Identification and validation of a novel ferroptosis-related gene signature for prognosis and potential therapeutic target prediction in cholangiocarcinoma.
Front Immunol
; 13: 1051273, 2022.
Article
em En
| MEDLINE
| ID: mdl-36733386
ABSTRACT
Cholangiocarcinoma (CCA) is a highly heterogeneous and aggressive malignancy of the bile ducts with a poor prognosis and high mortality rate. Effective targeted therapy and accurate prognostic biomarkers are still lacking. Ferroptosis is a form of regulated cell death implicated in cancer progression and has emerged as a potential therapeutic target in various cancers. However, a comprehensive analysis of ferroptosis-related genes (FRGs) for predicting CCA prognosis and therapeutic targets and determining the role of ferroptosis in CCA remain to be performed. Here, we developed a prognostic FRG signature using a least absolute shrinkage and selection operator Cox regression analysis in a training cohort. We then validated it using four independent public datasets. The six-FRG signature was developed to predict CCA patient survival, stratifying them into low-risk and high-risk groups based on survival time. Significantly, the high-risk CCA patients had shorter overall survival. A receiver operating characteristic curve analysis further confirmed the prognostic FRG signature's strong predictive ability, indicating that it was an independent prognostic indicator for CCA patients. Furthermore, the high-risk group was associated with fluke infection and high clinical stages. Cancer-associated fibroblast (CAF) score and CAF markers were significantly higher in the high-risk group than the low-risk group. Moreover, our FRG signature could predict immune checkpoint markers for immunotherapy and drug sensitivity. The mRNA expression levels of the six-FRG signature was validated in 10 CCA cell lines and dividing them into low-risk and high-risk groups using the FRG signature. We further showed that high-risk CCA cell lines were more resistant to ferroptosis inducers, including erastin and RSL3, than the low-risk CCA cell lines. Our study constructed a novel FRG signature model to predict CCA prognoses which might provide prognostic biomarkers and potential therapeutic targets for CCA patients. Ferroptosis sensitivity in high-risk and low-risk CCA cell lines suggests that ferroptosis resistance is associated with high-risk group CCA. Therefore, ferroptosis could be a promising therapeutic target for precision therapy in CCA patients.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias dos Ductos Biliares
/
Colangiocarcinoma
/
Ferroptose
Tipo de estudo:
Diagnostic_studies
/
Prognostic_studies
/
Risk_factors_studies
Limite:
Humans
Idioma:
En
Revista:
Front Immunol
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Tailândia