The Role of Ferroptosis-Related Molecules and Significance of Ferroptosis Score in Cervical Cancer

Abstract

Background. Ferroptosis, a form of cell death driven by iron-dependent lipid peroxidation, may be a potential treatment for many cancers, including cervical cancer (CC). However, the regulation of long noncoding RNAs (lncRNAs) in the process of ferroptosis and whether ferroptosis inducers could increase the cytotoxicity of conventional chemotherapy drugs remain to be further elucidated. Methods. We analyzed the variation of 55 differentially ferroptosis-related genes (FRGs) and the influence of mutations in CC patients. The patients with CC were classified into two ferroptosis clusters by the non-negative matrix factorization (NMF) algorithm. The principal components analysis (PCA) was used to measure the ferroptosis score (FerroScore) in patients with CC. Besides, FerroScore was used to predict the sensitivity of chemotherapy and responses to immunotherapy in patients with CC. Finally, experiments were performed to verify the regulatory effect of AC026790.1 on erastin-induced ferroptosis, as well as the effect of erastin in combination with cisplatin on the toxicity of CC cells (SiHa, HeLa). Result. There were significant differences in the overall survival and immune cell infiltration between the two ferroptosis clusters. Patients with low FerroScore were more sensitive to chemotherapy drugs such as cisplatin and docetaxel. The low-FerroScore group had higher CD8+ T cell infiltration and immune checkpoint expression, demonstrating that patients with lower FerroScores were more sensitive to immunotherapy, which was consistent with the result of the submap method. In vitro, overexpression of AC026790.1 could promote erastin-induced ferroptosis, and the combination of erastin and cisplatin could increase the toxicity of CC cells. Conclusion. FerroScore has a potential prognostic value for CC that may provide a reference for chemotherapy and immunotherapy. LncRNA AC026790.1 can influence ferroptosis, and the combination of ferroptosis inducers and chemotherapy drugs can provide a new perspective on cancer treatment.

Effects of BRD4 inhibitor JQ1 on the expression profile of super-enhancer related lncRNAs and mRNAs in cervical cancer HeLa cells

“…Although some lncRNAs are well characterized functionally, the vast majority of such molecules remain functionally uncharacterized. According to different functional modules, lncRNAs can be finely classified into immune-related lncRNAs ( Ye, Chen & Lu, 2021 ; Zheng et al, 2020 ), ferroptosis-related lncRNAs ( Jiang et al, 2022 ; Li et al, 2022 ), metabolism-related lncRNAs ( Lang, Huang & Cui, 2022 ; Lu et al, 2022 ), etc . Further, we speculated that super-enhancer-associated lncRNAs might be involved in this regulatory mechanism and were significantly regulated by enhancers, especially super-enhancers (SEs) ( Bian et al, 2021 ; Peng et al, 2022 ; Wang et al, 2020 ; Yan et al, 2021 ).…”

The dual role of ferroptosis in anthracycline-based chemotherapy includes reducing resistance and increasing toxicity

“…In contrast to the high-risk group, the low-risk group presented with higher sensitivity and better efficacy to multiple chemotherapeutic agents [93]. Similarly, Li et al [94] and Liu et al [95] also identified the predictive value of ferroptosis-related gene expression levels for chemotherapy sensitivity in cervical cancer and endometrial cancer, respectively. In the management of cervical cancer, the reduction of ROS could attenuate the cytotoxicity of DOX [96], while the upregulation of GSH-related genes represented by glutathione S-transferases M1 and Alpha 1-3 (GSTM1 and GSTA1-3), enzyme activities and transporter proteins may be crucial factors leading to the development of DOX resistance in cervical cancer cells [97].…”

Ferroptosis contributes to the progression of female-specific neoplasms, from breast cancer to gynecological malignancies in a manner regulated by non-coding RNAs: Mechanistic implications

“…This observation suggests that low-FerroScore patients may benefit more from checkpoint blockade therapy, which is consistent with the predictions of the submap algorithm. It has been proposed that combining immune checkpoint inhibitors with ferroptosis inducers could be a promising therapeutic strategy, leading to the development of novel combination therapies and immunotherapeutic agents [ 205 ].…”

“…Of these lncRNAs, AC026790.1 underwent additional validation in multiple ferroptosis-related experiments. Ferroptosis-related markers such as MDA, Fe 2+ , and ROS levels are found to increase in cells overexpressing AC026790.1 in comparison to the control group, indicating that AC026790.1 promotes erastin-induced ferroptosis [ 205 ]. The results show that AC026790.1 may be an important molecule in controlling ferroptosis in CC and may represent a viable target for CC treatment.…”