Urokinase-type plasminogen activator receptor promotes proliferation and invasion with reduced cisplatin sensitivity in malignant mesothelioma

Wang, Shenqi; Jiang, Li; Han, Yipeng; Chew, Shan Hwu; Ohara, Yuuki; Akatsuka, Shinya; Weng, Liang; Kawaguchi, Koji; Fukui, Takayuki; Sekido, Yoshitaka; Yokoi, Kohei; Toyokuni, Shinya

doi:10.18632/oncotarget.11829

Cited by 10 publications

(10 citation statements)

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“…Cells (2-10×10 3 per well; the same number of cells for each cell line) were seeded in a 96-well plate and MTT assay was performed using the method described previously [ 57 ]. For dose-response analyses, PEM concentration was 0.1, 0.5, 1, 5 and 10 μM.…”

Section: Methodsmentioning

confidence: 99%

“…Cell migration and invasion assays were performed using transwell permeable supports (Corning Incorporated, Life Science, New York, NY) with 8 μm-pore filters in the same manner as described [ 57 ]. We used 3 μl of Corning Matrigel matrix (Corning, typical protein concentration: 9-12 mg/ml) for coating each upper chamber for invasion according to the manufacturer's protocol.…”

Section: Methodsmentioning

confidence: 99%

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Connective tissue growth factor-specific monoclonal antibody inhibits growth of malignant mesothelioma in an orthotopic mouse model

et al. 2018

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Malignant mesothelioma is an aggressive neoplasm with no particularly effective treatments. We previously reported that overexpression of connective tissue growth factor (CTGF/CCN2) promotes mesothelioma growth, thus suggesting it as a novel molecular target. A human monoclonal antibody that antagonizes CTGF (FG-3019, pamrevlumab) attenuates malignant properties of different kinds of human cancers and is currently under clinical trial for the treatment of pancreatic cancer. This study reports the effects of FG-3019 on human mesothelioma in vitro and in vivo. We analyzed the effects of FG-3019 on the proliferation, apoptosis, migration/invasion, adhesion and anchorage-independent growth in three human mesothelioma cell lines, among which ACC-MESO-4 was most efficiently blocked with FG-3019 and was chosen for in vivo experiments. We also evaluated the coexistent effects of fibroblasts on mesothelioma in vitro, which are also known to produce CTGF in various pathologic situations. Coexistent fibroblasts in transwell systems remarkably promoted the proliferation and migration/invasion of mesothelioma cells. In orthotopic nude mice model, FG-3019 significantly inhibited mesothelioma growth. Histological analyses revealed that FG-3019 not only inhibited the proliferation but also induced apoptosis in both mesothelioma cells and fibroblasts. Our data suggest that FG-3019 antibody therapy could be a novel additional choice for the treatment of mesothelioma.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Connective tissue growth factor-specific monoclonal antibody inhibits growth of malignant mesothelioma in an orthotopic mouse model

et al. 2018

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“…PLAU is one of the pro-angiogenic factors that can be produced by TAMs [ 10 ]. It was shown to aid the invasion and metastasis of various types of cancer cells via binding to PLAUR, subsequently activating downstream pathways like ERK1/2 [ 46 ] and PI3K/Akt [ 47 ]. Moreover, the interaction of PLAU-PLAUR raised plasmin levels, contributing to the activation of matrix metalloproteinases [ 48 ].…”

Section: Discussionmentioning

confidence: 99%

Comparative proteomic analysis of cat eye syndrome critical region protein 1- function in tumor-associated macrophages and immune response regulation of glial tumors

et al. 2018

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IntroductionTumor associated macrophages (TAMs) promote tumor development, angiogenesis and distal metastasis. In previous studies, we showed that Cat Eye Syndrome Critical Region Protein 1 (CECR1) is expressed by M2-like TAMs in human glioma samples. CECR1 promoted M2 TAMs differentiation and affected glioma cell proliferation and migration. Here we investigated the proteomic profile of TAMs expressing CECR1 in absence or presence of glioma cells.ResultsCECR1 siRNA transfection upregulated 67 proteins in THP-1-derived Macrophages (MQs). Pathway annotation mapped this set to 3 major pathways relevant for MQ function, including ‘MHC-I antigen presentation’, ‘phagosome maturation’ and ‘endocytosis’. Co-culture of siCECR1 THP-1-derived MQs with U87 glioma cells attenuated the changes observed on protein and mRNA level in response to MQ CECR1 silencing. SiCECR1 in U87 co-cultured MQs was associated with an IL-10low, IL-12high M1-like phenotype. In U87 co-culture conditions, SiCECR1 also downregulated S20 proteasome complex proteins PSMA5, PSMA7, PSMC6 and PSMD8. This protein profile was linked to a low proliferation rate of siCECR1 MQs. Overlap analysis identified S100A9 and PLAU as CECR1-related proteins that were significantly correlated with expression of CECR1 and macrophage lineage markers in three large public GBM datasets.ConclusionThis study reports the molecular pathways and key molecules that are mediated by CECR1 function in THP- 1-derived MQs and TAMs in glioma.MethodsPMA-treated THP-1 cells (MQs) were siRNA transfected for CECR1 in vitro, with or without stimulation of the primary glioma cell line U87. Lysates were analyzed by (nano)LC-MS. Significant altered protein levels were identified (P < 0.05), followed by pathway annotation.

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“…Some of them have little or no expression in lung tissue but are overexpressed in MPM. PLAUR is a prognostic biomarker of human MPM, and is also associated with shorter survival time in a rat xenograft model of malignant mesothelioma (43). Similarly, FGFR1 and its novel interactor NRG1 had elevated mRNA expression in H2722 mesothelioma cell lines and in MPM tissue, both contributing to increased cell growth under tumorigenic conditions (44,45).…”

Section: Analysis With Other High-throughput Datamentioning

confidence: 98%

Mesothelioma Interactome with 367 Novel Protein-Protein Interactions

Yanamala

Boyce

et al. 2018

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Malignant pleural mesothelioma (MPM) is an aggressive cancer of the thorax with a median survival of one year. We constructed an 'MPM interactome' with over 300 computationally predicted PPIs and over 1300 known PPIs of 62 literature-curated genes whose activity affects MPM. Known PPIs of the 62 MPM associated genes were derived from BioGRID and HPRD databases. Novel PPIs were predicted by applying the HiPPIP algorithm, which computes features of protein pairs such as cellular localization, molecular function, biological process membership, genomic location of the gene, gene expression in microarray experiments, protein domains and tissue membership, and classifies the pairwise features as interacting or non-interacting based on a random forest model. To our satisfaction, the interactome is significantly enriched with genes differentially expressed in MPM tumors compared with normal pleura, and with other thoracic tumors. The interactome is also significantly enriched with genes whose high expression has been correlated with unfavorable prognosis in lung cancer, and with genes differentially expressed on crocidolite exposure. 28 of the interactors of MPM proteins are targets of 147 FDA-approved drugs. By comparing differential expression profiles induced by drug to profiles induced by MPM, potentially repurposable drugs are identified from this drug list. Development of PPIs of disease-specific set of genes is a powerful approach with high translational impactthe interactome is a vehicle to piece together an integrated view on how genes associated with MPM through various high throughput studies are functionally linked, leading to clinically translatable results such as clinical trials with repurposed drugs. The PPIs are made available on a webserver, called Wiki-Pi MPM at http://severus.dbmi.pitt.edu/wiki-MPM with advanced search capabilities.Recently, twenty four germline mutations were identified in 13 genes from 198 patients with malignant mesothelioma of pleural or peritoneal origin (11). Non-invasive pre-malignant phase is not seen in mesothelioma unlike other tumors, which necessitates expeditious discovery of genetic predispositions, molecular mechanisms and therapeutics for the disease (12).60% of the disease-associated missense mutations perturb protein-protein interactions (PPIs) in human genetic disorders (13). PPIs are intricately involved in biological functions and disease mechanisms, and may be exploited for drug-discovery (13). The molecular mechanisms of disease are often revealed by the PPIs of diseaseassociated genes. For example, the involvement of transcriptional deregulation in the pathogenesis of MPM was identified through mutations detected in BAP1 and its interactions with several proteins including BRCA1 revealed by co-immunoprecipitation (14). The PPI of BRCA1 with BAP1 was also central in understanding its role in growth-control pathways and cancer (15). Studies on BAP1 and BRCA1 later provided the basis for several clinical trials including testing of the drug Vinorelbine as a second...

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Urokinase-type plasminogen activator receptor promotes proliferation and invasion with reduced cisplatin sensitivity in malignant mesothelioma

Cited by 10 publications

References 51 publications

Connective tissue growth factor-specific monoclonal antibody inhibits growth of malignant mesothelioma in an orthotopic mouse model

Connective tissue growth factor-specific monoclonal antibody inhibits growth of malignant mesothelioma in an orthotopic mouse model

Comparative proteomic analysis of cat eye syndrome critical region protein 1- function in tumor-associated macrophages and immune response regulation of glial tumors

Mesothelioma Interactome with 367 Novel Protein-Protein Interactions

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