RESUMEN
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.
Asunto(s)
Regulación hacia Abajo , Ferroptosis , GTP Ciclohidrolasa , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares , MicroARNs , ARN Largo no Codificante , Humanos , Ferroptosis/genética , MicroARNs/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Células A549 , GTP Ciclohidrolasa/genética , GTP Ciclohidrolasa/metabolismo , Proliferación Celular , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Masculino , Línea Celular Tumoral , Femenino , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/patología , Adenocarcinoma del Pulmón/metabolismoRESUMEN
Long-term exposures to low-dose radiation (LDR) may trigger several specific biological responses, including dysregulation of the immune and inflammatory systems. Here, we examined whether biodosimetry of LDR can be used to protect tissues from radiation or assess cancer risk. Mice were subjected to gamma-irradiation with repeated or single-dose LDR, and then the organ indices, peripheral hemogram, and blood biochemistry were analyzed. An antibody array was applied followed by enzyme-linked immunosorbent assay to evaluate the utility of multiple plasma proteins as biomarkers of repeated LDR in a murine model. LDR induced inapparent symptoms but slight variations in peripheral blood cell counts and alterations in blood biochemical indicator levels. Specific plasma proteins in the LDR groups were altered in response to a higher dose of irradiation at the same time points or a single-dose equivalent to the same total dose. Plasma levels of interleukin (IL)-5, IL-12p40, P-selectin, and serum amyloid A1 were associated with the LDR dose and thus may be useful as dosimetric predictors of LDR in mice. Estimating the levels of certain plasma proteins may yield promising biodosimetry parameters to accurately identify individuals exposed to LDR, facilitating risk assessment of long-term LDR exposure in individuals.