Abstract
Objective: This study aimed to explore ferroptosis-related mRNAs as potential therapeutic targets for ovarian cancer treatment.Methods: Molecular subtypes were classified based on ferroptosis-related mRNAs via ConsensusClusterPlus package. The differences in prognosis, stromal score, immune score, immune function, and immune checkpoints were assessed between subtypes. Small molecular drugs were predicted via the CMap database. The sensitivity to chemotherapy drugs was estimated through the GDSC. A LASSO Cox regression model was conducted via the glmnet package, followed by a nomogram model.Results: Based on ferroptosis mRNA expression profile, two molecular subtypes (C1 and C2) were classified, with distinct clinical outcomes. C1 subtype exhibited higher stromal score, immune cell score (T helper, Treg, neutrophil) and immune function (APC co-inhibition, parainflammation and Type II IFN response). Higher mRNA expression levels of immune checkpoints (like PDCD1) were found in C1 than C2. Potential small molecular drugs (PI3K and mTOR inhibitors) were found for treatment of ovarian cancer. C1 was more sensitive to eight chemotherapy drugs (A.443654, AZD.0530, AZD6482, AZD7762, AZD8055, BAY.61.3606, Bicalutamide, and CGP.60474). A 15-ferroptosis-related mRNA signature was developed, which could robustly and independently predict the outcomes. Moreover, a nomogram was established combining the signature and age, which could intuitively and accurately predict the 5-year overall survival probability.Conclusion: Our study characterized two ferroptosis-related subtypes with distinct prognosis and tumor immune features, which could assist clinicians make decisions and individual therapy. Moreover, 15 ferroptosis-related mRNAs were identified, which could become potential therapeutic targets for ovarian cancer.
Highlights
Ovarian carcinoma is a highly lethal gynecological malignancy globally (1)
This study classified molecular subtypes based on the expression profiles of ferroptosis-related mRNAs in ovarian cancer via the ConsensusClusterPlus package in the The Cancer Genome Atlas (TCGA) ovarian cancer dataset
We found that CDKN1B, FAS, FOS, FOXO1, GABARAPL1, HDAC1, NFKB1, PEX3, PPP1R15A, and SIRT2 were all significantly lowly expressed in ovarian cancer than normal specimens (Figures 8A–J)
Summary
Ovarian carcinoma is a highly lethal gynecological malignancy globally (1). Because early symptoms are rare, ovarian cancer is usually diagnosed as advanced, partly leading to unfavorable clinical outcomes, with a 5-year overall survival (OS) of 45% (2). Recent findings demonstrate that ferroptosis, a novel cell death type with an iron-dependent mechanism, may participate in cancer progression (5). Activation of ferroptosis remarkably suppresses the proliferative capacity of ovarian cancer cells (6), indicating that inducing ferroptosis is a promising therapeutic strategy for ovarian cancer. Recent research has found that ferroptosis can be activated by TAZ-ANGPTL4-NOX2 axis for ovarian cancer, which provides a ferroptosis-inducing therapeutic implication (2). Immunotherapy such as immune checkpoint inhibitors has been applied in the treatment of ovarian cancer (7). CD8 + T cells induce tumor ferroptosis in immunotherapy (9). The roles and prognostic values of ferroptosis mRNAs remain to be illustrated in ovarian cancer
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