Tian Li

Metformin Enhances PD ‐ L1 Inhibitor Efficacy in Ovarian Cancer by Modulating the Immune Microenvironment and RBMS3 Expression

ABSTRACT Ovarian cancer (OC) is associated with poor prognosis and immune evasion through PD‐L1 expression. While anti‐PD‐L1 therapies have shown limited efficacy, combination strategies may enhance therapeutic outcomes. This study explores the potential of metformin to modulate the immune microenvironment and improve the efficacy of PD‐L1 inhibitors in OC. An immunocompetent C57BL/6 mouse model of OC was used to evaluate the effects of metformin and PD‐L1 inhibitors on tumor progression, immune cell infiltration, and cytokine expression. Mice received daily metformin treatment for 2 weeks, with PD‐L1 inhibitors administered twice weekly. Tumor growth was monitored via volume measurements, immune cell infiltration was assessed by flow cytometry, and cytokine levels (Granzyme B, IFN‐γ) were quantified using ELISA. Metformin significantly reduced tumor growth, increased CD8 + T cell infiltration, upregulated RBMS3, and elevated Granzyme B and IFN‐γ expression. Additionally, metformin downregulated PD‐L1 expression, and its combination with PD‐L1 inhibitors further enhanced CD8 + T cell activity. Silencing RBMS3 reversed these effects, underscoring its critical role in immune modulation. These findings suggest that metformin, in combination with PD‐L1 inhibitors, may enhance antitumor immune responses and improve treatment outcomes in OC. Targeting RBMS3 could represent a novel therapeutic approach for overcoming immune evasion in OC.

Comprehensive Analysis of the Control of Cancer Stem Cell Characteristics in Endometrial Cancer by Network Analysis

Background. Cancer stem cells play an important role in endometrial cancer (EC). It is closely related to self-renewal and therapeutic resistance of EC. Methods. In this study, WGCNA (weighted gene coexpression network analysis) was used to analyze the relationship between genes and clinical features. We also performed immune cell infiltration analysis of a key module by using ImmuCellAI (Immune Cell Abundance Identifier). Then, key genes were verified in the GEO database. Finally, causal relationship analysis and protein-protein interaction analysis were performed in DisNor tool and STRING. Result. The mRNA expression-based stemness index (mRNAsi) is significantly lower in normal tissues and is significantly higher in individuals with stage IV or high-grade cancer and those who are obese or postmenopausal. Nineteen key genes (ORC6, C1orf112, RAD54L, SGO2, BUB1, PLK4, KIF18B, BUB1B, TTK, NCAPG, XRCC2, CENPF, KIF15, RACGAP1, ARHGAP11A, TPX2, KIF14, KIF4A, and NCAPH) that were enriched mainly in terms related to the cell cycle and DNA replication were selected by weighted gene coexpression network analysis (WGCNA). Based on the key modules, the numbers of NKT cells, NK cells, and neutrophils in the normal group were significantly higher than those in the cancer group. PLK1, CDK1, and MAD2L1, which were correlated with upstream genes, may be an regulated upstream of key genes. Conclusion. PLK1, CDK1, and MAD2L1 which were strongly correlated with upstream genes may be a regulated upstream of key genes.

Human umbilical cord mesenchymal stem cells small extracellular vesicles-derived miR-370-3p inhibits cervical precancerous lesions by targeting DHCR24

Abstract Background Cervical cancer is often caused by persistent high-risk human papillomavirus (HPV) infection, causing precancerous lesions. Human umbilical cord mesenchymal stem cells-derived small extracellular vesicles (hucMSC-sEV) exhibit diverse effects on tumors. This study investigates hucMSC-sEV, the impact and mechanisms on HPV-positive cervical precancerous lesion cells to provide new treatment insights. Materials and Methods We previously obtained hucMSC and hucMSC-sEV. In vitro experiments evaluated hucMSC-sEV effects on the proliferation and migration of S12 cells (derived from cervical precancerous lesions). Bioinformatics identified key microRNA components, and their impact on S12 cell proliferation and migration was investigated. The target gene of the microRNA component was predicted and confirmed via bioinformatics and dual-luciferase reporter assays. Lentiviral systems overexpressed target gene in S12 cells to examine the effects on microRNA impacts. SH-42 inhibitor was used to investigate target gene treatment potential. Immunohistochemistry assessed target gene expression in cervical precancerous lesions tissue. Results hucMSC-sEV significantly inhibited S12 cell proliferation and migration. Bioinformatics identified miR-370-3p as an effective cargo, which also suppressed S12 cell proliferation and migration. miR-370-3p was confirmed targeting DHCR24 (24-Dehydrocholesterol Reductase). DHCR24 overexpression reversed miR-370-3p’s inhibitory effects, while SH-42 counteracted DHCR24 overexpression’s promoting effects. Clinical specimen analysis supported these findings, demonstrating a positive correlation between DHCR24 protein expression and cervical precancerous lesions’ progression. Conclusions hucMSC-sEV inhibits S12 cell proliferation and migration, mediated by miR-370-3p targeting DHCR24 to regulate cellular cholesterol content. DHCR24 inhibition reduces the cholesterol level and cell functions, suggesting its potential as a therapeutic target in cervical precancerous lesions.

Clinicopathologic and prognostic significance of tumor-associated macrophages in cervical cancer: a systematic review and meta-analysis

Abstract Objectives The role of tumor-associated macrophages (TAMs) in cervical cancer (CC) remains controversial. Here, we report a meta-analysis of the association between TAMs infiltration and clinical outcomes. Methods PubMed, Embase, Web of Science, and CNKI were searched systematically from inception until December 20, 2023. Studies involving TAMs and prognosis, clinical, or pathological features were included. Quality assessments of the selected studies were assessed. The fixed-effect or random-effects model, standard mean difference (SMD), odds ratios (OR), or hazard ratios (HR) with 95% confidence intervals (CIs) were used as the effect size estimate. Results 26 eligible studies with 2,295 patients were identified. Our meta-analysis revealed that TAMs were overexpressed in CC (OR = 12.93, 95% CI = 7.73–21.61 and SMD = 1.58, 95% CI = 0.95–2.21) and that elevated TAM levels were strongly associated with lymph node metastasis (LNM) (SMD = 0.51, 95% CI = 0.90–2.01) and FIGO stages (SMD = 0.46, 95% CI = 0.08–0.85). Subgroup analysis indicated a significant positive correlation between LNM and TAMs density in tumor stroma, but not in cancer nests (SMD = 0.58, 95% CI = 0.31–0.58). Furthermore, in early stage, a stronger correlation exists between LNM and TAM density (SMD = 1.21, 95% CI = 0.75–1.66). In addition, it revealed that patients with high TAMs expression had poorer overall survival (OS) (HR = 2.55 95% CI = 1.59–4.07) and recurrence-free survival (RFS) (HR = 2.17, 95% CI = 1.40–3.35). Conclusions Our analyses suggest that a high density of TAMs predicts adverse outcomes in CC.

Upregulation of FAM83F by c-Myc promotes cervical cancer growth and aerobic glycolysis via Wnt/β-catenin signaling activation

AbstractCervical cancer (CC) seriously affects women’s health. Therefore, elucidation of the exact mechanisms and identification of novel therapeutic targets are urgently needed. In this study, we identified FAM83F, which was highly expressed in CC cells and tissues, as a potential target. Our clinical data revealed that FAM83F protein expression was markedly elevated in CC tissues and was positively correlated with poor prognosis. Moreover, we observed that FAM83F knockdown significantly inhibited cell proliferation, induced apoptosis, and suppressed glycolysis in CC cells, while its overexpression displayed opposite effects. Mechanistically, FAM83F regulated CC cell growth and glycolysis by the modulation of Wnt/β-catenin pathway. The enhancing effects of FAM83F overexpression on CC cell proliferation and glycolysis could be impaired by the Wnt/β-catenin inhibitor XAV939. Moreover, we found that c-Myc bound to the FAM83F promoter and activated the transcription of FAM83F. Notably, knockdown of FAM83F impaired the enhancement of cell proliferation and glycolysis induced by ectopic c-Myc. Consistent with in vitro findings, results from a xenograft mouse model confirmed the promoting role of FAM83F. In summary, our study demonstrated that FAM83F promoted CC growth and glycolysis through regulating the Wnt/β-catenin pathway, suggesting that FAM83F may be a potential molecular target for CC treatment.

Jagged1 contained in MSC-derived small extracellular vesicles promotes squamous differentiation of cervical cancer by activating NOTCH pathway

Abstract Purpose Cervical cancer is the fourth most common cancer in women and poses a major threat to women's health, urgently requiring new treatment methods. Methods This study first successfully extracted and identified small extracellular vesicles secreted by human umbilical cord-derived mesenchymal stem cells. We studied the effects of MSC-sEV on the squamous differentiation levels of cervical cancer CaSki cells in vitro, and explored the effects of MSC-sEV on the NOTCH pathway, the growth, proliferation, migration abilities and squamous differentiation levels of cervical cancer cells. The roles of MSC-sEV were also verified in human keratinocyte HaCaT cells. Results The results showed that Jagged1 protein on MSC-sEV can bind to NOTCH1 on cervical cancer cells, activate NOTCH signaling, and promote squamous differentiation levels in CaSki cells, thus inhibiting the growth, proliferation and migration abilities of CaSki cells. MSC-sEV can also activate the NOTCH pathway in HaCaT cells, but promote the viability of HaCaT cells. Conclusion MSC-sEV can activate the NOTCH pathway to promote squamous differentiation of CaSki cells and inhibit the growth proliferation and migration abilities of CaSki cells which may be a new mechanism for cervical cancer treatment.