ABSTRACT
Extracellular vesicles (EVs) secreted from tumor-associated macrophages (TAMs) are known to generate an immune-suppressive environment conducive to the development of ovarian cancer (OC). We tried to elucidate the role of TAM-derived exosomal microRNA (miR)-29a-3p in OC. miR-29a-3p, forkhead box protein O3 (FOXO3), and programmed death ligand-1 (PD-L1) expression was determined and their interactions evaluated. EVs were isolated, followed by determination of the uptake of EVs by OC cells, after which the proliferation and immune escape facilities of the OC cells were determined. OC xenograft models were constructed with EVs in correspondence with in vivo experiments. Overexpressed miR-29a-3p was detected in OC, and miR-29a-3p promoted OC cell proliferation and immune escape. EVs derived from TAMs enhanced the proliferation of OC cells. miR-29a-3p was enriched in TAM-EVs, and TAM-EVs delivered miR-29a-3p into OC cells. Downregulated FOXO3 was identified in OC, whereas miR-29a-3p targeted FOXO3 to suppress glycogen synthase kinase 3ß (GSK3ß) activity via the serine/threonine protein kinase (AKT)/GSK3ß pathway. Inhibition of TAM-derived exosomal miR-29a-3p decreased PD-L1 to inhibit OC progression through the FOXO3-AKT/GSK3ß pathway in vitro and in vivo. Taken together, the current studies highlight the FOXO3-AKT/GSK3ß pathway and the mechanism by which TAM-derived exosomal miR-29a-3p enhances the expression of PD-L1 to facilitate OC cell proliferation and immune escape.
ABSTRACT
Accumulating evidence shows that the tumor microenvironment contributes to this phenomenon and that long non-coding RNAs (lncRNAs) are also involved in this process. In this study, we identified a new lncRNA small nucleolar RNA host gene 12 (SNHG12) and investigated its role in tumor immune escape. We analyzed the expression levels of interlukin (IL)-6R and programmed death-ligand 1 (PD-L1) in 51 ovarian cancer and 20 normal specimens by immunohistochemistry. The correlation between SNHG12 and IL-6R in clinical ovarian cancer samples was identified by RT-qPCR. We then performed SNHG12 gain- and loss-function experiments in order to investigate its role in the regulation of immune escape and the crosstalk between miR-21 and IL-6. T cell proliferation was assessed by flow cytometry. In vivo pro-immune escape activity of SNHG12 was assessed by tumor-xenograft mouse model. IL-6R and PD-L1 were found to be overexpressed in clinical ovarian cancer specimens. Meanwhile, SNHG12 and IL-6R expressions were positively correlated in clinical ovarian cancer samples. SNHG12 facilitated ovarian immune escape by promoting IL-6/miR-21 crosstalk between ovarian cancer cells and M2 macrophages. Notably, SNHG12 promoted IL-6R transcription by recruiting NF-κB1 to the IL-6R promoter. Our study reveals that SNHG12 facilitates ovarian cancer immune escape by upregulating IL-6R.
ABSTRACT
OBJECTIVE: To evaluate the pregnancy outcome of women with rheumatic heart disease. METHODS: Clinical data of 65 cases of pregnant women with rheumatic heart disease from Jan 1993 to July 2006 were analyzed. They were divided into four groups according to the degree of mitral stenosis: normal group (> 4.0 cm(2)), slight group (2.5 - 4.0 cm(2)), moderate group (1.5 - 2.5 cm(2)) and severe group (< 1.5 cm(2)); four groups according to the degree of pulmonary hypertension: normal group, slight group (pulmonary hypertension ranging from 31 to 49 mm Hg, 1 mm Hg = 0.133 kPa) moderate group (from 50 to 79 mm Hg) and severe group (equal to and more than 80 mm Hg); two groups according to heart operation: non-operated group and operated group; and four groups according to the degree of New York heart association (NYHA) class. The perinatal mortality and morbidity of mothers and fetus were analysed. RESULTS: (1) The rate of NYHA class IV was 80% (12/15 cases) in moderate-severe group of mitral stenosis and the rate of NYHA class I and II was 80% (16/20 cases) in normal group, with a significant difference between them (P < 0.05). (2) The rate of NYHA class I and II was 73% (24/33 cases) in group of normal pulmonary pressure and the rate of NYHA class IV was 6/7 in severe group of pulmonary hypertension (P < 0.05). (3) The rate of NYHA class I and II was 71% (10/14), and NYHA class III or IV was 14% (2/14) in heart operated women (P < 0.05). (4) The delivery week was 34.6 and the birth weight was 2176 g averagely in NYHA class IV group and had significant differences from NYHA class I group (P < 0.05). There were 9 cases of abortion medically (18.9%, 9/65), 18 of preterm labor medically (28%, 18/65), 4 of fetal growth restriction (FGR) (6%, 4/65) and 3 of perinatal mortality (5%, 3/65), which all happened in groups of NYHA class III and IV. (5) The rate of NYHA class III and IV was 6/7 in atrial fibrillation women. CONCLUSION: Pregnant women with rheumatic heart disease of moderate-severe mitral stenosis, severe pulmonary hypertension and atrial fibrillation are at high risk of heart failure. The fetal outcome is not good in cases of NYHA class III and IV.
