RESUMO
Blocking immune checkpoint CD47/SIRPα is a useful strategy to engineer macrophages for cancer immunotherapy. However, the roles of CD47-related noncoding RNA in regulating macrophage phagocytosis for lung cancer therapy remain unclear. This study aims to investigate the effects of long noncoding RNA (lncRNA) on the phagocytosis of macrophage via CD47 and the proliferation of non-small cell lung cancer (NSCLC) via TIPRL. Our results demonstrate that lncRNA KCTD21-AS1 increases in NSCLC tissues and is associated with poor survival of patients. KCTD21-AS1 and its m6A modification by Mettl14 promote NSCLC cell proliferation. miR-519d-5p gain suppresses the proliferation and metastasis of NSCLC cells by regulating CD47 and TIPRL. Through ceRNA with miR-519d-5p, KCTD21-AS1 regulates the expression of CD47 and TIPRL, which further regulates macrophage phagocytosis and cancer cell autophagy. Low miR-519d-5p in patients with NSCLC corresponds with poor survival. High TIPRL or CD47 levels in patients with NSCLC corresponds with poor survival. In conclusion, we demonstrate that KCTD21-AS1 and its m6A modification promote NSCLC cell proliferation, whereas miR-519d-5p inhibits this process by regulating CD47 and TIPRL expression, which further affects macrophage phagocytosis and cell autophagy. This study provides a strategy through miR-519-5p gain or KCTD21-AS1 depletion for NSCLC therapy by regulating CD47 and TIPRL.
Assuntos
Adenina , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , MicroRNAs , RNA Longo não Codificante , Humanos , Adenina/análogos & derivados , Autofagia/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Antígeno CD47/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Peptídeos e Proteínas de Sinalização Intracelular , Neoplasias Pulmonares/patologia , Macrófagos/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Fagocitose , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismoRESUMO
A series of bis-naphthalimide derivatives with different diamine linkers were designed and synthesized. All of the synthesized bis-naphthalimide derivatives were characterized by NMR and HRMS spectra. The binding ability between the compounds and CT DNA was evaluated by using UV-Vis titration experiments. The bis-naphthalimide compound with an ethylenediamine linker showed the largest binding constant with CT DNA. Hence, it was used as the model compound to study the DNA binding selectivity by UV-Vis titration aiming at different DNA duplexes. As a result, this compound showed binding preference to AT-rich duplexes. The DNA binding modes of the compounds were also measured by viscosity titration. The cytotoxicity of the compounds was evaluated by MTT assay. Compounds with 1,6-diaminohexane or 1,4-phenylenedimethanamine linkers showed higher cytotoxicity compared with other bis-naphthalimide derivatives.