Ying Zhu

Ursolic Acid Inhibits Glycolysis of Ovarian Cancer via KLF5/PI3K/AKT Signaling Pathway

Glycolysis is one of the key metabolic reprogramming characteristics of ovarian cancer. Ursolic Acid (UA), as a natural compound, exerts a beneficial regulatory effect on tumor metabolism. In this study, we have confirmed through RNA-seq analysis and a series of in vitro and in vivo functional experiments that UA significantly inhibits ovarian cancer cell proliferation, promotes tumor apoptosis, and reduces glycolysis levels. Additionally, it demonstrates synergistic therapeutic effects with cisplatin in both in vitro and in vivo experiments. Furthermore, at the molecular level, we found that UA inhibits glycolysis in ovarian cancer by binding to the transcription factor KLF5 and blocking the transcriptional expression of the downstream PI3K/AKT signaling pathway, thereby exerting its therapeutic effect. In conclusion, our research indicates that UA can inhibit the proliferation, apoptosis, and glycolysis levels of ovarian cancer cells through the KLF5/PI3K/AKT signaling axis. Our findings offer a new perspective on the therapeutic application of the natural compound UA in ovarian cancer and support its potential development as a candidate for chemotherapy.

Spatial Transcriptomics Depict Ligand–Receptor Cross-talk Heterogeneity at the Tumor-Stroma Interface in Long-Term Ovarian Cancer Survivors

Abstract Advanced high-grade serous ovarian cancer (HGSC) is an aggressive disease that accounts for 70% of all ovarian cancer deaths. Nevertheless, 15% of patients diagnosed with advanced HGSC survive more than 10 years. The elucidation of predictive markers of these long-term survivors (LTS) could help identify therapeutic targets for the disease, and thus improve patient survival rates. To investigate the stromal heterogeneity of the tumor microenvironment (TME) in ovarian cancer, we used spatial transcriptomics to generate spatially resolved transcript profiles in treatment-naïve advanced HGSC from LTS and short-term survivors (STS) and determined the association between cancer-associated fibroblasts (CAF) heterogeneity and survival in patients with advanced HGSC. Spatial transcriptomics and single-cell RNA-sequencing data were integrated to distinguish tumor and stroma regions, and a computational method was developed to investigate spatially resolved ligand–receptor interactions between various tumor and CAF subtypes in the TME. A specific subtype of CAFs and its spatial location relative to a particular ovarian cancer cell subtype in the TME correlated with long-term survival in patients with advanced HGSC. Also, increased APOE-LRP5 cross-talk occurred at the stroma-tumor interface in tumor tissues from STS compared with LTS. These findings were validated using multiplex IHC. Overall, this spatial transcriptomics analysis revealed spatially resolved CAF-tumor cross-talk signaling networks in the ovarian TME that are associated with long-term survival of patients with HGSC. Further studies to confirm whether such cross-talk plays a role in modulating the malignant phenotype of HGSC and could serve as a predictive biomarker of patient survival are warranted. Significance: Generation of spatially resolved gene expression patterns in tumors from patients with ovarian cancer surviving more than 10 years allows the identification of novel predictive biomarkers and therapeutic targets for better patient management. See related commentary by Kelliher and Lengyel, p. 1383

Clinicopathologic characteristics and survival outcomes in neuroendocrine carcinoma of the ovary

Neuroendocrine tumors are rare in the ovary. Definitive epidemiologic and prognostic information for neuroendocrine carcinoma of the ovary is lacking. This retrospective population-based study aimed to elucidate the demographic and clinicopathologic characteristics of neuroendocrine carcinoma of the ovary. Patients with neuroendocrine carcinoma of the ovary diagnosed between January 1994 and December 2014were identified from the Surveillance, Epidemiology, and End Results (SEER) database of the National Cancer Institute. Cancer-specific survival was calculated by Kaplan-Meier plots and comparisons were performed using the log-rank test. A Cox hazard regression analysis was performed to identify independent predictors of cancer-specific survival in patients with neuroendocrine carcinoma of the ovary. A total of 166 patients were included, and 21.1% were younger than 50 years old. The majority of patients (59.6%) presented with unilateral tumors. Patients with neuroendocrine carcinoma of the ovary had significantly worse survival compared with most subtypes of epithelial ovarian cancer (including serous, endometrioid, mucinous, and clear cell), and similar to ovarian carcinosarcoma. The rate of cancer-specific survival was significantly different under the SEER histologic stages. Patients with low-grade neuroendocrine carcinoma of the ovary had longer average survival times than those with high-grade neuroendocrine carcinoma of the ovary (HR 3.43, 95% CI 1.56 to 7.54, p=0.002). Patients with neuroendocrine carcinoma of the ovary who underwent surgery had significantly better survival than those who did not undergo surgery (HR 2.23; 95% CI 1.45 to 3.43, p=<0.05). Early clinical stage and low tumor grade independently predict better survival in patients with neuroendocrine carcinoma of the ovary. Surgery may be a useful therapy for neuroendocrine carcinoma of the ovary.

[Retracted] Network Pharmacology, Molecular Docking, and Experimental Validation to Unveil the Molecular Targets and Mechanisms of Compound Fuling Granule to Treat Ovarian Cancer

Background. Compound fuling granule (CFG) is a traditional Chinese medicine formula that is used for more than twenty years to treat ovarian cancer (OC) in China. However, the underlying processes have yet to be completely understood. This research is aimed at uncovering its molecular mechanism and identifying possible therapeutic targets. Methods. Significant genes were collected from Therapeutic Target Database and Database of Gene‐Disease Associations. The components of CFG were analyzed by LC‐MS/MS, and the active components of CFG were screened according to their oral bioavailability and drug‐likeness index. The validated targets were extracted from PharmMapper and PubChem databases. Venn diagram and STRING website diagrams were used to identify intersection targets, and a protein–protein interaction network was prepared using STRING. The ingredient‐target network was established using Cytoscape. Molecular docking was performed to visualize the molecule–protein interactions using PyMOL 2.3. Enrichment and pathway analyses were performed using FunRich software and Reactome pathway, respectively. Experimental validations, including CCK‐8 assay, wound‐scratch assay, flow cytometry, western blot assay, histopathological examination, and immunohistochemistry, were conducted to verify the effects of CFG on OC cells. Results. A total of 56 bioactive ingredients of CFG and 185 CFG‐OC‐related targets were screened by network pharmacology analysis. The potential therapeutic targets included moesin, glutathione S‐transferase kappa 1, ribonuclease III (DICER1), mucin1 (MUC1), cyclin‐dependent kinase 2 (CDK2), E1A binding protein p300, and transcription activator BRG1. Reactome analysis showed 51 signaling pathways (P &lt; 0.05), and FunRich revealed 44 signaling pathways that might play an important role in CFG against OC. Molecular docking of CDK2 and five active compounds (baicalin, ignavine, lactiflorin, neokadsuranic acid B, and deoxyaconitine) showed that baicalin had the highest affinity to CDK2. Experimental approaches confirmed that CFG could apparently inhibit OC cell proliferation and migration in vitro; increase apoptosis; decrease the protein expression of MUC1, DICER1, and CDK2; and suppress the progression and distant metastasis of OC in vivo. DICER1, a tumor suppressor, is essential for microRNA synthesis. Our findings suggest that CFG may impair the production of miRNAs in OC cells. Conclusion. Based on network pharmacology, molecular docking, and experimental validation, the potential mechanism underlying the function of CFG in OC was explored, which supplies the theoretical groundwork for additional pharmacological investigation.