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JQ1 effectively inhibits vasculogenic mimicry of pancreatic ductal adenocarcinoma cells via the ERK1/2-MMP-2/9 signaling pathway both in vitro and in vivo.

ABSTRACT: Vasculogenic mimicry (VM) is an alternative type of blood and nutrition supply that is associated with more aggressive tumor biology and increased cancer-related mortality. However, the clinical implications of VM remain unclear in patients with pancreatic ductal adenocarcinoma (PDAC). The aim of this study was to investigate the clinical significance of VM in PDAC patients and to seek a novel and more efficient treatment strategy by targeting this unique process. Here, cluster of differentiation 34 (CD34)/periodic acid-Schiff (PAS) double-staining of 76 PDAC clinical specimens revealed that VM expression was related to clinical stage (P=0.049) and lymph node metastasis (P=0.023). Notably, VM expression was correlated with a poor prognosis in patients with PDAC. Additionally, we discovered that there was a positive correlation between the expressions of VM and phosphorylated extracellular signal regulated kinase (p-ERK1/2) in 76 clinical samples (P<0.001). Moreover, our results further indicated that treatment with the ERK1/2 inhibitor SCH772984 effectively blocked VM formation by repressing the production of p-ERK1/2-MMP-2/9, which have been established as classical markers of VM. Further, JQ1, a bromodomain and extraterminal domain (BET) inhibitor, also exerted significant inhibitory efficiency against VM formation by decreasing the activation of ERK1/2-MMP-2/9. In conclusion, our work suggests that VM is a marker of poor prognosis in patients with PDAC and that JQ1 can inhibit VM formation via the ERK1/2-MMP-2/9 signaling pathway.

SUBMITTER: Zhuo M

PROVIDER: S-EPMC6413294 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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JQ1 effectively inhibits vasculogenic mimicry of pancreatic ductal adenocarcinoma cells via the ERK1/2-MMP-2/9 signaling pathway both in vitro and in vivo.

Zhuo Meng M Yuan Cuncun C Han Ting T Hu Hai H Cui Jiujie J Jiao Feng F Wang Liwei L

American journal of translational research 20190215 2

Vasculogenic mimicry (VM) is an alternative type of blood and nutrition supply that is associated with more aggressive tumor biology and increased cancer-related mortality. However, the clinical implications of VM remain unclear in patients with pancreatic ductal adenocarcinoma (PDAC). The aim of this study was to investigate the clinical significance of VM in PDAC patients and to seek a novel and more efficient treatment strategy by targeting this unique process. Here, cluster of differentiatio ...[more]

PMID: 30899402

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Project description:BackgroundThe eukaryotic translation initiation protein eIF5A is a highly conserved and essential factor that plays a critical role in different physiological and pathological processes including stress response and cancer. Different proteomic studies suggest that eIF5A may be a small ubiquitin-like modifier (SUMO) substrate, but whether eIF5A is indeed SUMOylated and how relevant is this modification for eIF5A activities are still unknown.MethodsSUMOylation was evaluated using in vitro SUMOylation assays, Histidine-tagged proteins purification from His6-SUMO2 transfected cells, and isolation of endogenously SUMOylated proteins using SUMO-binding entities (SUBES). Mutants were engineered by site-directed mutagenesis. Protein stability was measured by a cycloheximide chase assay. Protein localization was determined using immunofluorescence and cellular fractionation assays. The ability of eIF5A1 constructs to complement the growth of Saccharomyces cerevisiae strains harboring thermosensitive mutants of a yeast EIF5A homolog gene (HYP2) was analyzed. The polysome profile and the formation of stress granules in cells expressing Pab1-GFP (a stress granule marker) by immunofluorescence were determined in yeast cells subjected to heat shock. Cell growth and migration of pancreatic ductal adenocarcinoma PANC-1 cells overexpressing different eIF5A1 constructs were evaluated using crystal violet staining and transwell inserts, respectively. Statistical analysis was performed with GraphPad Software, using unpaired Student's t-test, or one-way or two-way analysis of variance (ANOVA).ResultsWe found that eIF5A is modified by SUMO2 in vitro, in transfected cells and under endogenous conditions, revealing its physiological relevance. We identified several SUMO sites in eIF5A and found that SUMOylation modulates both the stability and the localization of eIF5A in mammalian cells. Interestingly, the SUMOylation of eIF5A responds to specific stresses, indicating that it is a regulated process. SUMOylation of eIF5A is conserved in yeast, the eIF5A SUMOylation mutants are unable to completely suppress the defects of HYP2 mutants, and SUMOylation of eIF5A is important for both stress granules formation and disassembly of polysomes induced by heat-shock. Moreover, mutation of the SUMOylation sites in eIF5A abolishes its promigratory and proproliferative activities in PANC-1 cells.ConclusionsSUMO2 conjugation to eIF5A is a stress-induced response implicated in the adaptation of yeast cells to heat-shock stress and required to promote the growth and migration of pancreatic ductal adenocarcinoma cells.

Project description:Background: Lung cancer has a high incidence and mortality rate worldwide. Vasculogenic mimicry (VM) is a specific modality of tumor angiogenesis that could potentially be a new target for tumor therapy. The purpose of this study was to explore the role of VM-related genes in assessing the prognosis and immune landscape of lung cancer. Methods: VM-related genes were obtained from previous studies, and the expression data and clinical data of lung adenocarcinoma (LUAD) patients were obtained from the TCGA database and GEO database. We performed enrichment analysis of 24 VM-related genes and screened hub genes by constructing a protein-protein interaction network and using Cytoscape software. Subsequently, we developed the VM score based on univariate Cox regression analysis and Lasso analysis and validated the VM score on the GSE72094 dataset. In addition, we constructed a nomogram based on the VM score in the TCGA cohort. Finally, we explored the correlation between the VM score and the tumor microenvironment, immune cell infiltration, immune checkpoints, and drug sensitivity. Results: Enrichment analysis revealed that VM-related genes were associated with the HIF signaling pathway and angiogenic pathway. We developed a VM score based on 3 genes (EPHA2, LAMC2 and LOXL2) in LUAD patients. Kaplan-Meier analysis showed that the VM score was associated with poor prognosis in LUAD patients. The receiver operating characteristic curve suggested that the VM score and nomogram are valid predictors for the overall survival of LUAD patients. The VM score was significantly correlated with immune cell infiltration, such as naïve B cells, neutrophils, and eosinophils, and there was a difference in the TME between the high VM score group and the low VM score group. LUAD patients in the high VM score group were more sensitive to antitumor drugs. Conclusion: In summary, the VM score developed in this study is a valuable indicator for evaluating the prognosis and immune landscape of LUAD patients. VM may be a potential target for antitumor therapy in lung cancer.

Dataset Information

JQ1 effectively inhibits vasculogenic mimicry of pancreatic ductal adenocarcinoma cells via the ERK1/2-MMP-2/9 signaling pathway both in vitro and in vivo.

Publications

JQ1 effectively inhibits vasculogenic mimicry of pancreatic ductal adenocarcinoma cells via the ERK1/2-MMP-2/9 signaling pathway both in vitro and in vivo.

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