Yue Wang

Microbiome-driven resistance in cervical cancer therapy: from mechanistic dissection to clinical translation

Abstract Cervical cancer remains a major global health burden. Despite standard-of-care therapies, 30–50% of locally advanced-stage patients develop treatment resistance, leading to recurrence and mortality. While tumour-intrinsic mechanisms (e.g., DNA methylation, cancer-associated fibroblasts) explain only partial resistance heterogeneity, emerging evidence identifies the microbiome as a critical modulator of therapeutic efficacy. This review synthesizes recent advances demonstrating that vaginal microbial dysbiosis, characterized by Lactobacillus iners enrichment and L. crispatus depletion, drives resistance through lactate-mediated metabolic rewiring, immune checkpoint stabilization and drug metabolism alteration. Longitudinal studies reveal dynamic microbiome trajectories during therapy, with geographic variations (notably HIV co-infection in sub-Saharan Africa) further modulating treatment responses. We critically evaluate microbiome-based interventions, from probiotics to engineered bacteria, including synthetic biology-driven precision microbiome therapies, and establishing standardized multi-centre trial protocols. Bridging mechanistic insights with clinical application represents a paradigm shift towards microbiome-informed cervical cancer management.

Integrative Analysis of Shared Pathogenic Genes and Potential Mechanisms in Gardnerella vaginalis and Persistent HPV16 Infection

Bacterial vaginosis, often accompanied by Gardnerella vaginalis (GV) overgrowth, is associated with persistent high‐risk human papillomavirus (HR‐HPV) infection, particularly HPV16. This study integrated transcriptomic data from in vitro GV infection experiments and a GEO dataset (GSE75132) of HPV16 persistence to elucidate shared pathogenic mechanisms. Differential expression analysis identified 4115 genes modulated by GV infection and 861 by HPV16 persistence, with 74 common differentially expressed genes (DEGs) displaying consistent trends. Enrichment analyses revealed that these DEGs participate in metabolic pathways, immune defense, host–pathogen interactions, and carcinogenesis. Protein–protein interaction networks and Random Forest (RF) feature selection pinpointed radical S‐adenosyl methionine domain containing 2 (RSAD2) and Interferon‐induced protein with tetratricopeptide repeats 1 (IFIT1) as central hub genes. Upstream transcription analysis identified the homer_AGTTTCAGTTTC_ISRE motif and established a ceRNA network involving hsa‐miR‐654‐5p, IFIT1/RSAD2, and lncRNAs. Mendelian randomization (MR) and colocalization analyses linked RSAD2 downregulation to an increased risk of cervical carcinoma in situ (rs2595163, PPH4 = 0.62), while ROC analysis demonstrated strong diagnostic potential for the combined hub gene expression. Notably, single‐cell transcriptomics revealed distinct RSAD2 and IFIT1 expression patterns in immune and epithelial cells during the progression from HPV infection to cervical cancer. Collectively, these findings support RSAD2 and IFIT1 as promising biomarkers and therapeutic targets for HPV‐related cervical lesions.

Interleukin‐6 and Hypoxia Synergistically Promote EMT‐Mediated Invasion in Epithelial Ovarian Cancer via the IL‐6/STAT3/HIF‐1α Feedback Loop

Extensive peritoneal spread and capacity for distant metastasis account for the majority of mortality from epithelial ovarian cancer (EOC). Accumulating evidence shows that interleukin‐6 (IL‐6) promotes tumor invasion and migration in EOC, although the molecular mechanisms remain to be fully elucidated. Meanwhile, the hypoxic microenvironment has been recognized to cause metastasis by triggering epithelial–mesenchymal transition (EMT) in several types of cancers. Here, we studied the synergy between IL‐6 and hypoxia in inducing EMT in two EOC cell lines, A2780 cells and SKOV3 cells. Exogenous recombination of IL‐6 and autocrine production of IL‐6 regulated by plasmids both induced EMT phenotype in EOC cells characterized by downregulated E‐cadherin as well as upregulated expression of vimentin and EMT‐related transcription factors. The combined effects of IL‐6 and hypoxia were more significant than those of either one treatment on EMT. Suppression of hypoxia‐inducible factor‐1α (HIF‐1α) before IL‐6 treatment inhibited the EMT phenotype and invasion ability of EOC cells, indicating that HIF‐1α occupies a key position in the regulatory pathway of EMT associated with IL‐6. EMT score was found positively correlated with mRNA levels of IL‐6, signal transducer and activator of transcription 3 (STAT3), and HIF‐1α, respectively, in 489 ovarian samples from The Cancer Genome Atlas dataset. Next, blockade of the abovementioned molecules by chemical inhibitors reversed the alteration in the protein levels of EMT markers induced by either exogenous or endogenous IL‐6. These findings indicate a positive feedback loop between IL‐6 and HIF‐1α, and induce and maintain EMT phenotype through STAT3 signaling, which might provide a novel rationale for prognostic prediction and therapeutic targets in EOC.

miR-486 Promotes the Invasion and Cell Cycle Progression of Ovarian Cancer Cells by Targeting CADM1

Objective. To explore the role and possible underlying mechanism of miR-486 in ovarian cancer (OC) cells. Methods. The expression of miR-486 and CADM1 was detected by qRT-PCR in OC tissues and adjacent nontumor tissues and OC cell lines. The dual-luciferase reporter gene system was used to determine the targeting relationship between miR-486 and CADM1. CCK-8, colony formation assay, Transwell, and flow cytometry were performed to detect cell proliferation, cell invasion, cell cycle progression, and the apoptotic cell death, respectively. Western blot was carried out to detect the expression of CADM1 protein and the proteins associated with cell cycle progression. Results. miR-486 was significantly upregulated in OC tissues and cells, while CADM1 expression was significantly downregulated. Dual-luciferase reporter assays further confirmed that CADM1 was a target gene of miR-486. Interference with miR-486 could inhibit the proliferation and invasion and promoted the apoptosis of SKOV3 cells. Knocking down both miR-486 and CADM1 significantly increased the SKOV3 cell proliferation, invasion, and the number of cells transitioning from the G0/G1 phase into the S phase of cell cycle and reduced the cellular apoptosis. Western blot analysis revealed that the expression of cell cycle progression-related proteins (CyclinD1, CyclinE, and CDK6) was significantly reduced, and the p21 expression was increased when interfering with both miR-486 and CADM1 expression. Conclusion. Our results suggested that miR-486 could act as a tumor promoter by targeting CADM1 and be a potential therapeutic target for the treatment of OC.

The prognostic impact of myosteatosis on overall survival in gynecological cancer patients: A meta‐analysis and trial sequential analysis

AbstractMyosteatosis is a novel imaging biomarker for survival in gynecological cancer patients; however, the evidence is inconsistent. This meta‐analysis aims to investigate the impact of myosteatosis on overall survival in the gynecological oncology setting. Three databases (PubMed, EMBASE and Web of Science) were systematically searched for relevant literature up to October 30, 2021. A random‐effects model was used to evaluate the predictive effect of myosteatosis on overall survival in the gynecological cancer population. The Newcastle‐Ottawa Scale was used to assess the methodological quality of the included studies. Trial sequential analysis was used to control the risk of random errors. Twelve studies with a total of 2519 patients were included. Myosteatosis was associated with a 50% increased mortality risk (HR 1.50, 95% CI 1.24‐1.82, P < .001) in gynecological cancer patients. Subgroup analyses stratified by study design, statistical model, treatment, sample size and stage confirmed the predictive value of myosteatosis on survival. However, the prognostic ability of myosteatosis only was held in the American and European populations but lost in Asians. Additionally, myosteatosis was not associated with the increased mortality in endometrial and cervical cancers, except for ovarian cancers. Overall, myosteatosis is a powerful predictor of reduced overall survival in gynecological cancer patients.

Clinical efficacy of photodynamic therapy combined with CO2 laser in the treatment of vulvar squamous intraepithelial lesions

Comprehensive research data on the combination of 5-aminolevulinic acid (5-ALA) photodynamic therapy (PDT) and CO This study was a retrospective study. The subjects were 165 patients diagnosed with VSIL in the People's Hospital of Zhengzhou University. According to the patients' personal choice, they were divided into 5-ALA PDT group (n = 37), CO2 laser group (n = 78) and 5-ALA PDT combined with CO2 laser group (n = 50). The general condition, treatment times and adverse reactions of patients in each group were analyzed. All patients underwent HPV, TCT and colposcopy at 3 months and 6 months after treatment to evaluate the therapeutic effect, and biopsy was performed again if necessary. There was no statistically significant difference in the HPV negative conversion rates and lesions complete remission (CR) rates of both vulvar low-grade squamous intraepithelial lesions (VLSIL) and vulvar high-grade squamous intraepithelial lesions (VHSIL) patients among the three groups at 3 months after treatment. Regarding VLSIL, the HPV negative conversion rates for both the 5-ALA PDT group (51.7 %) and the combination group (51.9 %) were significantly higher than the CO The integration of 5-ALA PDT with CO₂ laser therapy not only reduces the overall treatment duration but also enhances treatment efficacy. Therefore, it is a promising option for treating VSIL.

Ultrasonic features of hidradenoma papilliferum: An unexpected mass in the vulvar

Hidradenoma papilliferum is a rare superficial mass with distinct ultrasonic features. It originates from mammary structures and is commonly observed in the anogenital region of women. We report a hidradenoma papilliferum with clear ultrasound images which have never be described before.

Targeting Ovarian Cancer Stem Cells by Dual Inhibition of the Long Noncoding RNA HOTAIR and Lysine Methyltransferase EZH2

Abstract The persistence of cancer stem cells (CSC) is believed to contribute to resistance to platinum-based chemotherapy and disease relapse in ovarian cancer, the fifth leading cause of cancer-related death among US women. HOXC transcript antisense RNA (HOTAIR) is a long, noncoding RNA (lncRNA) overexpressed in high-grade serous ovarian cancer and linked to chemoresistance. However, HOTAIR impacts chromatin dynamics in ovarian CSCs. Oncogenic lncRNA’s contributions to drug-resistant disease are incompletely understood. Here, we generated HOTAIR knockout (KO) high-grade serous ovarian cancer cell lines using paired CRISPR guide RNA design to investigate the function of HOTAIR. We show the loss of HOTAIR function resensitized ovarian cancer cells to platinum treatment and decreased the population of ovarian CSCs. Furthermore, HOTAIR KO inhibited the development of stemness-related phenotypes, including spheroid formation ability and expression of key stemness-associated genes ALDH1A1, NOTCH3, SOX9, and PROM1. HOTAIR KO altered the cellular transcriptome and chromatin accessibility landscape of multiple oncogenic-associated genes and pathways, including the NF-kB pathway. HOTAIR functions as an oncogene by recruiting enhancer of zeste homolog 2 (EZH2) to catalyze H3K27 trimethylation to suppress downstream tumor suppressor genes, and it was of interest to inhibit both HOTAIR and EZH2. In vivo, combining a HOTAIR inhibitor with an EZH2 inhibitor and platinum chemotherapy decreased tumor formation and increased survival. These results suggest a key role for HOTAIR in ovarian CSCs and malignant potential. Targeting HOTAIR in combination with epigenetic therapies may represent a therapeutic strategy to ameliorate ovarian cancer progression and resistance to platinum-based chemotherapy.