Correction: Oncogenomics of c-Myc transgenic mice reveal novel regulators of extracellular signaling, angiogenesis and invasion with clinical significance for human lung adenocarcinoma.
Ontology highlight
ABSTRACT:
SUBMITTER: Ciribilli Y
PROVIDER: S-EPMC6324690 | biostudies-literature | 2018 Dec
REPOSITORIES: biostudies-literature
Publications
Correction: Oncogenomics of c-Myc transgenic mice reveal novel regulators of extracellular signaling, angiogenesis and invasion with clinical significance for human lung adenocarcinoma.
Ciribilli Yari Y Borlak Jürgen J
Oncotarget 20181214 98
[This corrects the article DOI: 10.18632/oncotarget.21981.]. ...[more]
Similar Datasets
Project description:The c-Myc transcription factor is frequently deregulated in cancers. To search for disease diagnostic and druggable targets a transgenic lung cancer disease model was investigated. Oncogenomics identified c-Myc target genes in lung tumors. These were validated by RT-PCR, Western Blotting, EMSA assays and ChIP-seq data retrieved from public sources. Gene reporter and ChIP assays verified functional importance of c-Myc binding sites. The clinical significance was established by RT-qPCR in tumor and matched healthy control tissues, by RNA-seq data retrieved from the TCGA Consortium and by immunohistochemistry recovered from the Human Protein Atlas repository. In transgenic lung tumors 25 novel candidate genes were identified. These code for growth factors, Wnt/?-catenin and inhibitors of death receptors signaling, adhesion and cytoskeleton dynamics, invasion and angiogenesis. For 10 proteins over-expression was confirmed by IHC thus demonstrating their druggability. Moreover, c-Myc over-expression caused complete gene silencing of 12 candidate genes, including Bmp6, Fbln1 and Ptprb to influence lung morphogenesis, invasiveness and cell signaling events. Conversely, among the 75 repressed genes TNF? and TGF-? pathways as well as negative regulators of IGF1 and MAPK signaling were affected. Additionally, anti-angiogenic, anti-invasive, adhesion and extracellular matrix remodeling and growth suppressive functions were repressed. For 15 candidate genes c-Myc-dependent DNA binding and transcriptional responses in human lung cancer samples were confirmed. Finally, Kaplan-Meier survival statistics revealed clinical significance for 59 out of 100 candidate genes, thus confirming their prognostic value. In conclusion, previously unknown c-Myc target genes in lung cancer were identified to enable the development of mechanism-based therapies.
| S-EPMC5731916 | biostudies-literature
Project description:To study a complex network of gene expression changes underlying c-Myc-triggered carcinogenesis in lung we performed oligonucleotide array analysis of solid lung adenocarcinomas which developed in transgenic mice due to constitutive expression of c- Myc in alveolar type II epithelial cells and compared them with the non-transgenic lung as a control. The microarray analysis yielded 162 up regulated and 301 down regulated genes. The genes were further analyzed with regard to their biological functions, to known responsiveness to c-Myc and to the presence of potential c-Myc -binding sites in their promoters. We identified inappropriate expression of a variety of genes involved in the several pathways critical for the development of lung tumor: cell cycle, cell growth, cell death, adhesion, cytoskeleton organization, invasive and angiogenic capacity. Some genes identified in this study were known to be similarly changed in human malignancies and specifically in lung tumors which makes the SPC/c-Myc-transgenic mouse model useful for investigating human lung cancer. Many other genes differently expressed in lung tumors are novel targets for mechanism based therapies and serve as useful tumor markers. New c- Myc-responsive genes and putative c-Myc -targets identified in this study contributed to the collective examination of distinct c-Myc transcriptomes that are partly cell type- and species- specific The molecular rules defining c-Myc’s activity in lung cancer remain elusive. We therefore investigated the c-Myc gene networks in a transgenic mouse model of lung cancer. Genome wide gene expression profiling applied to histological well-defined tumors revealed 162 up and 301 repressed genes and identified novel c-Myc targeted cell cycle and apoptosis genes. To better understand transcriptional responses the co-occupancy of different transcription factors (TF) were analyzed. This defined composite modules with 64, 68, 96 and 92, 88 and 96% of tumor associated down-regulated genes having TF-binding sites for either c-Myc, Klf7, Gata3 or c-Myc, Sox18 and P53, respectively. The composite modules fitted 48% and 80% of regulated genes. Likewise, 75, 96, 89 and 44, 59 and 54% of up-regulated genes in tumor or non-tumor transgenic tissue were enriched for Myc, Elf5,Cebp and c-Myc, Hbp1 and Hif1 TF-binding sites, respectively to suggest diverse and distinct TF-clusters at different stages of disease. Importantly, the genes coding for TFs were regulated as well and electrophoretic mobility shift assay (EMSA) confirmed c-Myc DNA-binding activity at targeted promoters of regulated genes. Furthermore, computational biology defined Gata3, mortalin and moesin to function in master regulatory gene networks and experimental validation of the constructed networks was achieved by EMSA, RT-PCR, Western blotting and gene reporter assay. Lastly, evidence for c-Myc DNA binding activity at targeted gene promoters was also derived from published Chip-sequence data of 7 human cell lines and the clinical significance of findings can be demonstrated by their regulation in human lung cancer. In conclusion, novel c-Myc targeted cell cycle and apoptosis genes were identified to function in gene regulatory networks. The results of the present study improve an understanding of c-Myc transforming capacity and provide a molecular rationale for the development of molecularly targeted therapies.
2016-05-20 | GSE54829 | GEO
Project description:c-Myc's role in pulmonary cancer metabolism is uncertain. We therefore investigated c-Myc activity in papillary lung adenocarcinomas (PLAC). Genomics revealed 90 significantly regulated genes (> 3-fold) coding for cell growth, DNA metabolism, RNA processing and ribosomal biogenesis and bioinformatics defined c-Myc binding sites (TFBS) at > 95% of up-regulated genes. EMSA assays at 33 novel TFBS evidenced DNA binding activity and ChIP-seq data retrieved from public repositories confirmed these to be c-Myc bound. Dual-luciferase gene reporter assays developed for RNA-Terminal-Phosphate-Cyclase-Like-1(RCL1), Ribosomal-Protein-SA(RPSA), Nucleophosmin/Nucleoplasmin-3(NPM3) and Hexokinase-1(HK1) confirmed c-Myc functional relevance and ChIP assays with HEK293T cells over-expressing ectopic c-Myc demonstrated enriched c-Myc occupancy at predicted TFBS for RCL1, NPM3, HK1 and RPSA. Note, c-Myc recruitment on chromatin was comparable to the positive controls CCND2 and CDK4. Computational analyses defined master regulators (MR), i.e. heterogeneous nuclear ribonucleoprotein A1, nucleolin, the apurinic/apyrimidinic endonuclease 1, triosephosphate-isomerase 1, folate transporter (SLC19A1) and nucleophosmin to influence activity of up to 90% of PLAC-regulated genes. Their expression was induced by 3-, 3-, 6-, 3-, 11- and 7-fold, respectively. STRING analysis confirmed protein-protein-interactions of regulated genes and Western immunoblotting of fatty acid synthase, serine hydroxyl-methyltransferase 1, arginine 1 and hexokinase 2 showed tumor specific induction. Published knock down studies confirmed these proteins to induce apoptosis by disrupting neoplastic lipogenesis, by endorsing uracil accumulation and by suppressing arginine metabolism and glucose-derived ribonucleotide biosynthesis. Finally, translational research demonstrated high expression of MR and of 47 PLAC up-regulated genes to be associated with poor survival in lung adenocarcinoma patients (HR 3.2 p < 0.001) thus, providing a rationale for molecular targeted therapies in PLACs.
| S-EPMC5323172 | biostudies-literature
Project description:Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal forms of cancer. One major reason for this is that PDAC quickly metastasizes to other organs, thereby making its treatment difficult. The molecular machinery driving PDAC metastasis is still poorly understood. In this study, we applied an unbiased approach using CRISPR screening to identify genes that strongly regulate invasion (based on an in vitro assessment of their metastatic potential) in PANC-1, a PDAC cell line. Through CRISPR screening, we identified MBNL3 and KANSL2 as strong regulators of invasion in PANC-1 cells. We further validated MBNL3 and KANSL2 as regulators of PANC-1 cell invasion by using the doxycycline-inducible shRNA system. We also showed that MBNL3 and KANSL2 do not affect cell proliferation. Through our efforts, we have established a process to identify genes that regulate cell invasion and can be further investigated as potential targets for therapeutic intervention.
| S-EPMC6992758 | biostudies-literature
Project description:BackgroundNon-small cell lung cancer (NSCLC) is still one of the diseases with the highest mortality and morbidity, and lung adenocarcinoma (LUAD) accounts for more than half of all NSCLC cases in most countries. miRNA can be used as a potential biological marker and treatment for lung adenocarcinoma. However, the effect of miR-937-3p to the invasion and metastasis of LUAD cells is not clear.MethodsmiRNA microarray is used to analyze the expression of miRNA in lung adenocarcinoma tissue. Transwell migration, Wound-healing assay and Western blot analysis are used to analyze cell migration, invasion and epithelial-mesenchymal transition (EMT) capabilities. Tube formation is used to assess angiogenesis ability. In addition, dual luciferase reporter gene detection is used to identify the potential binding between miRNA and target mRNA. In vivo experiments were performed on male NOD/SCID nude mice by tail vein injection to establish a transplanted tumor model. The CHIP experiment is used to verify the transcription factors of miRNA.ResultIn our study, miR-937-3p was high-regulated in LUAD cell lines and tissues, and its expression level was related to tumor progression. We found that miR-937-3p high-expression has an effect on cell invasion and metastasis. In molecular mechanism, miR-937-3p causes SOX11 reduction by directly binding to the 3'-UTR of SOX11.In addition, MYC affects miR-937-3p transcription by binding to its promoter region.ConclusionsOur research shows that miR-937-3p is mediated by MYC and can control the angiogenesis, invasion and metastasis of LUAD by regulating SOX11, thereby promoting the progress of LUAD. We speculate that miR-937-3p can be used as a therapeutic target and potential biomarker for LUAD.
| S-EPMC8761314 | biostudies-literature
Project description:In lung cancer, antiangiogenic strategies targeting tumor-derived endothelial cells (TECs) afford a survival advantage, but the characteristics of TECs have not been comprehensively elucidated. Herein, high-purity (>?98%) TECs were obtained, and these cells retained expression of EC markers and exhibited high viability. ITRAQ-2DLC-MS/MS was performed to profile the proteome and the heterogeneity of ECs. Only 31 of 1820 identified proteins were differentially expressed between adenocarcinoma (ADC)- and squamous cell carcinoma (SCC)-derived TECs (TEC-A and TEC-S, respectively), and cadherin-2 (CDH2) was the most significantly upregulated protein in TEC-A samples. Positive immunostaining for CDH2 (score?>?3) was significantly more frequent in the endothelium of ADC tissues than in that of SCC tissues. Loss- or gain-of-function analysis showed that CDH2 significantly promoted in vitro and in vivo angiogenesis and sensitivity to the antagonist exherin. The MAPK/ERK and MAPK/JNK signaling pathways may play crucial roles in CDH2-induced HIF-1?/VEGF-mediated angiogenesis. Moreover, high CDH2 expression in TECs was significantly associated with tumor stage, visceral pleural metastasis, and decreased overall survival in patients with ADC but not SCC. Together, these data indicate the importance of CDH2 in angiogenesis and highlight its potential both for antiangiogenic therapy and as a candidate prognostic marker for ADC.
| S-EPMC6399986 | biostudies-literature
Project description:Clinical trials with antiangiogenic agents have not been able to validate plasma or serum levels of angiogenesis regulators as reliable markers of cancer presence or therapeutic response. We recently reported that platelets contain numerous proteins that regulate angiogenesis. We now show that accumulation of angiogenesis regulators in platelets of animals bearing malignant tumors exceeds significantly their concentration in plasma or serum, as well as their levels in platelets from non-tumor-bearing animals. This process is selective, as platelets do not take up a proportional amount of other plasma proteins (eg, albumin), even though these may be present at higher concentrations. We also find that VEGF-enriched Matrigel pellets implanted subcutaneously into mice or the minute quantities of VEGF secreted by microscopic subcutaneous tumors (0.5-1 mm(3)) result in an elevation of VEGF levels in platelets, without any changes in its plasma levels. The profile of other angiogenesis regulatory proteins (eg, platelet-derived growth factor, basic fibroblast growth factor) sequestered by platelets also reflects the presence of tumors in vivo before they can be macroscopically evident. The ability of platelets to selectively take up angiogenesis regulators in cancer-bearing hosts may have implications for the diagnosis and management of many angiogenesis-related diseases and provide a guide for antiangiogenic therapies.
| S-EPMC2661866 | biostudies-other
Project description:BACKGROUND The incidence, pathogenesis, and prognostic effect of microvascular invasion on pancreatic ductal adenocarcinoma (PDAC) remain controversial. This study aimed to summarize the incidence, pathogenesis, role in clinical management, recurrence, and prognostic significance of microvascular invasion in PDAC. MATERIAL AND METHODS A literature review and meta-analysis were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Systematic literature searches were conducted using PubMed and Google Scholar up to February 2021. RESULTS Seventeen studies were included in the meta-analysis. The incidence of microvascular invasion was 49.0% (95% confidence interval [CI], 43.8-54.5%) among PDAC patients who underwent surgery. The weighted multivariate Cox proportional hazards model hazard ratio for disease-free survival of 8 studies was 1.78 (95% CI 1.53-2.08, P<0.001), and there was no statistically significant difference between the subgroups (P=0.477). The hazard ratio for overall survival of 14 studies was 1.49 (95% CI 1.27-1.74, P<0.001), and there was no statistically significant difference between the subgroups (P=0.676). CONCLUSIONS Microvascular invasion occurred in nearly half of PDAC patients after surgery and was closely related to disease-free and overall survival. Understanding the role of microvascular invasion in PDAC will help provide more personalized and effective preoperative or postoperative strategies to achieve better survival outcomes.
| S-EPMC8378224 | biostudies-literature
Project description:Although devascularization caused by antiangiogenic therapy limits tumor growth, the benefits of antiangiogenic therapy are often transient, with tumor growth typically resuming through adaptive responses that need further characterization. Recent reports indicate that hypoxia in tumor microenvironments induces autophagy, a lysosomal degradation pathway that may promote tumor cell survival. We investigated the hypothesis that antiangiogenic therapy leads to hypoxia, which induces tumor cell autophagy as a cytoprotective adaptive response promoting evasion to antiangiogenic therapy. We found that patient specimens from glioblastomas evasive to bevacizumab exhibited nearly 80% more hypoxia than did pretreatment specimens from the same patients. Hypoxia (1% oxygen) induced autophagy in several primary glioblastoma cells and cell lines. Selective autophagy occurred independent of HIF-1?/AMPK hypoxia-upregulated pathways, while nonselective autophagy depended on both. Autophagy inhibitors transitioned hypoxic glioblastoma cells from autophagy to nonapoptotic cell death. Patient specimens from glioblastomas evading antiangiogenic therapy expressed 55% more autophagy-related BNIP3 than did pretreatment specimens from the same patients, with BNIP3 expression localizing to the increased hypoxic areas seen in the glioblastomas that evaded antiangiogenic therapy. Human glioblastoma xenografts exhibited persistent growth inhibition when treated with autophagy inhibitor chloroquine plus antiangiogenic bevacizumab; chloroquine prevented the evasive hypoxia-associated growth seen with bevacizumab alone and reversed the more than 2-fold increased expression of autophagy mediator BNIP3 seen in xenografts growing during bevacizumab monotherapy. These findings suggest that hypoxia-mediated autophagy promotes tumor cell survival after antiangiogenic therapy, a novel adaptive response to antiangiogenic therapy that can be pharmacologically disrupted to allow antiangiogenic therapy to fulfill its therapeutic promise.
| S-EPMC3222963 | biostudies-literature
Project description:Thrombospondins (TSPs) -1 and -2 were among the first protein inhibitors of angiogenesis to be identified, a property that was subsequently attributed to the interactions of sequences in their type I repeats with endothelial cell-surface receptors. The interactions of TSPs-1 and -2 with cell-surface receptors, proteases, growth factors, and other bioactive molecules, coupled with the absence of direct structural functions that can be attributed to these matrix proteins, qualify them for inclusion in the category of 'matricellular proteins'. The phenotypes of TSP-1, TSP-2, and double TSP-1/2-null mice confirm the roles that these proteins play in the regulation of angiogenesis, and provide clues to some of the other important functions of these multi-domain proteins. One of these functions is the ability of TSP-1 to activate the latent TGFbeta1 complex, a property that is not shared by TSP-2. A major pathway by which TSP1 or TSP2 inhibits angiogenesis involves an interaction with CD 36 on endothelial cells, which leads to apoptosis of both the liganded and adjacent cells. However a homeostatic mechanism, which inhibits endothelial cell proliferation, and may be physiologically preferable under some circumstances, has also been elucidated, and involves interaction with the very low density lipoprotein receptor (VLDLR). The interaction of TSP1with its receptor, CD47, further inhibits angiogenesis by antagonizing nitric oxide signaling in endothelial and vascular smooth muscle cells. Paradoxically, there is also evidence that TSP-1 can function to promote angiogenesis. This apparent contradiction can be explained by the presence of sequences in different domains of the protein that interact with different receptors on endothelial cells. The anti-angiogenic function of TSPs has spurred interest in their use as anti-tumor agents. Currently, peptide mimetics, based on sequences in the type I repeats of TSPs that have been shown to have anti-angiogenic properties, are undergoing clinical testing.
| S-EPMC2778581 | biostudies-other