Dataset Information

Identification of Ferroptosis-Related Gene Prognostic Signature and HSF1 for Reversing Doxorubicin and Gemcitabine Resistance in Uterine Carcinosarcoma.

ABSTRACT:

Purpose

Iron metabolism and ferroptosis play crucial roles in the pathogenesis of cancer. In this study, we aim to study the role of ferroptosis-related genes (FRGs) in uterine carcinosarcoma (UCS) and identify potential target for UCS.

Methods

Prognostic differentially expressed FRGs were identified of in the TCGA cohort. Integrated analysis, cox regression, and the least absolute shrinkage and selection operator (LASSO) methods of FRGs were performed to construct a multigene signature prognostic model. Moreover, a dataset from Gene Expression Omnibus (GEO) served as an external validation. HSF1 was knockdown in MES-SA and FU-MMT-1 cells, and cell viability, lipid ROS, and intracellular iron level were detected when combined with doxorubicin or gemcitabine.

Result

Five FRGs were selected to construct a prognostic model of UCS. The group with high-risk signature score exhibited obviously lower overall survival (OS) than the group with low risk signature score in both TCGA and validated GEO cohorts. Multivariate Cox regression analysis further indicated that the risk score was an independent factor for the prognosis of UCS patients. The high-risk group of UCS has a higher sensitivity in the treatment of doxorubicin and gemcitabine. Knocking down of HSF1 in MES-SA and FU-MMT-1 cells was more sensitive to doxorubicin and gemcitabine via increasing ferroptosis.

Conclusions

The five FRGs risk signature prognostic model having a superior and drug sensitivity predictive performance for OS in UCS, and HSF1 is a potential marker sensitive to doxorubicin and gemcitabine in UCS patients.

SUBMITTER: Han S

PROVIDER: S-EPMC8769820 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:It is reported that ferroptosis has close relation with tumorigenesis and drug resistance. However, the clinical significance of ferroptosis in lung adenocarcinoma (LUAD) remains elusive, and the potential targets for ferroptosis-based treatment are limited. In this study, we constructed a 15-gene prognostic signature predicting overall survival based on ferroptosis-related genes (ferroptosis driver genes VDAC2, GLS2, FLT3, TLR4, PHKG2, phosphogluconate dehydrogenase (PGD), PANX1, KRAS, PEBP1, ALOX15, and ALOX12B, and suppressor genes ACSL3, CISD1, FANCD2, and SLC3A2) in The Cancer Genome Atlas (TCGA)-LUAD cohort. The signature's predictive ability was validated in the GSE68465 and GSE72094 cohorts by survival analysis and independent prognostic analysis with clinical features. Nomograms were provided for clinical reference. Functional analysis revealed that ferroptosis was closely related to cell cycle, cell metabolism, and immune pathways. Pan-cancer analysis comprehensively analyzed these 15 genes in 33 cancer types, indicating that the heterogeneity of 15 genes was evident across different cancer types. Besides, these genes were critical regulators modulating drug resistance, tumor microenvironment infiltration, and cancer stemness. Then, we screened 10 genes (TLR4, PHKG2, PEBP1, GLS2, FLT3, ALOX15, ACSL3, CISD1, FANCD2, and SLC3A2) as potential targets for further research because their biological functions in ferroptosis were consistent with their prognostic significance. Somatic mutation and copy number variation analysis revealed that the alteration rates of KRAS, PGD, and ALOX15 were more than 1% and significantly associated with overall survival in LUAD. Moreover, the expression of KRAS and PGD was positively related to tumor mutation burden, indicating that KRAS and PGD could serve as novel biomarkers for predicting immunotherapy response rate. Our study identified and validated a ferroptosis-related gene signature for LUAD, provided a 10-gene set for future research, and screened KRAS and PGD as potential novel immunotherapy biomarkers.