Hypoxia-induced ZEB1 promotes cervical cancer immune evasion by strengthening the CD47-SIRPα axis.

BACKGROUND: The dynamic interaction between cancer cells and tumour-associated macrophages (TAMs) in the hypoxic tumour microenvironment (TME) is an active barrier to the effector arm of the antitumour immune response. Cancer-secreted exosomes are emerging mediators of this cancer-stromal cross-talk in the TME; however, the mechanisms underlying this interaction remain unclear. METHODS: Exosomes were isolated with ExoQuick exosome precipitation solution. The polarizing effect of TAMs was evaluated by flow cytometry, western blot analysis, immunofluorescence staining and in vitro phagocytosis assays. Clinical cervical cancer specimens and an in vivo xenograft model were also employed. RESULTS: Our previous study showed that hypoxia increased the expression of ZEB1 in cervical squamous cell carcinoma (CSCC) cells, which resulted in increased infiltration of TAMs. Here, we found that hypoxia-induced ZEB1 expression is closely correlated with CD47-SIRPα axis activity in CSCC, which enables cancer cells to evade phagocytosis by macrophages and promotes tumour progression. ZEB1 was found to directly activate the transcription of the CD47 gene in hypoxic CSCC cells. We further showed that endogenous ZEB1 was characteristically enriched in hypoxic CSCC cell-derived exosomes and transferred into macrophages via these exosomes to promote SIRPα+ TAM polarization. Intriguingly, exosomal ZEB1 retained transcriptional activity and reprogrammed SIRPα+ TAMs via activation of the STAT3 signalling pathway in vitro and in vivo. STAT3 inhibition reduced the polarizing effect induced by exosomal ZEB1. Knockdown of ZEB1 increased the phagocytosis of CSCC cells by macrophages via decreasing CD47 and SIRPα expression. CONCLUSIONS: Our results suggest that hypoxia-induced ZEB1 promotes immune evasion in CSCC by strengthening the CD47-SIRPα axis. ZEB1-targeted therapy in combination with CD47-SIRPα checkpoint immunotherapy may improve the outcomes of CSCC patients in part by disinhibiting innate immunity.

Superficial vaginal myofibroblastoma with mushroom-like appearance: A case report with colposcopic findings and literature review.

Superficial myofibroblastoma (SMF) of the lower female genital tract is a relatively rare benign mesenchymal tumor. The diagnosis is usually challenging as it shares several similar clinicopathological features with other tumors. Herein, we present a case of a 71-year-old Chinese female patient with postmenopausal vaginal bleeding. Colposcopy imaging revealed a well-circumscribed mass in the vagina with a wide pedicle, resembling a mushroom. The patient underwent surgery, and the tumor was histologically diagnosed as SMF. To the best of our knowledge, this is the first report of colposcopic imaging of a superficial vaginal myofibroblastoma. In this case study, we review the clinicopathological features of SMF of the lower female genital tract reported in the literature to improve the understanding of the disease.

FTO Inhibits Epithelial Ovarian Cancer Progression by Destabilising SNAI1 mRNA through IGF2BP2.

Fat mass and obesity-associated protein (FTO) regulates critical pathways in various diseases, including malignant tumours. However, the functional link between FTO and its target genes in epithelial ovarian cancer (EOC) development remains to be elucidated. In this study, the biological functions of FTO were verified in vitro and in vivo. The m6A modification and the binding sites of SNAI1 mRNA were confirmed by m6A RNA immunoprecipitation (MeRIP) and RIP experiments. The actinomycin D assay was used to test the stability of RNA. We found that FTO was downregulated with increased m6A levels in EOC. Reduced expression of FTO was associated with a higher FIGO stage in patients with EOC. Mechanistically, FTO decreased the m6A level and stability of SNAI1 mRNA, causing downregulation of SNAI1 and inhibiting epithelial-mesenchymal transition (EMT). Furthermore, FTO-mediated downregulation of SNAI1 expression depended on IGF2BP2, which acted as an m6A reader binding to the 3' UTR region of SNAI1 mRNA to promote its stability. In conclusion, FTO inhibits SNAI1 expression to attenuate the growth and metastasis of EOC cells in an m6A-IGF2BP2-dependent manner. Our findings suggest that the FTO-IGF2BP2-SNAI1 axis is a potential therapeutic target in EOC.

Wickerhamomyces anomalus relieves weaning diarrhea via improving gut microbiota and redox homeostasis using a piglet model.

Weaning stress commonly damages the intestinal barrier of mammals, resulting in gut microbiota dysbiosis, intestinal illness, and even severe diarrhea. Probiotics are used as a nutritional strategy to promote the health of humans and animals and the gut microbiota balance. Here Wickerhamomyces anomalus was applied as a probiotic supplement to a weaned piglet model to investigate its impacts on growth performance, antioxidant capacity, inflammation response, and intestinal health. Supplemental 1 g kg-1 108 cfu g-1W. anomalus 13611 significantly decreased the feed conversion ratio (FCR), alleviated diarrhea, improved the apparent total tract digestibility of neutral detergent fiber (NDF) and gross energy (GE), increased the concentration of total antioxidant capacity (T-AOC) and catalase (CAT) in serum, and decreased the concentration of malondialdehyde (MDA) and pro-inflammatory cytokines such as interleukin-1ß (IL-1ß) in serum. Importantly, supplementation of W. anomalus 13611 also improved the gut microbiota, decreasing the relative abundance of Oxalobacteraceae, enriching the relative abundances of Lactobacillaceae and Lactobacillus, and increasing the relative abundances of two species of Lactobacillus (helveticus and delbrueckii). In conclusion, W. anomalus 13611 could effectively promote growth performance and alleviate diarrhea in a model of weaned piglets, which may be related to improved antioxidant activity, anti-inflammatory response, and alteration in the structure of the gut microbiota.

PHGDH Inhibitor CBR-5884 Inhibits Epithelial Ovarian Cancer Progression via ROS/Wnt/ß-Catenin Pathway and Plays a Synergistic Role with PARP Inhibitor Olaparib.

PHGDH attaches importance to serine biosynthesis in cancer cells and maintaining mitochondrial redox homeostasis. However, the role of PHGDH inhibitor CBR-5884 in cell ROS level and its downstream pathways has not been explored in epithelial ovarian cancer. Thus, we investigated the function and possible mechanism of PHGDH inhibitor CBR-5884 on epithelial ovarian cancer in vitro and in vivo. A2780, OVCAR3, and ES-2 were treated with CBR-5884 at different concentrations or different time points. Results showed that CBR-5884 inhibited epithelial ovarian cancer cell proliferation, migration, and invasion and increases cell ROS level. Meanwhile, CBR-5884 exerts antitumor effect through activating ROS/Wnt/ß-catenin pathway. Besides, CBR-5884 exerts antitumor effect in vivo. What's more, we explored the effect of CBR-5884 with or without PARP inhibitor Olaparib, which showed that the two together had a larger effect. In conclusion, PHGDH inhibitor CBR-5884 inhibits epithelial ovarian cancer proliferation, migration, and invasion through activating ROS/Wnt/ß-catenin pathway and plays a synergistic role with PARP inhibitor olaparib, which provided a theoretical basis for PHGDH inhibitor CBR-5884 in clinical treatment.

Identification and Development of Subtypes With Poor Prognosis in Pan-Gynecological Cancer Based on Gene Expression in the Glycolysis-Cholesterol Synthesis Axis.

Objective: Metabolic reprogramming is an important biomarker of cancer. Metabolic adaptation driven by oncogenes allows tumor cells to survive and grow in a complex tumor microenvironment. The heterogeneity of tumor metabolism is related to survival time, somatic cell-driven gene mutations, and tumor subtypes. Using the heterogeneity of different metabolic pathways for the classification of gynecological pan-cancer is of great significance for clinical decision-making and prognosis prediction. Methods: RNA sequencing data for patients with ovarian, cervical, and endometrial cancer were downloaded from The Cancer Genome Atlas database. Genes related to glycolysis and cholesterol were extracted and clustered coherently by using ConsensusClusterPlus. The mutations and copy number variations in different subtypes were compared, and the immune scores of the samples were evaluated. The limma R package was used to identify differentially expressed genes between subtypes, and the WebGestaltR package (V0.4.2) was used to conduct Kyoto Encyclopedia of Genes and Genomes pathway and Gene Ontology functional enrichment analyses. A risk score model was constructed based on multivariate Cox analysis. Prognostic classification efficiency was analyzed by using timeROC, and internal and external cohorts were used to verify the robustness of the model. Results: Based on the expression of 11 glycolysis-related genes and seven cholesterol-related genes, 1,204 samples were divided into four metabolic subtypes (quiescent, glycolysis, cholesterol, and mixed). Immune infiltration scores showed significant differences among the four subtypes. Survival analysis showed that the prognosis of the cholesterol subtype was better than that of the quiescent subtype. A nine-gene signature was constructed based on differentially expressed genes between the cholesterol and quiescent subtypes, and it was validated by using an independent cohort of the International Cancer Genome Consortium. Compared with existing models, our nine-gene signature had good prediction performance. Conclusion: The metabolic classification of gynecological pan-cancer based on metabolic reprogramming may provide an important basis for clinicians to choose treatment options, predict treatment resistance, and predict patients' clinical outcomes.

Identification of prognostic and immune-related gene signatures in the tumor microenvironment of endometrial cancer.

Uterine corpus endometrial cancer (UCEC) is one of the most prevalent female malignancies in clinical practice. Due to the lack of effective biomarkers and personalized treatments, the prognosis of advanced-stage EC remains unfavorable. Modulation of the immune microenvironment is closely related to the onset and development of endometrial cancer. In the present study, we attempt to systematically analyze the characteristics of the immune microenvironment of endometrial cancer and investigate its association with clinical features by applying bioinformatics. RNA-Seq in TCGA (The Cancer Genome Atlas) and clinical follow-up information of patents were used for analysis. The Tumor Microenvironment (TME) score infiltration patterns of 523 endometrial cancer patients were evaluated using CIBERSORT. Random forest, multivariable cox analysis were used to build the TME score. Fisher's exact test was used to compare the genes that show significant differences in the frequency of mutations between groups. Two TME phenotypes were defined. There is a significant relationship between the TME score and grade. High TME score samples are highly expressed in immune activation, TGF pathway activation and immune checkpoint genes, and low TME score samples have high frequency mutations of PTEN, CSE1L and ITGB3. Therefore, describing the comprehensive landscape of UCEC's TME characteristics may help explain patients' response to immunotherapy and provide new strategies for cancer treatment.

Tryptophan (Trp) modulates gut homeostasis via aryl hydrocarbon receptor (AhR).

The intestinal homeostasis is an orchestrated dynamic equilibrium state composed of the coexistence and interactions among the nutrients, microbial flora, and immune system. The intestinal balance disorder can trigger a series of diseases, such as inflammatory bowel disease (IBD). Many of tryptophan (Trp) metabolites, such as kynurenine and indole, generated under a series of endogenous enzymes or microbial metabolism, have been reported enable to bind and activate the aryl hydrocarbon receptor (AhR), this series of process is termed the Trp-AhR pathway. The activated Trp-AhR pathway can induce the expression of downstream cytokines such as interleukin-22 (IL-22) and interleukin-17 (IL-17), thereby regulating the intestinal homeostasis. This review highlights the advance of Trp-AhR pathway in the regulation of intestinal homeostasis and provides some insights for the clinical strategies that expect to effectively prevent and treat gut diseases via intervening the Trp-AhR pathway.