Targeting hydrogen sulphide signaling in breast cancer
| Autor: | Nabil Ahmed, Khaled Sanber, Mohamed Z. Gad, Ahmed Z. Gad, Hafez Mohamed Hafez, Amira Abdel Motaal, Rana Ahmed Youness, Emad Khallaf, Gi-Ja Lee, Yong Jin Ahn |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
HCC Hepatocellular carcinoma Proliferation index CTL Cytotoxic T lymphocyte CD86 Cluster of differentiation 86 ULBP2/5/6 UL16 binding protein 2/5/6 PD-L1 Programmed death-ligand 1 Breast cancer 0302 clinical medicine miR-155/NOS2/NO signaling pathway NK Natural killer Hydrogen sulphide TNF-α Tumor necrosis factor-α Cytotoxic T cell miR-4317 Cytotoxicity ncRNAs Non-coding RNAs MICA/B MHC class I polypeptide-related sequence A/B lcsh:R5-920 CAR T cells Multidisciplinary siRNAs Small interfering RNAs biology CD80 Cluster of differentiation 80 Chemistry Transfection CAR Chimeric antigen receptor CBS Cystathionine β-synthase medicine.anatomical_structure 41BBL 41BB Ligand 030220 oncology & carcinogenesis Natural killer cells lcsh:Medicine (General) H2S Hydrogen sulphide TNBC Triple negative breast cancer BC Breast Cancer T cell Scr-siRNAs Scrambled siRNAs NO Nitric oxide Article HLA-DR Human Leukocytic antigen DR PI3K/AKT signaling pathway 03 medical and health sciences Scr-miRNAs Scrambled microRNAs medicine lcsh:Science (General) Protein kinase B ComputingMethodologies_COMPUTERGRAPHICS LDH Lactate dehydrogenase Assay Nitric oxide 51Cr-release Chromium release assay miRNA MicroRNA Cystathionine beta synthase 030104 developmental biology NOS2 Inducible nitric oxide synthase-2 Cell culture Cancer research biology.protein CSE Cystathionine γ-lyase NOS3 Endothelial nitric oxide synthase-3 NKG2D Natural Killer Group 2D KD Knock down IFN-γ Interferon gamma lcsh:Q1-390 |
| Zdroj: | Journal of Advanced Research Journal of Advanced Research, Vol 27, Iss, Pp 177-190 (2021) |
| ISSN: | 2090-1232 |
| DOI: | 10.1016/j.jare.2020.07.006 |
| Popis: | Graphical abstract Introduction Hydrogen sulphide (H2S) has been established as a key member of the gasotransmitters family that recently showed a pivotal role in various pathological conditions including cancer. Objectives This study investigated the role of H2S in breast cancer (BC) pathogenesis, on BC immune recognition capacity and the consequence of targeting H2S using non-coding RNAs. Methods Eighty BC patients have been recruited for the study. BC cell lines were cultured and transfected using validated oligonucleotide delivery system. Gene and protein expression analysis was performed using qRT-PCR, western blot and flow-cytometry. In-vitro analysis for BC hallmarks was performed using MTT, BrdU, Modified Boyden chamber, migration and colony forming assays. H2S and nitric oxide (NO) levels were measured spectrophotometrically. Primary natural killer cells (NK cells) and T cell isolation and chimeric antigen receptor transduction (CAR T cells) were performed using appropriate kits. NK and T cells cytotoxicity was measured. Finally, computational target prediction analysis and binding confirmation analyses were performed using different software and dual luciferase assay kit, respectively. Results The H2S synthesizing enzymes, cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE), exhibited elevated levels in the clinical samples that correlated with tumor proliferation index. Knock-down of CBS and CSE in the HER2+ BC and triple negative BC (TNBC) cells resulted in significant attenuation of BC malignancy. In addition to increased susceptibility of HER2+ BC and TNBC to the cytotoxic activity of HER2 targeting CAR T cells and NK cells, respectively. Transcriptomic and phosphoprotein analysis revealed that H2S signaling is mediated through Akt in MCF7, STAT3 in MDA-MB-231 and miR-155/ NOS2/NO signaling in both cell lines. Lastly, miR-4317 was found to function as an upstream regulator of CBS and CSE synergistically abrogates the malignancy of BC cells. Conclusion These findings demonstrate the potential role of H2S signaling in BC pathogenesis and the potential of its targeting for disease mitigation. |
| Databáze: | OpenAIRE |
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