Multiomics analysis of ovarian cancer and disulfidptosis
OC is a gynecological malignancy associated with high mortality rates [17]. It generally affects middle-aged and elderly women and is often asymptomatic in the early stage. OC patients with an insidious onset are often diagnosed at an advanced stage due to lack of early diagnostic markers, which increases the risk of metastasis and worsens prognosis [18]. The current standard of care for OC is a combination of surgery and chemotherapy, which has achieved limited efficacy. Therefore, it is crucial to identify novel biomarkers for early screening, improved prognosis prediction and effective therapeutic intervention in OC patients. Disulfidptosis is a newly discovered mechanism of programmed cell death, which may be a promising alternative target for cancer treatment. The aim of this study was to screen for disulfidptosis-related biomarkers in OC in order to identify potential prognostic indicators and therapeutic targets.
Summary of major findings
In this study, we analyzed the bulk RNA-seq data of 378 OC patients from TCGA-OV cohort, and the single-cell RNA-seq data of 4 high-grade SOC patients from GSE154600. Based on the disulfidptosis score, the individual cells in SOC patients were divided into subgroups that displayed distinct features, especially in cell communication. Seven prognostic genes were screened to construct a risk score-based predictive model, which was verified in an external cohort. The risk score was significantly associated with the immune landscape of OC. The oncogene IL1B had the highest risk coefficient and was further validated in cellular and animal models of OC. These findings provide novel insights into the molecular mechanisms of OC.
Biological functions of IL1B
Interleukin-1β (IL1B) is an inflammatory cytokine that plays a pivotal role in the host defense against injury and infection [19]. The pro-IL1B protein is primarily synthesized by activated macrophages, and is converted to its active form following proteolytic cleavage by caspase 1 (CASP1/ICE). As an inflammatory response mediator, IL1B is involved in a diverse range of cellular functions such as proliferation, differentiation, and apoptosis [20]. It is also a key player in the reproductive system [21], and regulates the ovulation process [22]. When administered ex vivo, IL1B effectively induces ovulation and synergizes with luteinizing hormone (LH) [23]. Furthermore, inactivation of the IL-1 receptor antagonist (IL-1RA) diminished LH-dependent ovulation [24]. IL1B and type I IL-1 receptor (IL-1R), along with other components of the intraovarian IL-1 system, are expressed during a brief periovulatory window [25]. In addition, IL1B prompts a multitude of ovulation-associated responses in rats, including stimulation of ovarian hyaluronic acid biosynthesis, perturbation of plasminogen activator and activation of nitric oxide (NO) synthase in the ovary, and cessation of follicular atresia [26]. IL1B is upregulated at the transcriptional level in the KGN cells by IL-15, which is markedly elevated in the follicular fluid of patients with polycystic ovary syndrome (PCOS) [27]. The production of IL1B by breast cancer cells is associated with bone metastasis in both clinical cohorts and pre-clinical in vivo models [28]. Furthermore, IL-1B is the master regulator of breast tumor progression, and blocking IL1B can not only slow tumor growth but also facilitate checkpoint inhibition [29]. Taken together, IL1B has an important role in ovarian function and malignant transformation.
IL-1B as a possible therapeutic target in OC
Although IL1B is an established oncogene in many cancers [30–33], it has not been validated in OC so far. Our findings suggest that IL1B is an oncogene that promotes OC cell proliferation, migration and invasion. We will explore the role of IL1B in disulfidptosis in our subsequent study.
Limitations and future work
There are some limitations in this study that ought to be considered. First, the disulfidptosis-based model was constructed I the basis of in-silico data, and needs to be validated further in animal models and clinical studies. The specific mechanisms underlying the function of these model genes also need further clarification. Although we identified IL1B as an oncogene, the role of free IL1B in the extracellular matrix was not discussed.