BackgroundIn recent years, circular RNAs (circRNAs), a new star of non-coding RNA, have been emerged as vital regulators and gained much attention for involvement of initiation and progression of diverse kinds of human diseases, especially cancer. However, regulatory role, clinical significance and underlying mechanisms of circRNAs in triple-negative breast cancer (TNBC) still remain largely unknown.MethodsHere, the expression profile of circRNAs in 4 pairs of TNBC tissues and adjacent non-tumor tissues was analyzed by RNA-sequencing. Quantitative real-time PCR and in situ hybridization were used to determine the level and prognostic values of circAGFG1 in two TNBC cohorts. Then, functional experiments in vitro and in vivo were performed to investigate the effects of circAGFG1 on tumor growth and metastasis in TNBC. Mechanistically, fluorescent in situ hybridization, dual luciferase reporter assay, RNA pull-down and RNA immunoprecipitation experiments were performed to confirm the interaction between circAGFG1 and miR-195-5p in TNBC.ResultsWe found that circAGFG1 was evidently up-regulated in TNBC, and its level was correlated with clinical stage, pathological grade and poor prognosis of patients with TNBC. The results indicated that circAGFG1 could promote TNBC cell proliferation, mobility and invasion as well as tumorigenesis and metastasis in vivo. Mechanistic analysis showed that circAGFG1 may act as a ceRNA (competing endogenous RNA) of miR-195-5p to relieve the repressive effect of miR-195-5p on its target cyclin E1 (CCNE1).ConclusionsOur findings suggest that circAGFG1 promotes TNBC progression through circAGFG1/miR-195-5p/CCNE1 axis and it may serve as a new diagnostic marker or target for treatment of TNBC patients.Electronic supplementary materialThe online version of this article (10.1186/s12943-018-0933-7) contains supplementary material, which is available to authorized users.

Background: Increasing studies have shown that circRNA is closely related to the carcinogenesis and development of many cancers. However, biological functions and the underlying molecular mechanism of circRNAs in triplenegative breast cancer (TNBC) remain largely unclear so far. Methods: Here, we investigated the expression pattern of circRNAs in four pairs of TNBC tissues and paracancerous normal tissues using RNA-sequencing. The expression and prognostic significance of circSEPT9 were evaluated with qRT-PCR and in situ hybridization in two TNBC cohorts. The survival curves were drawn by the Kaplan-Meier method, and statistical significance was estimated with the log-rank test. A series of in vitro and in vivo functional experiments were executed to investigate the role of circSEPT9 in the carcinogenesis and development of TNBC. Mechanistically, we explored the potential regulatory effects of E2F1 and EIF4A3 on biogenesis of circSEPT9 with chromatin immunoprecipitation (ChIP), luciferase reporter and RNA immunoprecipitation (RIP) assays. Furthermore, fluorescent in situ hybridization (FISH), luciferase reporter and biotin-coupled RNA pull-down assays were implemented to verify the relationship between the circSEPT9 and miR-637 in TNBC. Results: Increased expression of circSEPT9 was found in TNBC tissues, which was positively correlated with advanced clinical stage and poor prognosis. Knockdown of circSEPT9 significantly suppressed the proliferation, migration and invasion of TNBC cells, induced apoptosis and autophagy in TNBC cells as well as inhibited tumor growth and metastasis in vivo. Whereas up-regulation of circSEPT9 exerted opposite effects. Further mechanism research demonstrated that circSEPT9 could regulate the expression of Leukemia Inhibitory Factor (LIF) via sponging miR-637 and activate LIF/Stat3 signaling pathway involved in progression of TNBC. More importantly, we discovered that E2F1 and EIF4A3 might promote the biogenesis of circSEPT9. Conclusions: Our data reveal that the circSEPT9 mediated by E2F1 and EIF4A3 facilitates the carcinogenesis and development of triple-negative breast cancer through circSEPT9/miR-637/LIF axis. Therefore, circSEPT9 could be used as a potential prognostic marker and therapeutical target for TNBC.

SummaryBone marrow‐derived mesenchymal stem cells (BMMSCs) exhibit degenerative changes, including imbalanced differentiation and reduced proliferation during aging, that contribute to age‐related bone loss. We demonstrate here that autophagy is significantly reduced in aged BMMSCs compared with young BMMSCs. The autophagy inhibitor 3‐methyladenine (3‐MA) could turn young BMMSCs into a relatively aged state by reducing their osteogenic differentiation and proliferation capacity and enhancing their adipogenic differentiation capacity. Accordingly, the autophagy activator rapamycin could restore the biological properties of aged BMMSCs by increasing osteogenic differentiation and proliferation capacity and decreasing adipogenic differentiation capacity. Possible underlying mechanisms were explored, and the analysis revealed that autophagy could affect reactive oxygen species and p53 levels, thus regulating biological properties of BMMSCs. In an in vivo study, we found that activation of autophagy restored bone loss in aged mice. In conclusion, our results suggest that autophagy plays a pivotal role in the aging of BMMSCs, and activation of autophagy could partially reverse this aging and may represent a potential therapeutic avenue to clinically treat age‐related bone loss.

Epigenetics refers to the study of clonally inherited changes in gene expression without accompanying genetic changes. Previous research on the epigenetics of myelodysplastic syndromes (MDS) mainly focused on the inactivation of tumor suppressor genes as a result of DNA methylation. However, the basic molecular pathogenesis of epigenetics in MDS remains poorly understood. Recent studies have revealed that DNA methylation and histone modification may be controlled by Polycomb-group (PcG) proteins, which may give new clues toward understanding the epigenetic mechanism of MDS. In this study, we explored for the first time the expression of PcG genes, including EZH2, EED, SUZ12, RING1, and BMI1, in various MDS subsets and acute myeloid leukemia (AML), as well as the relationship between the expression of PcG genes and epigenetic alteration and prognosis-risk scoring. Patients with MDS/AML showed overexpression of EZH2, RING1, and BMI1 genes compared to their expression levels in patients with non-clonal cytopenia diseases. The MDS patients with DNA methylation had higher EZH2 expression than those without DNA methylation. The patients who received decitabine treatment presented significantly reduced expression of EZH2 and RING1 besides decreased p15(INK4B) methylation after decitabine treatment. Moreover, overexpression of EZH2, RING1, and BMI1 was always linked to poor prognostic scoring. In conclusion, overexpression of the EZH2, RING1, and BMI1 genes is common in MDS and indicate poor prognosis. The products of these genes might participate in epigenetic regulation of MDS. These studies may also contribute to our understanding of the effective mechanism of decitabine.

See also Hamasaki N. Unmasking Asian thrombophilia: is APC dysfunction the real culprit? This issue, pp 2016–8. Summary.  Background:  There are ethnic differences in the genetic risk factors for venous thrombosis (VT). The genetic causes of VT in the Chinese population are not fully understood. Objectives:  To identify possible common abnormal factors that could contribute to thrombosis susceptibility. Methods/Results:  We measured the levels of nine types of plasma coagulation factor, three types of anticoagulation factor and two types of fibrinolytic factor in 310 VT patients. Factor V activity was higher in 32 cases. Eleven of the 32 cases also had low protein C (PC) or protein S (PS) activities, indicating PC or PS deficiency. No other abnormalities were observed in the other 21 cases. All of the samples were sensitive to activated PC inactivation. Therefore, the abnormal factor involved may be FV inactivator or its cofactor rather than FV itself. Resequencing identified a common PROC c.574_576del variant in 10 of the 32 subjects. In a case–control study, this variant was detected in 68 of the 1003 patients and in 25 of the 1031 controls. It had an adjusted odds ratio of 2.71 (95% confidence interval [CI] 1.68–4.36). PC amidolytic activities of most variant carriers were similar to those of non‐carriers, but the mean anticoagulant activity was only 72.7 U dL−1. Expression studies in vitro showed that the anticoagulant activity of the mutant PC was 43.6% of that of the wild‐type PC. Conclusions:  We identified what is, so far, the most common genetic risk factor for VT in the Chinese population, with its prevalence being approximately 2.36%.