Ge Lou

Clinical and prognostic significance of FBXL6 expression in ovarian cancer

Growing evidence indicates that F-box and leucine-rich repeat protein 6 (FBXL6) is associated with the progression of various cancers, including gastric cancer, hepatocellular carcinoma, and colorectal cancer. This study focuses on the prognostic significance of FBXL6 in OC. Differential levels of FBXL6 in multiple cancers were evaluated using the TCGA and GSE26712 databases. We screened FBXL6-related differentially expressed genes using the GSE63885 dataset and conducted Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways analysis. The genes that associate with FBXL6 were screened using the "limma" package, the STRING database, and Cytoscape software, and the association was validated through Gene Expression Profiling Interactive Analysis. The potential substrates of FBXL6 were predicted using UbiBrowser2.0 database. FBXL6 protein levels in 84 OC samples were evaluated using immunohistochemistry. The prognostic significance of FBXL6 was explored using Kaplan-Meier and Cox regression analyses. Based on the Cox regression results, an FBXL6-based nomogram that can predict the overall survival (OS) rate were constructed. Moreover, we examined the net benefits and discriminative ability of the nomogram using the decision curve analysis (DCA), calibration plots, and receiver operating characteristic (ROC) curve. FBXL6 was elevated in OC tissues, and the overexpression of FBXL6 was linked to poor prognosis in OC patients. The ROC and DCA curves indicated that the prognostic value of the FBXL6-based nomogram model was superior to that of FBXL6, age, and FIGO stage alone. Elevated FBXL6 expression was an independent factor for OC, and an easily applied nomogram was developed to predict OS in OC patients.

m6A methylation-mediated regulation of LncRNA MEG3 suppresses ovarian cancer progression through miR-885-5p and the VASH1 pathway

Abstract Background Ovarian cancer poses a serious threat to women's health. Due to the difficulty of early detection, most patients are diagnosed with advanced-stage disease or peritoneal metastasis. We found that LncRNA MEG3 is a novel tumor suppressor, but its role in tumor occurrence and development is still unclear. Methods We investigated the expression level of MEG3 in pan-cancer through bioinformatics analysis, especially in gynecological tumors. Function assays were used to detect the effect of MEG3 on the malignant phenotype of ovarian cancer. RIP, RNA pull-down, MeRIP-qPCR, actinomycin D test were carried out to explore the m6A methylation-mediated regulation on MEG3. Luciferase reporter gene assay, PCR and Western blot were implemented to reveal the potential mechanism of MEG3. We further confirmed the influence of MEG3 on tumor growth in vivo by orthotopic xenograft models and IHC assay. Results In this study, we discovered that MEG3 was downregulated in various cancers, with the most apparent downregulation in ovarian cancer. MEG3 inhibited the proliferation, migration, and invasion of ovarian cancer cells. Overexpression of MEG3 suppressed the degradation of VASH1 by negatively regulating miR-885-5p, inhibiting the ovarian cancer malignant phenotype. Furthermore, we demonstrated that MEG3 was regulated at the posttranscriptional level. YTHDF2 facilitated MEG3 decay by recognizing METTL3‑mediated m6A modification. Compared with those injected with vector control cells, mice injected with MEG3 knockdown cells showed larger tumor volumes and faster growth rates. Conclusion We demonstrated that MEG3 is influenced by METTL3/YTHDF2 methylation and restrains ovarian cancer proliferation and metastasis by binding miR-885-5p to increase VASH1 expression. MEG3 is expected to become a therapeutic target for ovarian cancer.

Hypoxic tumour-derived exosomal miR-1225-5p regulates M2 macrophage polarisation via toll-like receptor 2 to promote ovarian cancer progress

Tumor-secreted exosomes are critical for the functional regulation of tumor-associated macrophages (TAMs). This study aimed to explore how exosomes secreted by ovarian carcinoma cells regulate the phenotype and function of macrophages. Hypoxic treatment of A2780 cells was postulated to mimic the tumor microenvironment, and exosomes were co-cultured with TAMs. miR-1225-5p was enriched in hypoxic exosomes and contributed to M2 macrophage polarizationby modulating Toll-like receptor 2 expression (TLR2). Furthermore, hypoxia-treated macrophages promote ovarian cancer cell viability, migration, and invasion via the wnt/β-catenin pathway. This study clarified that exosomal miR-1225-5p promotes macrophage M2-like polarization by targeting TLR2 to promote ovarian cancer, which may via the wnt/β-catenin pathway.

Revealing the inhibitory effect of VASH1 on ovarian cancer from multiple perspectives

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Loss of SMURF2 expression enhances RACK1 stability and promotes ovarian cancer progression

AbstractReceptor for activated C kinase 1 (RACK1) has been confirmed to take part in multiple biological events and the mechanism supporting abnormal RACK1 expression in ovarian cancer (OC) remains to be characterized. Here, we identified Smad ubiquitin regulatory factor 2 (SMURF2) as a bona fide E3 ligase of RACK1 in OC. SMURF2 effectively added the K6, K33 and K48 ubiquitin chains to the RACK1, resulting in polyubiquitination and instability of RACK1. PCAF promoted acetylation of RACK1 at K130, leading to SMURF2-mediated RACK1 ubiquitination inhibited and promote OC progression. The expression levels of SMURF2 and RACK1 were negatively correlated. SMURF2 was abnormal low expression in human ovarian cancer, resulting in decreased ubiquitination of RACK1 and increased stability, which promoted OC progression, and strongly associated with poor patients’ prognosis. In general, our results demonstrated that SMURF2 plays a pivotal role in stabilizing RACK1, which in turn facilitates tumorigenesis in OC, suggesting that SMURF2-RACK1 axis may prove to be potential targets for the treatment of OC.

Hypoxia-induced PPFIA4 accelerates the progression of ovarian cancer through glucose metabolic reprogramming

Dysregulated glycolysis promotes growth and metastasis, which is one of the metabolic characteristics of ovarian cancer. Based on bioinformatics analysis, liprin-alpha-4 (PPFIA4) is a gene associated with hypoxia, and we aimed to investigate the potential mechanism of PPFIA4 during the reprogramming of glucose metabolism in ovarian cancer cells. Currently, the cell viability of ovarian cancer cells under the hypoxia treatment was evaluated by CCK-8 assay, and cell migration and invasion were measured by transwell assay and western blot. The effects of hypoxia treatment on glucose uptake, lactate production, extracellular acidification rate (ECAR), adenosine triphosphate (ATP), reactive oxygen species (ROS), Nicotinamide adenine dinucleotide phosphate (NADPH) and its oxidized form NADP + , and oxygen consumption rate (OCR) in ovarian cancer cells were examined. Then PPFIA4 was identified through bioinformatic analysis, and the regulatory effects of PPFIA4 on glucose metabolic reprogramming. Our data suggested that hypoxia enhanced the migration and invasion ability of ovarian cancer cells in vitro, and promoted the glucose metabolic reprogramming of ovarian cancer cells. Ovarian cancer cell viability, migration, and invasion were inhibited after PPFIA4 knockdown. Inhibition of PPFIA4 inhibited hypoxic-induced glucose metabolic reprogramming in ovarian cancer cells. In addition, PPFIA4 was found to bind to hypoxia-inducible factor 1alpha (HIF1A), and HIF1A prominently induced PPFIA4 expression. Collectively, HIF1A mediated upregulation of PPFIA4 and promoted reprogramming of glucose metabolism in ovarian cancer cells. Therefore, PPFIA4 may be a therapeutic target for ovarian cancer intervention.

CBL0137 activates ROS/BAX signaling to promote caspase-3/GSDME-dependent pyroptosis in ovarian cancer cells

Curaxin CBL0137 was designed to regulate p53 and nuclear factor-κB simultaneously and exhibits antitumor activity by inhibiting tumor cell proliferation and inducing apoptosis in multiple cancers. However, whether CBL0137 can induce pyroptosis has not yet been reported. This study demonstrated that CBL0137 induces caspase-3/gasdermin E (GSDME)-dependent pyroptosis via the reactive oxygen species (ROS)/BAX pathway. In ovarian cancer cells, CBL0137 inactivated the chromatin remodeling complex which could facilitate chromatin transcription, leading to the decreased transcription of antioxidant genes and oxidation and causing increased ROS levels. BAX was recruited on the mitochondrial membrane by mitochondrial ROS and induced the release of cytochrome c to cleave caspase-3. This led to the cleavage of the N-terminal of GSDME to form pores on the cell membrane and induced pyroptosis. Results of in vivo experiments revealed that CBL0137 also had anti-tumor effects on ovarian cancer cells in vivo. Our study outcomes reveal the mechanisms and targets of CBL0137 inducing pyroptosis in ovarian cancer cells and indicate that CBL0137 is a promising therapeutic agent for ovarian cancer.

Immunoscore system combining CD8 and PD-1/PD-L1: A novel approach that predicts the clinical outcomes for cervical cancer

Purpose: Immunoscore was established to evaluate the prognosis of cancer patients. However, the feasibility of Immunoscore for the prognosis of cervical cancer remains unknown. To find other prognostic markers that contribute to immunological importance, immune checkpoint inhibitors targeting programmed cell death protein (PD-1), or its ligand, PD-L1, are of enormous interest. Our purpose is to investigate the expression of CD8 and PD-1/PD-L1 and their potential role in Immunoscore, supplementing the tumor/node/metastasis (TNM) classification of cervical cancer. Methods: Immunoscore was assessed according to the density of PD-1, PD-L1, and CD8 by immunohistochemistry. The association with overall survival and disease-free survival was assessed by the Kaplan–Meier method. To evaluate the effect of Immunoscore, a Cox proportional hazard regression classification was conducted. To compare the prognostic accuracies of Immunoscore and TNM staging, receiver operating characteristic curves were plotted. Results: Patients with PD-L1positive and PD-1high in immune cells had poorer overall survival and disease-free survival; however, PD-L1positive in tumor cells that infiltrated more CD8+ T cells were related to better overall survival and disease-free survival. These immune factors can be independent predictors for prognoses. According to these factors, a new Immunoscore system with priority in predicting prognoses was established. In receiver operating characteristic analysis for predictions of overall survival (the area under curve (AUC) = 0.833 vs. 0.766) and disease-free survival (AUC = 0.861 vs. 0.729), Immunoscore is more accurate than TNM staging. Conclusions: Thus, this Immunoscore system is an accurate predictive marker, which can be an important supplement to TNM staging for cervical cancer.

First-line bevacizumab plus chemotherapy in Chinese patients with stage III/IV epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer: a phase III randomized controlled trial

First-line bevacizumab plus carboplatin and paclitaxel (CP) is approved for stage III/IV ovarian cancer treatment following initial surgical resection, based on global phase III GOG-0218 and ICON7 trials. This study evaluated the efficacy and safety of bevacizumab + CP as first-line ovarian cancer therapy in Chinese patients. Patients with newly diagnosed, International Federation of Gynecology and Obstetrics (FIGO) stage III/IV epithelial ovarian, fallopian tube, or primary peritoneal cancer post-primary surgery were randomized 1:1 to receive 6 cycles of CP with bevacizumab/placebo, followed by bevacizumab/placebo maintenance until unacceptable toxicity or disease progression. Primary endpoint was investigator-assessed progression-free survival (PFS). Stratification factors were FIGO stage and debulking status (stage III optimally debulked vs stage III suboptimally debulked vs stage IV) and Eastern Cooperative Oncology Group performance status (0 vs 1 or 2). Of randomized patients, 51 received bevacizumab + CP and 49 received placebo + CP. Median PFS was 22.6 months with bevacizumab + CP (95% confidence interval [CI]=18.6, not estimable) and 12.3 months (95% CI=9.5, 15.0) with placebo + CP (stratified hazard ratio=0.30; 95% CI=0.17, 0.53). Treatment-related grade 3/4 adverse events occurred in 46 of 49 (94%) patients receiving bevacizumab + CP, and 34 of 50 (68%) receiving placebo + CP. Bevacizumab + CP showed clinically meaningful improvement in PFS vs placebo + CP, consistent with GOG-0218 results. Safety data were aligned with the known bevacizumab safety profile. These results support first-line bevacizumab + CP therapy in Chinese patients with ovarian cancer. ClinicalTrials.gov Identifier: NCT03635489.