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BG-P400TAT, A Dual Targeting of Norepinephrine Transporter Function and Thyrointegrin αvβ3 receptors to Treat Neuroblastoma cancer

ABSTRACT: To explore molecular mechanisms of anti-cancer activities of BG-P400-TAT, genome-wide expression profiling experiments were carried out . Human neuroblastoma SKNAS cells were treated with 30µM of the BG-P400-TAT for 48 hours, harvested, and immediately processed for RNA isolation from three biological replicates of control and drug-treated cells. BG-P400-TAT targets among intracellular multiprotein complexes NF-kB complex, Survivin complex, Bcl-2 complex, and VEGF-A complex and integrated with signal transduction pathways of EGF, FGF1, AR, estradiol, TNF, and IL-1

ORGANISM(S): Homo sapiens

PROVIDER: GSE183170 | GEO | 2021/09/03

REPOSITORIES: GEO

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Project description:In vertebrates, non-lens bg-crystallins are widely expressed in various tissues, but their functions are unknown. The molecular mechanisms of trefoil factors, initiators of mucosal healing and being greatly involved in tumorigenesis, have remained elusive.A naturally existing 72-kDa complex of non-lens bg-crystallin (a-subunit) and trefoil factor (b-subunit), named bg-CAT, was identified from frog Bombina maxima skin secretions. Its a-subunit and b-subunit (containing three trefoil factor domains), with a non-covalently linked form of ab2, show significant sequence homology to ep37 proteins, a group of non-lens bg-crystallins identified in newt Cynops pyrrhogaster and mammalian trefoil factors, respectively. The bg-CAT showed multiple cellular effects on human umbilical vein endothelial cells. Low dosages of bg-CAT (25-50 pM) were able to stimulate cell migration and wound healing. At high concentrations, it induced cell detachment (EC50 10 nM) and apoptosis. The bg-CAT was rapidly endocytosed via intracellular vacuole formation. Under confocal microscope, some of the vacuoles were translocated to nucleus and partially fused with nuclear membraneï®. However, what exactly target of bg-CAT act on HUVECs nuclear is still unknown. Primary cultured HUVECs treated with bg-CAT (25 nM, 2 h) were selected for RNA extraction and hybridization on Affymetrix microarrays. We sought to obtain the genome wide level of significant differential gene expression induced by bg-CAT on HUVECs in order to get clues about bg-CAT action mechanisms. These findings illustrate novel cellular functions of non-lens bg-cyrstallins and action mechanism via association with trefoil factors, serving as clues for investigating the possible occurrence of similar molecules and action mechanisms in mammals. Experiment Overall Design: We used microarrays to analysis genome wide level of significant differential gene expression induced by bg-CAT on HUVECs.Four independent biological replicates of HUVECs treated with bg-CAT (25 nM, 2 h) were compared with normal control by SAM. The significant differential expression of 123 genes (fold changeâ¥3, q value =0, FDR (false discovery rate)=0). 121 genes were up-regulated, among which members of nuclear receptor subfamily 4 (NR4A) were the most prominent. Only 2 genes were down-regulated (including collagen type I) (Supporting information Fig. S1 and Table S1 in accompanying publication). Members of NR4A exhibit differential roles in determining cell growth or cell death depending on its location in the nucleus or mitochondria. NR4A1 (also called Nur77, TR3) mediates cell apoptosis through translocation from nucleus to mitochondria and induction of cytochrome c releasing . Significant activation of NR4A members suggests these orphan nuclear receptors may be involved in the mediation of bg-CAT biological functions, like proapoptotic action of the protein at high concentrations. Up-regulated expression of a number of matrix metalloproteinases by bg-CAT could facilitate cell migration and detachment. The bg-CAT also induced the expression of a number of cytokines, including interleukin 1, interleukin 8 and interleukin 6, as well as various chemokines in HUVECs. These data provide clues for study in detail of molecular pathways through which bg-CAT exerts its biological functions.

Project description:Hematopoietic stem cells (HSCs) derive from the hemogenic endothelium of the dorsal aorta, which develops in spatial and functional proximity to the heart anlagen in the human embryo. Despite the biomedical importance of HSCs, their in vitro induction and niche-like stabilization in a proper developmental context is challenging and poorly established. The underlying reasons include the poorly understood signals controlling HSC formation and the lack of unequivocal markers specifying their stages of differentiation and maturation. Our recently established human pluripotent stem cell (hPSC)-derived heart-forming organoids (HFOs) represent complex, well-patterned multi-tissue structures recapitulating key aspects of heart, foregut and vasculature development. Modulating HFO development by the stage-dependent supplementation of hemato-endothelial factors, we here report the generation of blood-generating-HFOs (BG-HFOs). While maintaining their well-patterned heart anlagen, BG-HFOs comprise a dense, mesenchyme-embedded endothelial layer giving rise to hematopoietic cells thereby resembling – in vitro - aspects of the intra-embryonic region giving rise to definitive hematopoiesis in vivo. Single cell-RNA sequencing of BG-HFOs revealed a gene expression signature of hematopoietic progenitor cells (HPCs) as well as patterns resembling hematopoietic derivatives such as erythroid, megakaryocytic and myeloid cells. Notably, BG-HFO-derived CD34pos CD43pos and CD34neg CD43pos cells display erythroid and myeloid potential in colony forming unit (CFU) assays, while CD34pos CD43neg HPCs retain lymphoid potential, observed via generation of T-cell progenitors in artificial thymic organoid (ATO)-based assays. This suggests presence of different multipotent HPCs in BG-HFOs and a potential transient downregulation of CD43 in lymphoid-restricted HPCs. Together, BG-HFOs represent the first human model of cardiac, endothelial and multipotent-hematopoietic cell co-development. The study promotes research on the multi-tissue interactions of hematopoiesis in vitro, overcoming limitations of such studies in the human embryo.

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BG-P400TAT, A Dual Targeting of Norepinephrine Transporter Function and Thyrointegrin αvβ3 receptors to Treat Neuroblastoma cancer

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