Metabolism-related gene vaccines and immune infiltration in ovarian cancer: A novel risk score model of machine learning.

BACKGROUND: The present study aims to develop a metabolic gene signature to evaluate the survival rate of ovarian cancer (OC) patients and analyze the potential mechanisms of metabolic genes in OC because the difficulty in early detection of OC often leads to poor treatment outcomes. METHODS: A non-negative matrix factorization algorithm was applied to determine molecular subtypes according to metabolism genes. To build a risk prognosis model, least absolute shrinkage and selection operator multivariate Cox analysis was carried out with weighted correlation network analysis (WCGNA). Glycolytic flux and mitochondrial function were evaluated by conducting seahorse analysis. RESULTS: On the basis of metabolism-related genes, the two subtypes of OC samples present in The Cancer Genome Atlas database were distinguished. An analysis of WGCNA identified 1056 genes. Lastly, a 10-gene signature (CMAS, ADH1B, PLA2G2D, BHMT, CACNA1C, AADAC, ALOX12, CYP2R1, SCN1B and ME1) was constructed that demonstrated promising performance in predicting outcome in patients with OC. The RiskScore of the gene signature was linked to microenvironment cell infiltration and immune checkpoint. Higher RiskScores were associated with poorer results for OC patients. Seahorse analysis shows the influence of CMAS in cell energy metabolism. CONCLUSIONS: In the present study, a novel marker for evaluating the survival of OC patients was developed through the creation of a gene signature incorporating metabolism-related genes. Our knowledge of immunotherapy and microenvironment cell infiltration may be enriched by evaluating metabolism-related gene modification patterns.

The intervention effect of nicotine on cervical fibroblast-myofibroblast differentiation in lipopolysaccharide-induced preterm birth model through activating the TGF-ß1/Smad3 pathway.

Currently, the clinical treatment of preterm birth, mainly using uterine contraction inhibitors, does not fundamentally reduce the incidence of premature birth (PTB). Premature cervical ripening is an important factor in PTB. We previously found that nicotine-treated pregnant murine had significant cervical resistance to stretch and higher collagen cross-links compared to the control animals, and nicotine prolonged gestation and inhibited cervical ripening. However, the regulatory effects of nicotine on premature cervical ripening and its role in PTB remain unclear. To investigate the effects of nicotine on cervical TGF-ß1/Smad3 pathway and fibroblast-myofibroblast differentiation regulated by this pathway in PTB-like models. Intraperitoneal injection with 15 µg lipopolysaccharide (LPS) in 200 µl PBS into pregnant mice was used to induce the PTB-like model. Mice were randomly divided into four groups: control group, LPS-treated group, LPS + Nicotine co-treated group and LPS + Nicotine+α-BGT co-treated group. Pregnancy outcomes were monitored. The collagen content was assessed by Picrosirius red staining. Expressions of genes and proteins in the TGF-ß/Smad3 pathway were detected by double immunofluorescence staining and quantitative Real-time PCR (qRT-PCR). myofibroblast differentiation were investigated by double immunofluorescence staining and qRT-PCR. Ultrastructures were analyzed by conventional transmission electron microscopy. The rate of PTB and neonatal mortality at birth was significantly higher in the LPS-treated group than in the control group; collagen content also decreased remarkably; the expression of TGF-ß1 in macrophages and p-Smad3 in fibroblasts were reduced; the expression of α-smooth muscle actin (α-SMA, markers for activated fibroblasts) was down-regulated while the expression of calponin and smoothelin (markers for fibroblasts at rest) was up-regulated. Nicotine improved pregnancy outcomes and inhibited collagen degradation, activated the TGF-ß1/Smad3 pathway and promoted cervical fibroblast-myofibroblast differentiation in PTB-like mice; such effects could be reversed by α-bungarotoxin (α-BGT). Nicotine inhibited premature cervical ripening in PTB-like models in relation with up-regulating the TGF-ß/Smad3 pathway and promoting fibroblast to differentiate into myofibroblasts.

FOXC1 promotes proliferation and epithelial-mesenchymal transition in cervical carcinoma through the PI3K-AKT signal pathway.

Recently, Forkhead box C1 (FOXC1) has been identified to play important roles in human cancers. However, the clinical significance and biological role of FOXC1 in cervical cancer remains unclear. Here, we showed that FOXC1 was frequently overexpressed in cervical cancer versus adjacent non-tumor tissues. Overexpression of FOXC1 was significantly correlated with tumor stage (P=0.011), tumor size (P=0.034), stromal invasion (P=0.001), and lymph nodes metastasis (P=0.008). Survival analysis further suggested that high FOXC1 expression was significantly correlated with poor overall survival (P=0.007) and recurrence-free survival (P=0.003) in cervical cancer patients. Moreover, we found that knock-down of FOXC1 by short hairpin RNAi significantly suppressed cervical cancer cells proliferation, migration, and invasion in vitro. Mechanistic studies showed that the FOXC1 requires PI3K/AKT signaling for its regulation of cell proliferation, migration and invasion. Our findings indicate that FOXC1 plays an important oncogenic role in cervical cancer progression.

Prognostic significance of discoidin domain receptor 2 (DDR2) expression in ovarian cancer.

Increasing evidence has suggested that discoidin domain receptor 2 (DDR2) plays an important role in cancer development and metastasis. However, the correlation between DDR2 expression and clinical outcome in ovarian cancer has not been investigated. In this study, DDR2 expression was examined by Real-time PCR in surgically resected ovarian cancer and normal ovary tissues. Besides, DDR2 expression was analyzed immunohistochemically in 103 ovarian cancer patients, and the correlation between DDR2 expression with clinicopathologic factors was analyzed. The result showed that DDR2 mRNA expression was upregulated in ovarian cancer tissues compared with normal ovary tissues. Statistical analysis revealed that DDR2 expression correlated with tumor stage (P = 0.008) and peritoneal metastasis (P = 0.009). Patients with high DDR2 expression showed poorer 5-year overall survival (P = 0.005), and DDR2 remained an independent prognostic marker for OS (P = 0.013) in multivariate analysis. Our results suggest that DDR2 might be closely associated with ovarian cancer progression and metastasis. Its high expression may serve as a potential prognostic biomarker in human ovarian cancer.

Increased expression of microRNA-196a predicts poor prognosis in human ovarian carcinoma.

OBJECTIVE: Overexpression of MicroRNA-196a (miR-196a) has recently been reported in different types of human cancers. However, the prognostic value of miR-196a in ovarian carcinoma remains unknown. In this study, we investigated the expression of miR-196a in ovarian carcinoma and its relationship with tumor progression and clinical prognosis. METHODS: The expression level of miR-196a was examined by quantitative Real-time PCR (qRT-PCR) in surgically removed ovarian cancer tissues and ovarian cancer cell lines. The correlation between miR-196a expression and clinical features and prognosis were statistically analyzed. RESULTS: The results showed that the miR-196a expression was significantly upregulated in tumor tissues and ovarian cancer cell lines compared with that in normal ovarian surface tissues and normal ovarian epithelial cells. Moreover, miR-196a expression was positively correlated with FIGO stage (P<0.001), tumor size (P=0.020), and lymph nodes metastasis (P=0.019). Kaplan-Meier analysis demonstrated that high levels of miR-196a expression was associated with poorer overall survival (P<0.001) and recurrent-free survival (P=0.003), especially in patients with advanced disease (P=0.002). Multivariate analysis suggested that miR-196a expression was an independent prognostic factor for overall survival of patients with ovarian carcinoma. CONCLUSIONS: In conclusion, miR-196a may play an important role in the progression of ovarian carcinoma, and could be used as an independent prognostic biomarker for patients with ovarian carcinoma.