Identification of a Ferroptosis-Related Prognostic Gene PTGS2 Based on Risk Modeling and Immune Microenvironment of Early-Stage Cervical Cancer

Abstract

Background. Cervical cancer (CC) has long been a concern, as a gynecological cancer type of high-risk. At present, there are few studies on the early detection of CC at the genetic level. The breakthrough is to recognize CC patients tending to have a worse prognosis by checking the expression pattern of ferroptosis-related genes, which enjoy a great potential of being applied to cancer treatment. Methods. Data used in this study was obtained from a series of public online databases, integrated with ferroptosis-related gene collection stored from the FerrDb database and GeneCards database. The least absolute shrinkage and selection operator- (LASSO-) penalized analysis was taken for modeling, and before, univariate Cox regression analysis got done to shrink the candidates’ range. Several analyses were made for the evaluation of the efficacy of the new model, based on CC patients’ overall survival (OS). Tumor microenvironment- (TME-) related analyses were conducted by various algorithms on different populations, comprising CIBERSORT, ssGSEA, XCELL, etc. Nonnegative matrix factorization (NMF) clustering got applied to find that ferroptosis-marker genes affect prognosis more than “driver” and “suppressor”. Hub-gene PTGS2 was screened out by protein-protein interaction analysis and real-time qPCR after ferroptosis induction, and ELISA was conducted for further verification on the correlation between ferroptosis and M1 polarization. Results. The twenty-five ferroptosis-related genes model can estimate the prognosis of patients independently of other clinical factors, and the low-risk score group shows higher expression of immune-enhancing cells, noteworthily for M1 macrophages. It is experimentally validated that the M1 marker TNF-α significantly increased after coculturing M1 macrophages and SiHa cells processed with ferroptosis inductor before. The key gene to the model, PTGS2, presented to be a risk factor in cervical cancer, and its low-expression group has stronger immune activity and higher tumor mutation burden, with the significantly highly mutated gene TENM2 in it showing high drug sensitivity and neoantigen for patients with its mutant-type. Meanwhile, it influences macrophage polarization. Conclusion. Prognosis of early-stage cervical cancer patients can be exactly predicted on ferroptosis-related genes. Among model genes, PTGS2 may have a major impact by affecting macrophage polarization and mutation effects.

EPAS1, a hypoxia‐ and ferroptosis‐related gene, promotes malignant behaviour of cervical cancer by ceRNA and super‐enhancer

“…Hypoxia induces resistance to ferroptosis in cervical cancer cells 59 . D‐mannose alleviates osteoarthritis progression via EPAS1 through ferroptosis 60 . EPAS1 promotes ferroptosis via hypoxia‐related genes in clear cell carcinomas 52,53 .…”

“… 59 D‐mannose alleviates osteoarthritis progression via EPAS1 through ferroptosis. 60 EPAS1 promotes ferroptosis via hypoxia‐related genes in clear cell carcinomas. 52 , 53 Therefore, studying HFRGs is important for clarifying the malignant biological behaviour of cervical cancer.…”

Ferroptosis: Mechanism and potential applications in cervical cancer

“…Jiang et al established a new predictive model that integrated 7 lncRNAs related to ferroptosis through analysis, which improve the predictive value and guided personalized treatment in patients with CC ( Jiang et al, 2022 ). In the study by Zou et al, the ferroptosis-related gene PTGS2 turned out to be a key prognostic gene for an early-stage CC model associated with the immune microenvironment ( Zou et al, 2022 ). Li et al established a ferroptosis score (FerroScore) that was used to predict the sensitivity to chemotherapy and responses to immunotherapy in patients with CC.…”

Comprehensive transcriptomic and metabolomic analyses reveal the link between ferroptosis and gut microbiota in CRC

“…It has been reported that in head and neck squamous cell carcinoma, ferroptosis and growth inhibition induced by xCT knockdown or the ferroptosis inducer elastin can be reversed by IL-6, thereby promoting tumorigenesis and progression [31]. In cervical cancer, the PTGS2 low expression group has stronger immune activity and higher tumor mutation burden, which is considered to be a risk factor for cervical cancer [32]. Xiao et al demonstrated that NOX4 expression was up-regulated in gastric adenocarcinoma tissue compared with normal gastric mucosal tissue, which can serve as an effective therapeutic target and biomarker for gastric adenocarcinoma [33].…”