RESUMO
Ischemic stroke (IS) is one of the most impairing complications of sickle cell anemia (SCA), responsible for 20% of mortality in patients. Rheological alterations, adhesive properties of sickle reticulocytes, leukocyte adhesion, inflammation and endothelial dysfunction are related to the vasculopathy observed prior to ischemic events. The role of the vascular endothelium in this complex cascade of mechanisms is emphasized, as well as in the process of ischemia-induced repair and neovascularization. The aim of the present study was to perform a comparative transcriptomic analysis of endothelial colony-forming cells (ECFCs) from SCA patients with and without IS. Next, to gain further insights of the biological relevance of differentially expressed genes (DEGs), functional enrichment analysis, protein-protein interaction network (PPI) construction and in silico prediction of regulatory factors were performed. Among the 2469 DEGs, genes related to cell proliferation (AKT1, E2F1, CDCA5, EGFL7), migration (AKT1, HRAS), angiogenesis (AKT1, EGFL7) and defense response pathways (HRAS, IRF3, TGFB1), important endothelial cell molecular mechanisms in post ischemia repair were identified. Despite the severity of IS in SCA, widely accepted molecular targets are still lacking, especially related to stroke outcome. The comparative analysis of the gene expression profile of ECFCs from IS patients versus controls seems to indicate that there is a persistent angiogenic process even after a long time this complication has occurred. Thus, this is an original study which may lead to new insights into the molecular basis of SCA stroke and contribute to a better understanding of the role of endothelial cells in stroke recovery.
Assuntos
Anemia Falciforme , Acidente Vascular Cerebral , Humanos , Células Endoteliais/metabolismo , Transcriptoma , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/complicações , Anemia Falciforme/complicações , Isquemia , Perfilação da Expressão Gênica , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Família de Proteínas EGF/genética , Família de Proteínas EGF/metabolismoRESUMO
Studies indicate EGFL7 as an important gene in controlling angiogenesis and cancer growth, including in colorectal cancer (CRC). Anti-EGFL7 agents are being explored, yet without promising results. Therefore, the role of EGFL7 in CRC carcinogenesis should be investigated. This study aimed to evaluate the prognostic value of EGFL7 expression in CRC and the signaling pathways influenced by this gene. EGFL7 expression was evaluated through immunohistochemistry in 463 patients diagnosed with CRC and further associated with clinicopathological data, angiogenesis markers and survival. In silico analyzes were performed with colon adenocarcinoma data from The Cancer Genome Atlas. Analysis of enriched gene ontology and pathways were performed using the differentially expressed genes. 77.7% of patients presented low EGFL7 expression, which was associated with higher lymph node spread and invasion of lymphatic vessels, with no impact on survival. Additionally, low EGFL7 expression was associated with high VEGFR2 expression. Finally, we found in silico that EGFL7 expression was associated with cell growth, angiogenesis, and important pathways such as VEGF, Rap-1, MAPK and PI3K/Akt. Expression of EGFL7 in tumor cells may be associated with important pathways that can alter functions related to tumor invasive processes, preventing recurrence and metastatic process.
Assuntos
Adenocarcinoma , Neoplasias do Colo , Neoplasias Colorretais , Vasos Linfáticos , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Fatores de Crescimento Endotelial/genética , Família de Proteínas EGF/metabolismo , Processos Neoplásicos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Fatores de Transcrição/metabolismo , Linfonodos/metabolismo , Vasos Linfáticos/metabolismo , Neoplasias Colorretais/genética , Proteínas de Ligação ao Cálcio/genéticaRESUMO
EGFL7 is a proangiogenic factor. It has been widely described with having a vital role in tubulogenesis and regulation of angiogenesis, mainly during embryogenesis and organogenesis. It has been mainly associated with NOTCH pathway, but there are reports showing association with MAPK and integrin pathways. Given its association with angiogenesis and these other pathways, there are several studies associating EGFL7 with carcinogenesis. In fact, most of the studies have pointed to EGFL7 as an oncogene, and some of them suggest EGFL7 expression as a possible biomarker of prognosis or use for a patient's follow-up. Here, we review the molecular pathways which EGFL7 is associated and highlight several studies describing the role of EGFL7 in tumorigenesis, separated by tumor type. Besides its role on angiogenesis, EGFL7 may act in other pathways as oncogene, which makes it a possible biomarker and a candidate to targeted therapy.