Cytokine

The potential role of interleukins and interferons in ovarian cancer

Ovarian cancer poses significant challenges and remains a highly lethal disease with limited treatment options. In the context of ovarian cancer, interleukins (ILs) and interferons (IFNs), important cytokines that play crucial roles in regulating the immune system, have emerged as significant factors influencing its development. This article provides a comprehensive review of the involvement of various ILs, including those from the IL-1 family, IL-2 family, IL-6 family, IL-8 family, IL-10 family, and IL-17 family, in ovarian cancer. The focus is on their impact on tumor growth, metastasis, and their role in evading immune responses within the tumor microenvironment. Additionally, the article conducts an in-depth examination of the oncogenic or antitumor roles of each IL in the context of ovarian cancer pathogenesis and progression. Besides, we elucidated the enhancements in the treatment of ovarian cancer through the utilization of type-I IFN and type-II IFN. Recent research has shed light on the intricate mechanisms through which specific ILs and IFNs contribute to the advancement of the disease. By incorporating recent findings, this review also seeks to inspire further investigations into unexplored mechanisms, fostering ongoing research to develop more effective therapeutic strategies for ovarian cancer. Moreover, through an in-depth analysis of IL- and IFN-associated clinical trials, we have highlighted their promising potential of in the treatment of ovarian cancer. These clinical trials serve to reinforce the significant outlook for utilizing ILs and IFNs as therapeutic agents in combating this disease.

Long non-coding RNA Linc00657 up-regulates Skp2 to promote the progression of cervical cancer through lipid reprogramming and regulation of immune microenvironment

More and more evidence shows that long non-coding RNA (lncRNA) plays an important role in the biological behavior of many kinds of malignant tumors, but the specific function of lncRNA Linc00657 in cervical cancer is still unknown. The purpose of this study is to explore the effect of Linc00657 on the malignant progression of cervical cancer and its potential mechanism. In two kinds of cervical cancer cell lines and normal cervical epithelial cells, qRT-PCR showed increased expression of Linc00657 in cervical cancer cells. Through MTT, clone formation test, flow cytometry, wound healing test and Transwell test, it has been found that overexpression of Linc00657 could promote the proliferation,migration and invasion of cervical cancer cells，and inhibit apoptosis. Through the StarBase database, it was found that there may be a mutual regulatory relationship between Linc00657 and Skp2, and Skp2 may be the downstream target of Linc00657. QRT-PCR detection confirmed that the expression of Skp2 was increased in cervical cancer cells with overexpression of Linc00657. TIMER2 database found that Skp2 was associated with lipid metabolic enzymes and immune cell infiltration. It was found that Linc00657 knockdown inhibited tumor growth and metastasis and inhibited the expression of Skp2 in vivo. In short, our research shows that Linc00657 has carcinogenic properties in cervical cancer, and LINC00657 promotes the occurrence of cervical cancer by up-regulating the expression of Skp2. We predict that Linc00657/mir30s/Skp2 axis plays a role in the malignant progression of cervical cancer. In addition, Skp2 may participate in cancer immune response and promote lymph node metastasis of cervical cancer through lipid reprogramming. These findings also provide promising targets for the diagnosis and treatment of cervical cancer.

An association of circulating Tregs and Th17 cells producing IL-21 and IL-22 with the ROMA in ovarian cancer patients

The purpose of the present study was to assess the association of regulatory T cells (Tregs; CD4

Identification of two theranostic biomarker panels for epithelial ovarian cancer

Epithelial Ovarian cancer (EOC) is the leading cause of death associated with gynecologic tumors. Because the disease is asymptomatic in early-stage, the majority of patients are not diagnosed until late stages, highlighting the need for the development of novel diagnostic biomarkers. Mediators of tumoral microenvironment may affect EOC progression and resistance to treatment. Analysis of serum proteins to identify a panel of theranostic biomarkers for EOC. Serum levels of 65 analytes were determined in EOC patients, and healthy controls with the ProcartaPlex Human Immune Monitoring 65-Plex Panel. Twenty-one analytes: 7 cytokines (IFN-γ, IL-12p70, IL-13, IL-18 and TSLP), 7 chemokines (Eotaxin, eotaxin-2, IP-10, BLC, I-TAC, SDF-1α, and fractalkine), 2 growth factors (MMP-1, VEGF-α), and 5 soluble receptors (APRIL, CD40L, TWEAK, CD30 and TNFRII; were significantly differentially expressed between the two groups. ROC curves showed that only seven of them (IL-9, TNF-α, Eotaxin, IP-10, BLC, Fractalkine, and Tweak) had AUC values greater than 0.70 and thus had potential clinical utility. Moreover, five cytokines: IFN-γ, IL-1 β, IL-8, MIP-1β, and TNF-α are positively associated with patients who developed resistance to taxol-platinum-based chemotherapy (CT). This study has revealed a first panel of 7 analytes (IL-9, TNF-α, Eotaxin, IP-10, BLC, Fractalkine and Tweak) that can be used for early detection of EOC and a second panel of five cytokines (IFN-γ, IL-1β, IL-8, MIP-1β, TNF-α) that can help clinicians to identify EOC patients who are at higher risk to develop resistance to CT of EOC.

Meta-analyses reveal serum or plasma Interleukin-6 as a biomarker for malignant ovarian neoplasia

Interleukin-6 (IL-6) has been implicated in various malignancies, including ovarian cancer. However, mixed results have been observed regarding IL-6 levels in different ovarian conditions. This meta-analysis was performed to determine IL-6 levels in the peritoneal fluid and peripheral blood among patients with various adnexal masses. Most popular English databases were searched using a predefined search formula. All studies comparing IL-6 levels in plasma, serum or peritoneal fluid of patients with benign tumors, ovarian neoplasms, and healthy controls were included based on inclusion and exclusion criteria. 5953 patients from 22 primary publications raging from 1994 to 2021 were included in the meta-analyses. A pooled IL-6 Mean Difference (MD) of 41 pg/mL for malignant tumors compared to benign ones, with a Confidence Interval (CI) between 19.8 and 62.2, a Z-score of 3.79, and statistical significance with a p = 0.0002 was observed. Pooled results for healthy versus benign ovarian conditions showed an MD of 5.45 pg/mL for serum or plasma IL-6 measurements in favor of benign tumors (CI:0.66-10.25, Z = 2.23 and p = 0.03). The analysis showed an MD for IL-6 levels of 19.59 pg/mL for healthy controls versus malignant ovarian tumors. Peritoneal fluid measurements regarding IL-6's levels showed no significant difference between benign or malignant masses. Higher levels of plasma or serum IL-6 in ovarian neoplasia patients compared to benign conditions or healthy controls identify IL-6 as a discerning factor between benign or malignant ovarian tumors and a potential biomarker for ovarian malignancy.

Prioritization and Meta-analysis of regulatory SNPs identified IL6, TGFB1, TLR9 and MMP7 as significantly associated with cervical cancer

Cervical cancer is a leading women cancer globally with respect to both incidence and mortality. Its increased risk has been linked with HPV infection and genetic variations like single nucleotide polymorphisms (SNPs). Although, studies have been published which evaluates the effect of SNPs in a few candidate genes, however the role of number of regulatory SNPs (rSNPs) in cervical cancer is not available. As literature evidence has shown that non-coding rSNPs are related with increasing cervical cancer risk, we undertook this study to prioritize the important rSNPs and elucidate their role. A search was conducted in PubMed up to December 2020, which led to the identification of 263 articles and 969 SNPs in the non-coding region. These 969 SNPs were analysed through rSNPBase and RegulomeDB, leading to identification of 105 rSNPs. Afterwards, a regulatory module was constructed using protein-protein interaction data and a hub of highly interacting 23 target genes (corresponding to 34 rSNPs) was identified using MCODE. To further understand the mechanism of action of the 34 rSNPs, their transcription factor information with respect to cervical cancer was retrieved. To evaluate the pooled effect of these prioritized polymorphisms in cervical cancer patients, a meta-analysis was performed on 10,537 cases and 11,252 controls from 30 studies corresponding to 8 rSNPs. It led to identification of polymorphisms in IL6 (rs2069837), TGFB1 (rs1800469), TLR9 (rs187084) and MMP7 (rs11568818) which are significantly (p < 0.05) associated with increased cervical cancer risk at the population level. Overall, the study demonstrates that rSNPs targeting immune and inflammatory genes (IL1B, IL6, IL10, IL18, TGFB1, CCR5, CD40, TLR9, and MMP7) are associated with cervical cancer.

Inflammation and thrombotic risk in late-stage cervical cancer: An exploratory study of coagulation and cytokine profiles in a South African cohort

This exploratory study investigates the possible relationship between inflammation and thrombosis in cervical cancer patients in South Africa, highlighting the need for improved thrombotic risk profiling. Thromboelastography (TEG) was used to assess coagulation parameters in platelet-poor plasma (PPP) from a small cohort of late-stage (III and IV) cervical cancer patients (n = 19) and healthy controls (n = 15). Parameters assessed included clotting time, clot formation speed, and clot strength. A Luminex Multiplex assay was used to measure interferon-γ (IFN-γ), interleukin-1β (IL-1β), IL-6, vascular endothelial growth factor-A (VEGF-A), and tumour necrosis factor-α (TNF-α) in PPP. Haematological profiles were also evaluated. Cervical cancer patients displayed a significantly shortened clotting time (p = 0.0044) and increased clot strength (p = 0.0003), suggesting enhanced coagulation. IL-1β was notably elevated (p = 0.0200), consistent with an inflammatory environment. Higher lymphocyte, neutrophil, and platelet counts (p = 0.0162, 0.0420, and 0.0374, respectively) were observed, indicating a possible prothrombotic state. These findings suggest a potential link between inflammation and thrombosis in cervical cancer patients. However, due to this study's small sample size and exploratory nature, direct relationships between these factors have yet to be definitively established and remain speculative. Thrombotic risk profiling may still offer value in managing patients, but further investigation is required to confirm these preliminary observations.

Inhibition of adenosine deaminase activity reverses resistance to the cytotoxic effect of high adenosine levels in cervical cancer cells

Adenosine (ADO) generation in the tumor microenvironment (TME) plays important roles in the promotion of tumor growth, invasion, and metastasis and in suppression of the antitumor immune response. Recently, adenosine deaminase (ADA) activity in the TME has been proposed to be a compensatory mechanism against toxic accumulation of ADO in cancerous tissues. In the present study, the expression and functional activity of ADA in cervical cancer (CeCa) tumor cells were analyzed: C33A (HPV-), CaSki (HPV + ), and HeLa (HPV + ) cells. CeCa tumor cells, as well as activated T lymphocytes (ATLs), which were used as a positive control, showed different ADA contents in the membrane and intracellularly and a strong ability to convert ADO into inosine (INO). Treatment of tumor cells with EHNA, a specific ADA inhibitor, decreased the viability of CeCa tumor cells in a dose-dependent manner. In C33A (EHNA half maximal inhibitory concentration (IC

Resveratrol interrupts Wnt/β-catenin signalling in cervical cancer by activating ten-eleven translocation 5-methylcytosine dioxygenase 1

Epigenetic modification can be a key weapon employed by both sides of the battle between Cervical Cancer progression due to persistent high-risk papillomavirus (hr-HPV) infection and the development of anti-cancer modalities. Alongside the overactivated Wnt/β-catenin activity, reduced TET1 expression and ratio of 5-hydroxymethylcytosine (5hmC) to 5-methylcytosine (5mC) were found in cervical cancer, which was correlated with lymph node metastasis. After treating cervical cancer cells with Resveratrol (RES), we found that TET1 expression was elevated and Wnt/β-catenin pathway activity was suppressed. Therefore, the aim of this study is to investigate the influence of resveratrol on the TET1 and Wnt/β-catenin pathways, and to elucidate the molecular mechanisms involved in this process, thereby clarifying the potential value of RES in the treatment of cervical cancer. Our data illustrate the TET1-mediated epigenetic modulation was an integral part of the effects of RES on the Wnt/β-catenin pathway in cervical cancer.

Evidence that the viral oncoproteins E6 and E7 of HPV induce the expression of a functional IL-2R on cervical cancer cells

HPV-positive (HPV+) cervical cancer (CC) cells have been reported to express the IL-2 receptor (IL-2R) in contrast to virus-negative CC cells. This work was carried out to evaluate whether HPV infection induces IL-2R expression in CC cells. The analysis of the IL-2R expression data collected from The Cancer Genome Atlas (TCGA) and Genotype Tissue Expression project (GTEx) using the Xena platform demonstrate a higher expression of IL-2R subunits in CC tumors in comparison with normal tissues. Moreover IL-2Rβ expression is consistently higher in HPV+ tumors versus HPV- tumors. Furthermore, it was demonstrated that transfection of the HPV E6/E7 genes into the C33A (HPV-) cell line promotes IL-2R expression and regulates proliferation in response to exogenous IL-2. Additionally, we found that HPV+ cell lines enhances their proliferation in co-culture with peripheral blood lymphocytes (PBLs). To corroborate that the viral proteins E6 and E7 were related to the effects mediated by IL-2, we used cells derived from the HeLa cell line in which the expression of E6/E7 has decreased, we found that it loses the ability to respond to the exogenous IL-2 stimuli. Finally, the importance of IL-2R in CC, as an immune escape mechanism, is discussed.

Prognostic value and clinical significance of IL-33 expression in patients with uterine corpus endometrial carcinoma

Uterine corpus endometrial carcinoma (UCEC) is one of the most common malignant tumours of the female genital tract. In the occurrence, progression and prognosis of UCEC, chronic inflammation plays an important role, making it pivotal to identify inflammatory response-related endometrial diseases. The cytokine interleukin-33 (IL-33) plays significant roles in immune responses, and has been associated with inappropriate allergic reactions, autoimmune diseases, and cancer pathology. In the past decade, studies have begun to uncover the pivotal roles of IL-33 in shaping tumour microenvironment (TME), where it may promote or inhibit tumorigenesis and development depending on the specific tumour types. However, the association between IL-33 expression and UCEC remains unclear. Here we investigated the expression profiles of IL-33 in pan-cancer based on TCGA database. Then, differential gene expression analysis and correlation analysis of IL-33 was investigated in UCEC. In addition, functional enrichment analysis and Kaplan-Meier survival analysis were performed to predict the potential function of IL-33 and its role in the prognosis of UCEC patients. Also, a nomogram model was constructed to predict the prognosis of UCEC. The expression of the inflammatory factor NF-κB p65 and the IL-33, along with its receptor ST2, was analyzed in UCEC tumour tissues and normal tissues of clinical specimens through immunohistochemical staining. Meanwhile, we used toluidine blue staining and methanol Congo red staining to observe the infiltration of mast cells and eosinophils in the endometrial tissue. The results of Kaplan-Meier plotter data indicated that patients with lower IL-33 expression had poorer progression-free interval than those with higher expression. Based on the results of multifactor Cox regression, a nomogram was generated to predict UCEC occurrence risk and prognosis. Clinical specimen characteristics also confirmed a negative correlation between IL-33 expression and UCEC staging and grading. This comprehensive analysis of IL-33, based on bioinformatics and immunohistochemistry, revealed that IL-33 has the function of inhibiting UCEC occurrence and progression and can be served as a beneficial prognostic marker in the clinic.