Youguo Chen

Background: Epithelial ovarian cancer (EOC) remains the most lethal gynecological malignancy. Single-targeted ADCs/PDCs are limited by “on-target, off-tumor” toxicity. We developed FMM-66, a dual-ligand peptide-drug conjugate targeting FOLR1 and c-Met, to improve tumor-selective drug delivery. Methods: FMM-66 was rationally designed by integrating FOLR1- and c-Met-targeting peptide ligands into a single PDC architecture. Binding and cellular internalization assays were performed in ovarian cancer cell lines with different FOLR1/c-Met expression profiles, as well as in engineered overexpression cell models, to comprehensively evaluate the targeting properties of FMM-66. Antitumor efficacy, intratumoral pharmacokinetics, and biodistribution were evaluated in female BALB/c nude mice bearing Caov3 xenografts, with the single-ligand PDCs FA-MMAE and GE137-MMAE as comparators. Normal-tissue biodistribution and systemic safety were further assessed in female Sprague–Dawley rats. Results: FMM-66 demonstrated enhanced binding affinity and significantly increased cellular internalization compared with single-ligand PDCs in vitro. Receptor-blocking experiments confirmed contributions from both FOLR1 and c-Met, whereas internalization was driven predominantly by FOLR1. In vivo studies revealed potent tumor growth inhibition and superior tumor accumulation in FOLR1/c-Met double-positive ovarian tumors than the single-ligand comparators. Furthermore, FMM-66 exhibited rapid systemic clearance while released MMAE showed prolonged intratumoral exposure. At the therapeutic-equivalent dose in rats, no significant biochemical abnormalities or body-weight loss were observed; transient ALT, AST, creatinine, and urea elevations at the higher dose largely resolved by Day 14. Conclusions: FMM-66 demonstrated enhanced tumor accumulation and potent antitumor efficacy, with preliminary tolerability at the tested dose levels. These findings support dual-ligand targeting as a promising strategy for improving tumor-selective payload delivery and warrant further preclinical evaluation of FMM-66.

SIK2 is an oncogene capable of autophosphorylation and plays a critical role in regulating ovarian tumor metabolism,1 cell division and mitotic progression,2,3 DNA repair, lipid synthesis, and the ...

Fatty acid-binding protein 5 (FABP5) is highly expressed in various tumor cell types and is associated with cancer progression. The aim of this study is to clarify the role of FABP5 in cervical cancer to determine its potential value as a clinical treatment target. Online bioinformatics platforms and immunohistochemistry (IHC) were used to analyze FABP5 expression and function in cervical squamous cell carcinoma (CESC). In vitro experiments revealed that overexpression of FABP5 significantly enhanced the proliferation, migration, and invasion abilities of cervical cancer cells. Moreover, resistance to the killing effects of cisplatin and paclitaxel was observed. RNA sequencing (RNA-seq) results and oil red cell (ORO) staining experiments revealed the key role of FABP5 in cellular metabolism. Protein‒protein interaction (PPI) network analysis revealed that by inhibiting the activation of the key lipid regulation signaling pathways PPARγ/CPT1A and ATP5A1, overexpression of FABP5 not only increased the energy reserves of cells but also reduced the level of reactive oxygen species (ROS) produced by fatty acid β-oxidation. Further experiments revealed that exogenous drugs could reduce the cellular energy reserve and activate PPARγ/CPT1A and ATP5A1. In conclusion, FABP5 increases cellular energy reserves while maintaining cells in a low-ROS state by inhibiting PPARγ/CPT1A signaling and downregulating the expression of the respiratory chain component ATP5A1. The PPARγ/CPT1A signaling pathway may represent one of the key mechanisms through which cells defend against exogenous ROS.

Dibutyl phthalate (DBP), a widely used plasticizer, has been implicated in various health concerns, including potential carcinogenic effects. However, the molecular mechanisms underlying DBP’s toxicological effects on ovarian cancer remain poorly understood. This study aimed to computationally investigate the potential association between DBP and ovarian cancer through network toxicology and bioinformatics approaches. Transcriptomic data from GSE26712 identified ovarian cancer-related differentially expressed genes (DEGs). DBP targets were curated from SEA, SwissTargetPrediction, CTD, and TargetNet. Intersecting genes were analyzed via protein-protein interaction (PPI) networks, functional enrichment, and gene set variation analysis (GSVA). Machine learning (SVM, LASSO, RF) pinpointed key targets, validated through ROC analysis, molecular docking, tumor immune infiltration assessment, and immunofluorescence staining of clinical samples. We identified 27 shared targets linking DBP to ovarian cancer, with CTNNB1, SOD2, and KDR as central PPI nodes. Enriched pathways included Wnt signaling, apoptosis, immune responses, and fatty acid biosynthesis. GSVA highlighted dysregulation in T-cell proliferation, cytokine activity, and hypoxia response. Machine learning converged on three key genes: KDR, ANXA3, and FOLR1. ROC analysis confirmed exceptional diagnostic accuracy. These genes correlated significantly with immune infiltration. Molecular docking revealed strong DBP binding to targets. Immunofluorescence validated differential protein expression: KDR, and ANXA3 were downregulated, while FOLR1 was upregulated in cancer tissues. This integrative computational study reveals a potential molecular link between DBP and ovarian cancer, proposing that DBP may influence ovarian cancer-associated pathways. The identified hub genes KDR, ANXA3, and FOLR1 represent promising diagnostic biomarkers. Our findings provide a hypothesis-generating framework suggesting that DBP exposure could contribute to ovarian carcinogenesis by disrupting key biological pathways and modulating the tumor immune microenvironment, warranting further experimental investigation. The online version contains supplementary material available at 10.1007/s12672-026-04897-2.

Globally, ovarian cancer remains a leading cause of gynecologic cancer death. This poor prognosis is primarily attributed to advanced disease at diagnosis, a high propensity for recurrence, and the inadequate therapeutic efficacy of current standard regimens. Emerging evidence has established the functional significance of transfer RNA-derived small RNAs (tsRNAs) in tumor biology. Nevertheless, their exact mechanisms and roles in ovarian cancer pathogenesis are not yet fully understood. Our research was designed to profile tsRNA expression, verify its presence in ovarian cancer tissues and established cell lines, and leverage cellular and animal models to decipher the functional roles and molecular mechanisms of these molecules. Our analysis revealed that tsRNA-Ala-3–0030 is significantly upregulated in ovarian cancer models. Higher expression levels of this tsRNA were associated with enhanced malignant behaviors, including proliferation, migration, and invasion. The suppression of tsRNA-Ala-3–0030 expression attenuated these malignant phenotypes, whereas its overexpression promoted tumor progression in both cellular cultures and xenograft models. Mechanistically, tsRNA-Ala-3–0030 directly targeted the tumor suppressor ZNF70, leading to its downregulation and consequent promotion of ovarian cancer growth and metastasis. Restoration of ZNF70 expression reversed the oncogenic effects of tsRNA-Ala-3-0030, confirming its pivotal role in mediating this pathway. Collectively, our findings reveal tsRNA-Ala-3–0030 as a previously unrecognized oncogenic regulator that promotes ovarian cancer progression through ZNF70 downregulation. This study elucidates a tsRNA-dependent tumorigenic mechanism and positions tsRNA-Ala-3–0030 as a dual-purpose prognostic indicator and therapeutic target, advancing personalized treatment strategies.

Ovarian cancer remains one of the most lethal malignancies affecting women, with its high mortality rate primarily attributed to the aggressive metastatic nature of the disease, leading to late-stage diagnoses. The challenges posed by tumor metastasis and treatment resistance significantly complicate disease management and substantially reduce survival rates. Thus, elucidating the mechanisms underlying ovarian cancer metastasis is crucial for developing targeted therapies and improving patient outcomes. In this study, through single-nucleus RNA sequencing and analysis of clinical samples, we identify PABPC3 as a key regulator of ovarian cancer metastasis and patient survival. Functional experiments reveal that PABPC3 knockdown markedly inhibits ovarian cancer cell proliferation and migration, whereas its overexpression exerts the opposite effects. Furthermore, in vivo models confirm that PABPC3 overexpression significantly enhances metastatic potential. Mechanistically, PABPC3 promotes tumor metastasis by modulating the expression of CLDN1, a critical component of tight junctions. PABPC3 knockdown leads to a significant upregulation of CLDN1, while simultaneous CLDN1 knockdown partially rescues the migration-inhibitory effects induced by PABPC3 depletion. Additionally, clinical analyses demonstrate that high PABPC3 expression correlates with shorter overall survival, even among patients receiving chemotherapy. Notably, increased PABPC3 protein levels in metastatic lesions are associated with reduced progression-free survival. In conclusion, this study underscores the pivotal role of PABPC3 in ovarian cancer metastasis and patient prognosis, highlighting it as a potential therapeutic target for improving clinical outcomes.

Background: Beyond supporting cancer cell proliferation, tumor growth relies on the ability of cancer cells to evade immune surveillance. Identifying novel molecules that promote tumor immune escape may help develop more effective immunotherapeutic strategies. The histone acetyltransferase E1A-binding protein p300 (EP300) is a key epigenetic regulator that modulates gene transcription through chromatin remodeling and acetylation of histones and transcription factors. However, its role in regulating immune evasion remains incompletely understood. This study investigates the impact of EP300 on tumor immune escape and suggests its potential as an immunotherapeutic target. Methods: We analyzed tissue microarrays from patients with lung adenocarcinoma using immunohistochemistry to compare EP300 expression between cancerous tissues and benign tissues. Ep300 -knockout cancer cells were generated using CRISPR-Cas9. Animal models were employed to assess the effect of Ep300 depletion on tumor progression and intratumoral CD8 ⁺ T cell infiltration. RNA sequencing, chromatin immunoprecipitation sequencing, flow cytometry, and western blot were used to explore the mechanism by which EP300 regulates antigen-presenting gene expression. Results: EP300 was significantly upregulated in cancerous tissues compared with benign tissues. Genetic ablation of Ep300 in cancer cells markedly suppressed tumor growth in vivo and enhanced CD8 ⁺ T-cell infiltration. Mechanistically, EP300 upregulates suppressor of cytokine signaling 1 (SOCS1) expression, thereby inhibiting signal transducer and activator of transcription 1 phosphorylation. This leads to downregulation of antigen-presenting genes, enabling cancer cells to evade immune surveillance by CD8 ⁺ T cells. Conclusions: EP300 facilitates tumor immune evasion by suppressing antigen-presenting gene expression via SOCS1 upregulation. Our findings reveal a novel role for EP300 in mediating immune escape and propose a potential therapeutic strategy to enhance antitumor immunity.

Cervical cancer (CC) is a prevalent gynecological malignancy, with lymph node metastasis (LNM) serving as a critical factor influencing patient prognosis. SORBS3, an adaptor protein with two known isoforms (α and β), has been implicated in tumor suppression, but the specific roles of its isoforms in CC metastasis remains unexplored. This study aimed to identify the functional isoform of SORBS3 driving LNM suppression and elucidate its mechanisms. Proteomic analysis of clinical CC tissues and metastatic lymph nodes revealed progressive downregulation of SORBS3. The mRNA and protein levels of SORBS3-α and SORBS3-β were subsequently examined in normal cervical epithelial and CC cell lines. Functional studies, including siRNA-mediated knockdown of SORBS3-α, lentiviral-mediated overexpression and knockdown of SORBS3-β, Transwell migration, lymphangiogenesis assays, and in vivo footpad xenograft models, were conducted to evaluate the role of SORBS3 isoforms in LNM. SORBS3 DNA methylation mechanisms were analyzed by MSP and Targeted Bisulfite sequencing. Mechanistic insights were derived from Co-IP, ubiquitination assays, RNA-seq, and LC–MS/MS. Knockdown of SORBS3-α had no effect on CC cell migration, invasion, or lymphangiogenesis. In contrast, SORBS3-β overexpression markedly suppressed CC cell invasion, lymphangiogenesis, and adhesion to lymphatic endothelial cells, whereas its knockdown significantly promoted these phenotypes. Promoter hypermethylation driven by DNMT-1 inhibited SORBS3 expression in CC. SORBS3- β directly binds to β-catenin and recruits UBA1 to enhance its ubiquitination and degradation, thereby inhibiting Wnt/β-catenin signaling. This inhibition reduced accumulation of β-catenin and downregulated the pro-lymphangiogenic gene VEGFC, ultimately suppressing lymphangiogenesis and LNM. In vivo, SORBS3-β overexpression attenuated lymphatic metastasis in nude mice, whereas its knockdown promoted metastasis. SORBS3-β is the major isoform of SORBS3 that inhibits lymphatic metastasis of cervical cancer by degrading β-catenin through UBA1-mediated ubiquitination, blocking Wnt/β-catenin signaling and downstream lymphangiogenesis pathways, thereby inhibiting lymphatic metastasis. Our findings elucidate key molecular mechanisms underlying cervical cancer lymph node metastasis, offering potential therapeutic targets.metastasis.

Background: Aberrant expression of tumor protein D52 (TPD52) is associated with some tumors. The role of TPD52 in uterine corpus endometrial carcinoma (UCEC) remains uncertain. Objective: We aimed to investigate the involvement of TPD52 in the pathogenesis of UCEC. Methods: We employed bioinformatics analysis and experimental validation in our study. Results: Our findings indicated that elevated TPD52 expression in UCEC was significantly associated with various clinical factors, including clinical stage, race, weight, body mass index (BMI), histological type, histological grade, surgical approach, and age (p < 0.01). Furthermore, high TPD52 expression was a predictor of poorer overall survival (OS), progress-free survival (PFS), and disease-specific survival (DSS) (p = 0.011, p = 0.006, and p = 0.003, respectively). TPD52 exhibited a significant correlation with DSS (HR: 2.500; 95% CI: 1.153-5.419; p = 0.02). TPD52 was involved in GPCR ligand binding and formation of the cornified envelope in UCEC. Moreover, TPD52 expression was found to be associated with immune infiltration, immune checkpoints, tumor mutation burden (TMB)/ microsatellite instability (MSI), and mRNA stemness indices (mRNAsi). The somatic mutation rate of TPD52 in UCEC was 1.9%. A ceRNA network of AC011447.7/miR-1-3p/TPD52 was constructed. There was excessive TPD52 protein expression. The upregulation of TPD52 expression in UCEC cell lines was found to be statistically significant. Conclusion: TPD52 is upregulated in UCEC and may be a useful patent for prognostic biomarkers of UCEC, which may have important value for clinical treatment and supervision of UCEC patients.