RESUMO
The mechanisms underlying the sustained activation of the PI3K/AKT and Wnt/ß-catenin pathways mediated by HOTAIR in cervical cancer (CC) have not been extensively described. To address this knowledge gap in the literature, we explored the interactions between these pathways by driving HOTAIR expression levels in HeLa cells. Our findings reveal that HOTAIR is a key regulator in sustaining the activation of both signaling pathways. Specifically, altering HOTAIR expression-either by knockdown or overexpression-significantly influenced the transcriptional activity of the PI3K/AKT and Wnt/ß-catenin pathways. Additionally, we discovered that HIF1α directly induces HOTAIR transcription, which in turn leads to the epigenetic silencing of the PTEN promoter via DNMT1. This process leads to the sustained activation of both pathways, highlighting a novel regulatory axis involving HOTAIR and HIF1α in cervical cancer. Our results suggest a new model in which HOTAIR sustains reciprocal activation of the PI3K/AKT and Wnt/ß-catenin pathways through the HOTAIR/HIF1α axis, thereby contributing to the oncogenic phenotype of cervical cancer.
Assuntos
Metilação de DNA , Subunidade alfa do Fator 1 Induzível por Hipóxia , PTEN Fosfo-Hidrolase , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , RNA Longo não Codificante , Neoplasias do Colo do Útero , Via de Sinalização Wnt , Humanos , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/patologia , Feminino , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , PTEN Fosfo-Hidrolase/genética , Fosfatidilinositol 3-Quinases/metabolismo , Via de Sinalização Wnt/genética , Células HeLa , Metilação de DNA/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Regulação Neoplásica da Expressão Gênica , beta Catenina/metabolismo , beta Catenina/genética , Regiões Promotoras Genéticas/genética , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , DNA (Citosina-5-)-Metiltransferase 1/genéticaRESUMO
Amoebiasis in humans is caused by the protozoan parasite Entamoeba histolytica, which cytotoxic activity has been demonstrated on a wide variety of target cells. The process involves the adherence of the parasite to the cell, and such adherence is mediated by an amoebic surface lectin, known as Gal/GalNAc lectin. It is composed of heavy, intermediate, and light subunits. The carbohydrate recognition domain (CRD) has been identified within a cysteine-rich region in the lectin heavy subunit and has an amino acid sequence identity to the receptor-binding domain of hepatocyte growth factor (HGF). Recombinant CRD has been previously shown to compete with HGF for binding to the c-Met receptor IgG fusion protein. In the present study, we searched for evidence of interaction between the Gal/GalNAc lectin at the surface of trophozoites with the c-Met receptor expressed at the surface of HepG2 in coculture assays. Immunoprecipitation of the coculture lysate indicated interaction of the c-Met with a 60 kDa peptide recognized by antiamoebic lectin antibody. Colocalization of both molecules was detected by fluorescence confocal microscopy. Incubation of HepG2 cells with HGF before coculture with trophozoites prevents the cytotoxic effect caused by the parasites but not their adherence to the cells. Our results point to Gal/GalNAc lectin as a ligand of the c-Met receptor at the surface of HepG2 cells.
RESUMO
We describe the events triggered by a sub-lethal concentration of airborne particulate matter (PM(10)) in A549 cells, which include the formation DNA double-strand breaks, gammaH2A.X generation, and 53BP1 recruitment. To protect the genome, cells activated ATM/ATR/Chk1/Chk2/p53 pathway but, after 48 h, cells turned into a senescence-like state. Trolox, an antioxidant, was able to prevent most of the alterations observed after particulate matter exposure, demonstrating the important role of ROS as mediator of PM(10)-induced genotoxicity and suggesting that DNA damage could be the mechanisms by which particulate matter augment the risk of lung cancer.