RESUMEN
Ionizing radiation exposure can cause damage to diverse tissues and organs, with the hematopoietic system being the most sensitive. However, limited information is available regarding the radiosensitivity of various hematopoietic cell populations in the bone marrow due to the high heterogeneity of the hematopoietic system. In this study, we observed that granulocyte-macrophage progenitors, hematopoietic stem/progenitor cells, and B cells within the bone marrow showed the highest sensitivity, exhibiting a rapid decrease in cell numbers following irradiation. Nonetheless, neutrophils, natural killer (NK) cells, T cells, and dendritic cells demonstrated a certain degree of radioresistance, with neutrophils exhibiting the most pronounced resistance. By employing single-cell transcriptome sequencing, we investigated the early responsive genes in various cell types following irradiation, revealing that distinct gene expression profiles emerged between radiosensitive and radioresistant cells. In B cells, radiation exposure led to a specific upregulation of genes associated with mitochondrial respiratory chain complexes, suggesting a connection between these complexes and cell radiosensitivity. In neutrophils, radiation exposure resulted in fewer gene alterations, indicating their potential for distinct mechanisms in radiation resistance. Collectively, this study provides insights into the molecular mechanism for the heterogeneity of radiosensitivity among the various bone marrow hematopoietic cell populations.
Asunto(s)
Radiación Ionizante , Análisis de la Célula Individual , Transcriptoma , Animales , Ratones , Análisis de la Célula Individual/métodos , Transcriptoma/efectos de la radiación , Células de la Médula Ósea/efectos de la radiación , Células de la Médula Ósea/metabolismo , Ratones Endogámicos C57BL , Tolerancia a Radiación/genética , Perfilación de la Expresión Génica , Células Madre Hematopoyéticas/efectos de la radiación , Células Madre Hematopoyéticas/metabolismo , Neutrófilos/efectos de la radiación , Neutrófilos/metabolismoRESUMEN
Ferroptosis, a recently discovered type of programmed cell death triggered by excessive accumulation of irondependent lipid peroxidation, is linked to several malignancies, including nonsmall cell lung cancer. Long noncoding RNAs (lncRNAs) are involved in ferroptosis; however, data on their role and mechanism in cancer therapy remains limited. Therefore, the aim of the present study was to identify ferroptosisassociated mRNAs and lncRNAs in A549 lung cancer cells treated with RASselective lethal 3 (RSL3) and ferrostatin1 (Fer1) using RNA sequencing. The results demonstrated that lncRNA lung cancerassociated transcript 1 (LUCAT1) was significantly upregulated in lung adenocarcinoma and lung squamous cell carcinoma tissues. Coexpression analysis of differentially expressed mRNAs and lncRNAs suggested that LUCAT1 has a crucial role in ferroptosis. LUCAT1 expression was markedly elevated in A549 cells treated with RSL3, which was prevented by coincubation with Fer1. Functionally, overexpression of LUCAT1 facilitated cell proliferation and reduced the occurrence of ferroptosis induced by RSL3 and Erastin, while inhibition of LUCAT1 expression reduced cell proliferation and increased ferroptosis. Mechanistically, downregulation of LUCAT1 resulted in the downregulation of both GTP cyclohydrolase 1 (GCH1) and ferroptosis suppressor protein 1 (FSP1). Furthermore, inhibition of LUCAT1 expression upregulated microRNA (miR)34a5p and then downregulated GCH1. These results indicated that inhibition of LUCAT1 expression promoted ferroptosis by modulating the downregulation of GCH1, mediated by miR34a5p. Therefore, the combination of knocking down LUCAT1 expression with ferroptosis inducers may be a promising strategy for lung cancer treatment.