Yunyan Zhang

Assessment of cancer-associated fibroblast signature genes in ovarian cancer patients: impact on immunity, drug resistance, and prognosis

Ovarian cancer (OC) is women's third most common gynecologic tumor and is highly lethal. Cancer-associated fibroblasts (CAFs) are associated with cancer at all stages of disease progression and are involved in biological processes, including inflammatory processes, tumor development occurrence, and immune rejection. This study aimed to construct prognosis-related CAFs regulatory factors to predict the survival of OC patients. Datasets of OC patients with complete clinical information were collected from the Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA) databases. First, we identified potential regulator factors of CAFs in OC based on the xCell algorithm and weighted gene co-expression analysis (WGCNA). Further screening using one-way cox regression analysis and LASSO regression models yielded 22 prognosis-related CAFs regulatory factors, using which a model was constructed. Subsequently, the diagnostic effectiveness of the model was assessed using receiver operating characteristic (ROC) curves, and the validity of the CAFs regulatory factors survival model was verified in three additional independent datasets and single cell data. Meanwhile, experimental validation was conducted using immunohistochemistry and Western blot. The results showed that GAS1 (Growth arrest specific 1) exhibited a higher expression pattern in fibroblasts from ovarian cancer patients. The assessment of resistance and immune checkpoint differences across various risk score groups indicates that the CAFs regulatory factor survival model is practical for guiding systemic treatment. In summary, this study establishes a prognostic model composed of 22 CAFs regulatory factors to predict the prognosis of ovarian cancer (OC), providing new perspectives for the clinical treatment of OC.

Excavation of Molecular Subtypes of Cervical Cancer Based on DNA Methylation Patterns

Background: Cervical cancer remains a major cause of cancer-related death among women worldwide. Despite advances in treatment, prognosis remains poor for many patients due to tumor heterogeneity. DNA methylation, an epigenetic modification, is known to influence tumor development, but its role in defining molecular subtypes and prognostic stratification in cervical cancer remains inadequately understood. Methods: We analyzed DNA methylation profiles from 287 cervical cancer samples obtained from the UCSC Xena database. Univariate and multivariate Cox regression analyses were applied to identify prognostic CpG sites, as these models allow evaluation of individual and combined effects of methylation sites on patient survival. Consensus clustering was performed to define robust molecular subtypes based on methylation patterns, providing insights into tumor heterogeneity. Differentially methylated regions were identified using the Quantitative Differentially Methylated Regions (QDMR) software, an entropy-based tool validated for detecting subtype-specific methylation markers. A Bayesian classifier was constructed and validated in training and test cohorts to evaluate the predictive accuracy of these markers for subtype classification. Additionally, immune cell infiltration was estimated using computational algorithms to assess tumor microenvironment differences, and chemosensitivity was predicted to explore potential clinical implications of the methylation subtypes. Results: Four distinct methylation-based subtypes differed in methylation patterns, histological types, clinical stages, and metastatic status. A total of 501 subtype-specific methylation sites were identified. The Bayesian classifier demonstrated strong predictive performance, with an area under the receiver operating characteristic (ROC) curve (AUC) of 0.824 based on 10-fold cross-validation, indicating high classification accuracy and robustness. The immune microenvironment composition varied markedly among subtypes. Notably, Cluster 1 had elevated infiltration of central memory CD8+ and effector memory CD4+ T cells, whereas Cluster 4 exhibited reduced immune activation and the lowest immune checkpoint expression. These findings indicate subtype-specific differences in potential responsiveness to immunotherapy. Conclusions: These DNA methylation-driven subtypes highlight the heterogeneity of cervical cancer and offer new insights for personalized therapy.

RecQ protein‐like 4 drives cisplatin chemosensitivity of cervical cancer cells by modulating annexin A2

AbstractCervical cancer is a common malignant tumor in women with high morbidity and mortality. Chemotherapy drugs such as cisplatin (DDP) are easy to cause chemotherapy resistance and affect the therapeutic effect. Hence, it is critical to design new therapies that can reverse chemotherapy resistance and increase sensitivity to chemotherapy drugs. This study investigated the function of RecQ protein‐like 4 (RECQL4) in DDP‐resistant cervical cancer cells and its regulatory mechanism. By constructing DDP‐resistant Hela and CaSki cell lines, it was found that RECQL4 expression was elevated. RECQL4 knockdown is able to promote apoptosis, DNA damage, and increase the DDP sensitivity in cervical cancer cells. In vivo experiments have demonstrated that knockdown of RECQL4 suppresses tumor growth and promotes tumor apoptosis. Next, we investigated the potential regulatory relationship of RECQL4 to Annexin A2 (ANXA2). The results demonstrated that RECQL4 binds to ANXA2. Knockdown of RECQL4 downregulates the ANXA2 expression via promoting ubiquitination. Furthermore, we also found that ANXA2 overexpression partially abolished the role of RECQL4 knockdown in promoting apoptosis and DNA damage of cervical cancer cells, suggesting that RECQL4 plays a role in DDP sensitivity of cervical cancer cells by mediating ANXA2. In conclusion, the present study suggests that knocking down RECQL4 reduces DDP sensitivity in cervical cancer cells by modulating ANXA2. Targeting RECQL4 therapy may be a new strategy to improve chemosensitivity of cervical cancer cells.

Overexpression of DTL enhances cell motility and promotes tumor metastasis in cervical adenocarcinoma by inducing RAC1-JNK-FOXO1 axis

AbstractCervical adenocarcinoma is an important disease that affects young women and it has a high mortality and poor prognosis. Denticleless E3 ubiquitin protein ligase homolog (DTL) gene with oncogenic function has been evaluated in several cancers. Through this study, we aimed to clarify the clinical and molecular characteristics of cervical adenocarcinoma involving overexpression of DTL and elucidate its molecular mechanism. Bioinformatics analysis was performed through multiple databases. RNA sequencing was used to obtain differentially expressed genes after DTL was overexpressed in cells. The role of DTL in cervical adenocarcinoma was explored through in vitro and in vivo experiments. We found that DTL has an unfavorable prognostic implication for patients with cervical adenocarcinoma. Overexpression of DTL induced the migration and invasion of tumor cells in vitro and promoted intra-pulmonary metastasis in vivo. In addition, DTL activated JNK through RAC1 and upregulated FOXO1 to induce epithelial–mesenchymal transition, and the migration and invasion of tumor cells. Therefore, we conclude that overexpression of DTL enhanced cell motility and promoted tumor metastasis of cervical adenocarcinoma by regulating the RAC1-JNK-FOXO1 axis. These results suggest that DTL may become a potential therapeutic target for antitumor metastasis of cervical adenocarcinoma.

Efficacy and Safety of the Anti–PD-L1 mAb Socazolimab for Recurrent or Metastatic Cervical Cancer: a Phase I Dose-Escalation and Expansion Study

Abstract Purpose: This study (ClinicalTrials.gov identifier, NCT03676959) is an open, phase I dose-escalation and expansion study investigating the safety and efficacy of the recombinant, fully human anti–programmed death ligand 1 (PD-L1) mAb socazolimab in patients diagnosed with recurrent or metastatic cervical cancer. Patients and Methods: Patients received socazolimab every 2 weeks until disease progression. The study was divided into a dose-escalation phase and a dose-expansion phase. Safety and tolerability were primary endpoints of the dose-escalation phase. The primary endpoints of the dose-expansion phase were safety and the objective response rate (ORR) of the 5 mg/kg dose. Efficacy was assessed by the third-party independent review committee (IRC) using the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). Results: 104 patients were successfully enrolled into the study. Twelve patients were included in the dose-escalation phase, with one complete response and two partial responses in the 5 mg/kg treatment group. Ninety-two patients (5 mg/kg) were enrolled in the dose-expansion phase. Fifty-four patients (59.3%) had baseline PD-L1–positive tumor expression (combined positive score ≥1). ORR was 15.4% [95% confidence interval (CI), 8.7%–24.5%]. Median PFS was 4.44 months (95% CI, 2.37–5.75 months), and the median OS was 14.72 months (95% CI, 9.59–NE months). ORR of PD-L1–positive patients was 16.7%, and the ORR of PD-L1–negative patients was 17.9%. No treatment-related deaths occurred. Conclusions: Our study demonstrates that socazolimab has durable safety and efficacy for the treatment of recurrent or metastatic cervical cancer and exhibits a safety profile similar to other anti–PD-1/PD-L1 mAbs.

Mesenchymal stem cell-derived extracellular vesicles alleviate cervical cancer by delivering microRNA-331-3p to reduce LIM zinc finger domain containing 2 methylation in tumor cells

Abstract The aim of this study is to investigate if extracellular vesicles (EVs) from bone marrow mesenchymal stem cells (BMSCs) deliver microRNA (miR)-331-3p to regulate LIM zinc finger domain containing 2 (LIMS2) methylation in cervical cancer cells. Cervical cancer cells were incubated with EVs from BMSCs with altered expression of miR-331-3p, DNA methyltransferase 3 alpha (DNMT3A) or/and LIMS2 and then subjected to 5-ethynyl-2′-deoxyuridine, Transwell, flow cytometry and western blotting analyses. Dual-luciferase reporter assay was conducted to verify the binding between miR-331-3p and DNMT3A. A xenograft model was established to evaluate the effect of BMSC-derived EV-miR-331-3p on cervical tumor growth. miR-331-3p was lowly and DNMT3A was highly expressed in cervical cancer. BMSC-derived EVs delivered miR-331-3p to control the behaviors of cervical cancer cells. miR-331-3p inhibited the expression of DNMT3A by binding DNMT3A mRNA. DNMT3A promoted LIMS2 methylation and reduced the expression of LIMS2. Overexpression of DNMT3A or silencing of LIMS2 in BMSCs counteracted the tumor suppressive effects of miR-331-3p. BMSC-derived EV-miR-331-3p also inhibited the growth of cervical tumors in vivo. BMSC-derived EVs alleviate cervical cancer partially by delivering miR-331-3p to reduce DNMT3A-dependent LIMS2 methylation in tumor cells.

Signature involved in immune-related lncRNA pairs for predicting the immune landscape of cervical cancer

Background Immune-related long non-coding RNAs (irlncRNAs) are known to hold great promise as superior biomarkers for cervical cancer-related immunotherapeutic response and the tumor immune microenvironment. Here, we constructed a prognostic signature based on irlncRNA pairs (IRLPs). Methods The samples were downloaded from The Cancer Genome Atlas and the Genotype-Tissue Expression databases. The least absolute shrinkage and selection operator Cox regression was performed to construct the prognostic model. Receiver operating characteristic (ROC) curve and nomogram were plotted to validate accuracy of the model. Next, we estimated the immune cell infiltration and the correlation between risk score and the expression of genes related to immune checkpoint. Finally, we calculated the score of the Tumor Immune Dysfunction and Exclusion (TIDE) algorithm and the half maximal inhibitory concentration of the chemotherapeutic agent to evaluate the response to immunotherapy and chemotherapy. Results We constructed a prognostic signature that consisted of 11 irlncRNAs. The area under the curve values of the 1-, 3-, and 5-year ROC curves were 0.844, 0.891, and 0.871, respectively. The expression of CTLA-4, HAVCR2, IDO1, LAG3, and PDCD1 were negatively correlated with risk scores. The score of TIDE in the high-risk group was significantly higher than in the low-risk group ( P < 0.01). Patients in the low-risk subgroup were more sensitive to chemotherapeutic agents, such as axitinib and docetaxel, whereas patients in the low-risk subgroup were more sensitive to mitomycin C. Conclusion Our study highlighted the value of the 11 IRLPs signatures to predict the prognosis and the response to immunotherapy and chemotherapeutics for patients with cervical cancer.

Prognostic prediction in primary cervical squamous cell carcinoma with serum squamous cell carcinoma antigen ≥ 10 ng/mL: development and validation of a nomogram model based on inflammatory biomarkers and clinical factors

Cervical cancer remains a significant health burden worldwide, particularly in patients with markedly elevated pretreatment serum squamous cell carcinoma antigen levels (≥ 10 ng/mL), who often have poor outcomes. Accurate prognostic tools for this high-risk population are limited. We conducted a single-center retrospective study including 355 patients with primary cervical squamous cell carcinoma who received radiotherapy between 2020 and 2023. Clinical characteristics and inflammation-related hematological indices, including hemoglobin-to-red cell distribution width ratio and neutrophil-to-lymphocyte ratio, were collected. Univariate and multivariate Cox regression analyses were performed to identify independent prognostic factors for overall survival. A nomogram incorporating these variables, along with clinical stage and treatment modality, was developed and validated. Hemoglobin-to-red cell distribution width ratio, neutrophil-to-lymphocyte ratio, clinical stage, and treatment modality were independent predictors of survival. The nomogram achieved a concordance index of 0.729 in the training cohort and 0.704 in the validation cohort. The area under the time-dependent receiver operating characteristic curves for overall survival at 1, 2, and 3 years were 0.76, 0.81, and 0.79 in the training cohort, and 0.80, 0.75, and 0.71 in the validation cohort. Decision curve analysis demonstrated a consistent net clinical benefit, and risk stratification based on total scores effectively distinguished high- and low-risk groups. This study developed and validated a clinically useful nomogram integrating inflammation-related hematological indices and clinical parameters to predict survival in high-risk cervical cancer patients. The model demonstrates favorable predictive accuracy and may guide individualized treatment strategies, supporting its potential for clinical application.

A Clinical Study of PD-L1 Antibody ZKAB001（Drug Code） in Recurrent or Metastatic Cervical Cancer

This is a Phase 1, open-label, dose-escalation, and multidose study, aiming to investigate the safety, tolerability and pharmacokinetics(PK) of ZKAB001 (a fully human monoclonal antibody targeting the Programmed Death - Ligand 1 (PD-L1) membrane receptor on T lymphocytes and other cells of the immune system) administered every 14 days in subjects with recurrent or metastatic cervical cancer.