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Abstract Background Pediatric low-grade gliomas (pLGGs), particularly incompletely resected supratentorial tumours, can undergo progression after surgery. However to date, there are no predictive biomarkers for progression. Here, we aimed to identify pLGG-specific microRNA signatures and evaluate their value as a prognostic tool. Methods We identified and validated supratentorial incompletey resected pLGG-specific microRNAs in independent cohorts from four European Pediatric Neuro-Oncology Centres. Results These microRNAs demonstrated high accuracy in differentiating patients with or without progression. Specifically, incompletely resected supratentorial pLGGs with disease progression showed significantly higher miR-1248 combined with lower miR-376a-3p and miR-888-5p levels than tumours without progression. A significant (p

Background: Pediatric low-grade gliomas (pLGGs), particularly incompletely resected supratentorial tumours, can undergo progression after surgery. However to date, there are no predictive biomarkers for progression. Here, we aimed to identify pLGG-specific microRNA signatures and evaluate their value as a prognostic tool. Methods: We identified and validated supratentorial incompletey resected pLGG-specific microRNAs in independent cohorts from four European Pediatric Neuro-Oncology Centres. Results: These microRNAs demonstrated high accuracy in differentiating patients with or without progression. Specifically, incompletely resected supratentorial pLGGs with disease progression showed significantly higher miR-1248 combined with lower miR-376a-3p and miR-888-5p levels than tumours without progression. A significant (p < 0.001) prognostic performance for miR-1248 was reported with an area under the curve (AUC) of 1.00. We also highlighted a critical oncogenic role for miR-1248 in gliomas tumours. Indeed, high miR-1248 levels maintain low its validated target genes (CDKN1A (p21)/FRK/SPOP/VHL/MTAP) and consequently sustain the activation of oncogenic pathways. Conclusions: Altogether, we provide a novel molecular biomarker able to successfully identify pLGG patients associated with disease progression that could support the clinicians in the decision-making strategy, advancing personalized medicine. [ABSTRACT FROM AUTHOR]

Fang Du,1 Tao Guo,2 Chenghua Cao3 1Department of Hematology and Oncology, No. 988 Hospital of Joint Logistic Support Force of the Chinese People’s Liberation Army, Zhengzhou, Henan Province, People’s Republic of China; 2Pediatric Intensive Care, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, People’s Republic of China; 3Translational Research Institute, Henan University, Kaifeng, Henan Province, People’s Republic of ChinaCorrespondence: Fang DuDepartment of Hematology and Oncology, No. 988 Hospital of Joint Logistic Support Force of the Chinese People’s Liberation Army, No. 602 Jianshe Road, Zhengzhou, Henan Province, People’s Republic of ChinaEmail faex164@126.comBackground: Recent evidence suggests that long non-coding RNAs (lncRNAs) are emerging as key determinants of esophageal squamous cell carcinoma (ESCC) progression. This study aimed to investigate the role of lncRNA UPK1A antisense RNA 1 (UPK1A-AS1) in ESCC cell proliferation, invasion, and migration.Methods: The expression levels of UPK1A-AS1 and miR-1248 were determined using quantitative reverse transcriptase-polymerase chain reaction. The functional role of UPK1A-AS1 in ESCC was investigated using subcellular localization assay, Cell Counting Kit-8 assay, colony formation assay, scratch-healing assay, and transwell invasion assay. The functional interaction between UPK1A-AS1 and miR-1248 was assessed using luciferase reporter and RNA pull-down assays.Results: Twenty dysregulated lncRNAs were detected in ESCC. Downregulation of UPK1A-AS1 was observed in ESCC tissues and cell lines. Functionally, upregulation of UPK1A-AS1 suppressed the proliferation, migration, and invasion of ESCC cells. Moreover, an inverse correlation between UPK1A-AS1 and miR-1248 expression was observed in ESCC specimens, and miR-1248 was identified as a direct target of UPK1A-AS1. Furthermore, we found that UPK1A-AS1 exerts its anti-cancer effects partially through sponging miR-1248 in ESCC cells.Conclusion: UPK1A-AS1 suppressed the proliferation, migration, and invasion of ESCC cells partially by sponging miR-1248. Hence, our findings provide novel insights into the regulatory pathway involved in ESCC development.Keywords: esophageal squamous cell carcinoma, long non-coding RNA, UPK1A antisense RNA 1, miR-1248

Background: Circular RNA (circRNA) is a key regulator of cancer, and it has been proved to be involved in the regulation of cancer progression including non-small cell lung cancer (NSCLC). Circ-PITX1 was found to be a significantly upregulated circRNA in NSCLC, and its role and potential mechanism in NSCLC progression deserve further investigation. Methods: The expression levels of circ-PITX1, microRNA (miR)-1248 and cyclin D2 (CCND2) were examined by quantitative real-time PCR (qRT-PCR). Cell proliferation, apoptosis, cell cycle process, migration and invasion were determined using cell counting kit 8 (CCK8) assay, colony formation assay, flow cytometry, wound healing assay and transwell assay. Xenograft models were built to explore the role of circ-PITX1 in NSCLC tumor growth in vivo. The glycolysis and glutamine metabolism of cells were assessed by detecting the consumptions of glucose and glutamine, cell extracellular acidification rate (ECAR), and the productions of lactate, α-ketoglutaric acid (α-KG) and ATP. The protein levels of hexokinase 2 (HK-2), glutaminase 1 (GLS1) and CCND2 were tested by Western blot (WB) analysis. Dual-luciferase reporter assay and RIP assay were employed to verify the interaction between miR-1248 and circ-PITX1 or CCND2. Results: Circ-PITX1 was upregulated in NSCLC and its silencing could inhibit the proliferation, migration, invasion, cell cycle process, glycolysis, glutamine metabolism, and promote the apoptosis of NSCLC cells in vitro, as well as reduced tumor growth in vivo. In the terms of mechanism, we found that circ-PITX1 could act as a sponge of miR-1248, and miR-1248 could target CCND2. In addition, miR-1248 inhibitor reversed the inhibitory effect of circ-PITX1 knockdown on NSCLC progression. Similarly, CCND2 overexpression also reversed the suppressive effect of miR-1248 on NSCLC progression. Moreover, circ-PITX1 positively regulated CCND2 expression by sponging miR-1248. Conclusion: Circ-PITX1 served as a sponge of miR-1248 to promote NSCLC progression by upregulating CCND2. [ABSTRACT FROM AUTHOR]

Background/Aims: MicroRNAs (miRNAs) play an essential role in the tumorigenesis of osteosarcoma (OS). However, the effects of miR-1248 on chemo-resistant potential of OS have not been studied. Here, we addressed this question. Methods: The levels of miR-1248 and apoptotic protein angiotensin II type 1 receptor (AGTR1) in OS specimens were examined by RT-qPCR and Western blotting, respectively. The relationship between miR-1248 and AGTR1 was determined by analysis of Spearman’s Rank Correlation Coefficients. The patient survival was determined with Kaplan-Meier curves. Bioinformatics analyses were done to predict microRNAs (miRNAs) that target AGTR1. The functional binding of miRNAs to AGTR1 mRNA was examined by a dual luciferase reporter assay. Cell viability was determined by an CCK-8 assay. Apoptosis was determined by a fluorescence-based apoptosis assay. Results: The levels of miR-1248 were significantly elevated while the levels of AGTR1 were significantly decreased in OS specimens than in paired adjacent normal tissue. The levels of miR-1248 were negatively correlated to the levels of AGTR1. Moreover, the patients with high miR-1248 levels had poorer survival than those with low MiR-1248 levels, and the patients with low AGTR1 levels had poorer survival than those with high AGTR1 levels. MiR-1248 inhibited protein translation of AGTR1, through binding to the 3’-UTR of the AGTR1 mRNA. The AGTR1-mediated cell apoptosis was suppressed by overexpressing miR-1248, and was augmented by depleting miR-1248. Conclusion: Increased miR-1248 expression in OS may inhibit AGTR1-mediated cancer cell death in chemotherapy. The outcome of chemotherapy may be improved by the suppression of miR-1248 in OS cells.

The circular RNA (circRNA) circEPSTI1 has been recently identified as a new cancer-associated circRNA in multiple types of cancer. However, the involvement of circEPSTI1 in non-small cell lung cancer (NSCLC) remains unexplored. The purpose of this study was to explore the expression pattern and function of circEPSTI1 in NSCLC. We found that circEPSTI1 expression was significantly elevated in NSCLC. In vitro experiments elucidated that knockdown of circEPSTI1 caused a significant reduction in NSCLC cell proliferation and invasion. Moreover, circEPSTI1 was identified as an miRNA sponge of miRNA-1248. Knockdown of circEPSTI1 markedly increased the expression of miR-1248 in NSCLC cells. Upregulation of miR-1248 significantly restricted the proliferation and invasion of NSCLC cells. Inhibition of miR-1248 promoted the proliferation and invasion of NSCLC cells and blocked the circEPSTI1 knockdown-mediated inhibitory effect on NSCLC cell proliferation and invasion. Subsequent data revealed that the tumor-promoting gene tripartite motif-containing protein 24 (TRIM24) is a target gene of miR-1248. The upregulation of TRIM24 partially reversed circEPSTI1 knockdown- or miR-1248 overexpression-induced tumor suppressive effect in NSCLC cells. In summary, our data demonstrate that downregulation of circEPSTI1 represses the proliferation and invasion of NSCLC by inhibiting TRIM24 via miR-1248 upregulation. Image 1 • Expression of circEPSTI1 was elevated in NSCLC. • Knockdown of circEPSTI1 had tumor-inhibition role in NSCLC. • circEPSTI1 acted as a sponge of miR-1248. • TRIM24 was a target gene of miR-1248. • circEPSTI1 regulates NSCLC by miR-1248/TRIM24 axis. [ABSTRACT FROM AUTHOR]

Despite being an attractive cell type for mesenchymal stem cell (MSC) transplantation therapy for wound healing, human adipose-derived stem cells (hADSCs) from diabetes mellitus (DM) patients result in remarkable retention of stem cell activity due to diabetes-induced glucolipotoxicity. We explored the effect of diabetes and medium containing AGEs on the cell activity, phenotype, multipotency, angiogenic potential, and the therapeutic effect of hADSCs. Then, miRNA-1248 was selected by miRNA microarray analysis to further study the core molecular pathways that regulate the wound healing ability of hADSCs. hADSCs isolated from DM patients or cultured in medium containing AGEs in vitro exhibited decreased effectiveness in stem cell therapy. The expression of miRNA-1248 was decreased in the hADSCs of DM patients and hence failed to positively regulate stem cell activity, differentiation functions, and angiogenesis promotion effect. This concomitantly increased the expression of CITED2, an inhibitor of HIF-1α, thus influencing growth factors that promote angiogenesis, cellular proliferation, and wound healing. Overall, our data demonstrated that the glucolipotoxicity-impaired wound healing ability of hADSCs might occur through the miR-1248/CITED2/HIF-1α pathway. MiRNA-1248 may have potential to be used as a novel therapeutic target for wound healing in DM patients or restoring the wound healing ability of diabetic hADSCs.

Background: Sjögren's syndrome (SS) is one of the most common autoimmune disorders leading to exocrine gland dysfunction. Both immune-dependent processes - like Type I Interferon (IFN) signaling and immune-independent processes - such as calcium signaling in epithelial cells - contribute to disease pathophysiology. However, a mechanistic link between these processes has not been demonstrated., Methods: Primary human salivary gland cells were used to evaluate the differential expression of miRNAs with smRNA-seq in primary epithelial cells culture and digital PCR was conducted in SS human salivary glands (SG) biopsies to verify the results. With siRNA screening and pull-down assays to establish the role of miRNA in IFN activation., Findings: Activation of IFN-β by miR-1248 is through the direct association with both RIG-I and AGO2. Further functional studies establish a unique dual functional role of miR-1248 in phSG cells: i) activation of the RIG-I pathway by acting as ligand of this sensor leading to IFN production and ii) regulation of the expression of mRNAs through the canonical microRNA function. Importantly, ITPR3, a key component of calcium signaling in epithelial cells, that has previously shown to be downregulated in SS SG, was directly targeted and downregulated by miR-1248, inducing the same functional calcium signaling changes as observed in SS SGs., Interpretation: Identification of the first endogenous mammalian microRNA that binds to RIG-I inducing IFN production but also demonstrate a novel pathophysiological underlying mechanism in which miR-1248 overexpression links two major pathways associated with SS, namely activation of IFN production with modulation of calcium signaling. Together, these findings suggest a unifying hypothesis for the immune-independent and -dependent processes contributing to the pathogenesis of SS. FUND: This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Dental and Craniofacial Research (NIDCR)., (Copyright © 2019. Published by Elsevier B.V.)

Background/aims: MicroRNAs (miRNAs) play an essential role in the tumorigenesis of osteosarcoma (OS). However, the effects of miR-1248 on chemo-resistant potential of OS have not been studied. Here, we addressed this question., Methods: The levels of miR-1248 and apoptotic protein angiotensin II type 1 receptor (AGTR1) in OS specimens were examined by RT-qPCR and Western blotting, respectively. The relationship between miR-1248 and AGTR1 was determined by analysis of Spearman's Rank Correlation Coefficients. The patient survival was determined with Kaplan-Meier curves. Bioinformatics analyses were done to predict microRNAs (miRNAs) that target AGTR1. The functional binding of miRNAs to AGTR1 mRNA was examined by a dual luciferase reporter assay. Cell viability was determined by an CCK-8 assay. Apoptosis was determined by a fluorescence-based apoptosis assay., Results: The levels of miR-1248 were significantly elevated while the levels of AGTR1 were significantly decreased in OS specimens than in paired adjacent normal tissue. The levels of miR-1248 were negatively correlated to the levels of AGTR1. Moreover, the patients with high miR-1248 levels had poorer survival than those with low MiR-1248 levels, and the patients with low AGTR1 levels had poorer survival than those with high AGTR1 levels. MiR-1248 inhibited protein translation of AGTR1, through binding to the 3'-UTR of the AGTR1 mRNA. The AGTR1-mediated cell apoptosis was suppressed by overexpressing miR-1248, and was augmented by depleting miR-1248., Conclusion: Increased miR-1248 expression in OS may inhibit AGTR1-mediated cancer cell death in chemotherapy. The outcome of chemotherapy may be improved by the suppression of miR-1248 in OS cells., (© 2018 The Author(s). Published by S. Karger AG, Basel.)