage 4, and N0<N1) and effectively stratifies the fatality risk. OIP5 promotes ACHN pRCC cell proliferation and xenograft formation. RNA-seq reveals network alterations related to immune regulation, metabolism, and hypoxia in ACHN OIP5 tumors compared to empty vector tumors. A set of DEGs was derived from ACHN OIP5 xenografts and primary pRCCs (n=282) contingent to OIP5 upregulation; both DEG sets share 66 overlap genes. Overlap66 effectively predicts overall survival (p<2e-16) and relapse (p<2e-16) possibilities. The prediction is associated with a good out-of-sample performance, supporting its clinical applications. High-risk tumors stratified by Overlap66 risk score possess an immune suppressive environment, evident by elevations in Treg cells and PD1 expression in CD8 T cells. Upregulation of PLK1 occurs in both xenografts and primary pRCC tumors with OIP5 elevations. PLK1 displays a synthetic lethality relationship with OIP5; PLK1 inhibitor BI2356 causes G2/M arrest in ACHN OIP5 cells in vitro and significantly inhibits the growth of xenografts formed by ACHN OIP5 cells in vivo. Conclusions: Our research reveals that OIP5 and its network possess robust prognostic and therapeutic potentials; the prognostic value of Overlap66 and the therapeutic potential of PLK1 inhibitors may pave the way for developing personalized medicine for pRCC management.

YAP1 mediates gastric adenocarcinoma peritoneal metastases that are attenuated by YAP1 inhibition

Gut ◽  
2020 ◽  
Vol 70 (1) ◽  
pp. 55-66
Author(s):  
Jaffer A Ajani ◽  
Yan Xu ◽  
Longfei Huo ◽  
Ruiping Wang ◽  
Yuan Li ◽  
...  
Keyword(s):  
Gastric Adenocarcinoma ◽  
Tumour Growth ◽  
Malignant Ascites ◽  
Tumour Cells ◽  
Rna Seq ◽  
Molecular Events ◽  
Advanced Gastric Adenocarcinoma

ObjectivePeritoneal carcinomatosis (PC; malignant ascites or implants) occurs in approximately 45% of advanced gastric adenocarcinoma (GAC) patients and associated with a poor survival. The molecular events leading to PC are unknown. The yes-associated protein 1 (YAP1) oncogene has emerged in many tumour types, but its clinical significance in PC is unclear. Here, we investigated the role of YAP1 in PC and its potential as a therapeutic target.MethodsPatient-derived PC cells, patient-derived xenograft (PDX) and patient-derived orthotopic (PDO) models were used to study the function of YAP1 in vitro and in vivo. Immunofluorescence and immunohistochemical staining, RNA sequencing (RNA-Seq) and single-cell RNA-Seq (sc-RNA-Seq) were used to elucidate the expression of YAP1 and PC cell heterogeneity. LentiCRISPR/Cas9 knockout of YAP1 and a YAP1 inhibitor were used to dissect its role in PC metastases.ResultsYAP1 was highly upregulated in PC tumour cells, conferred cancer stem cell (CSC) properties and appeared to be a metastatic driver. Dual staining of YAP1/EpCAM and sc-RNA-Seq revealed that PC tumour cells were highly heterogeneous, YAP1high PC cells had CSC-like properties and easily formed PDX/PDO tumours but also formed PC in mice, while genetic knockout YAP1 significantly slowed tumour growth and eliminated PC in PDO model. Additionally, pharmacologic inhibition of YAP1 specifically reduced CSC-like properties and suppressed tumour growth in YAP1high PC cells especially in combination with cytotoxics in vivo PDX model.ConclusionsYAP1 is essential for PC that is attenuated by YAP1 inhibition. Our data provide a strong rationale to target YAP1 in clinic for GAC patients with PC.

scholarly journals Smarca5 mediated epigenetic programming facilitates fetal HSPC development in vertebrates

Blood ◽  
2020 ◽  
Author(s):  
Yanyan Ding ◽  
Wen Wang ◽  
Dongyuan Ma ◽  
Guixian Liang ◽  
Zhixin Kang ◽  
...  
Keyword(s):  
Chromatin Remodeling ◽  
Chromatin Accessibility ◽  
Rna Seq ◽  
Chromatin Remodeler ◽  
Dynamic Changes ◽  
Functional Assays ◽  
Epigenetic Programming

Nascent HSPCs acquire definitive hematopoietic characteristics only when they develop into fetal HSPCs; however, the mechanisms underlying fetal HSPC development are poorly understood. Here, we profiled the chromatin accessibility and transcriptional features of zebrafish nascent- and fetal HSPCs using ATAC-seq and RNA-seq and revealed dynamic changes during HSPC transition. Functional assays demonstrated that chromatin remodeler-mediated epigenetic programming facilitates fetal HSPC development in vertebrates. Systematical screening of chromatin remodeler-related genes identified that smarca5 is responsible for the maintenance of chromatin accessibility at promoters of hematopoiesis-related genes in fetal HSPCs. Mechanistically, Smarca5 interacts with Nucleolin to promote chromatin remodeling, thereby facilitating genomic binding of transcription factors to regulate expression of hematopoietic regulators such as bcl11ab. Our results unravel a new role of epigenetic regulation and reveal that Smarca5-mediated epigenetic programming is responsible for fetal HSPC development, which will provide new insights into the generation of functional HSPCs both in vivo and in vitro.

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