Identification of a novel circular RNA circZNF652/miR-486-5p/SERPINE1 signaling cascade that regulates cancer aggressiveness in glioblastoma (GBM).

Circular RNAs (circRNAs) are closely associated with cancer development in glioblastoma (GBM), and this study aims to explore the molecular mechanisms of a novel circular RNA circZNF652 in regulating GBM aggressiveness. The present study found that CircZNF652 and SERPINE1 were upregulated, while miR-486-5p was downregulated in GBM tissues and cell lines, and GBM patients with high expression of CircZNF652 and SERPINE1, and patients with low expression of miR-486-5p tended to have a worse prognosis. Further results validated that both silencing of circZNF652 and miR-486-5p overexpression suppressed cell growth, migration, invasion, epithelial-mesenchymal transition (EMT) and tumorigenesis in GBM cells in vitro and in vivo. Next, the underlying mechanisms were investigated, and we found that circZNF652 sponged miR-486-5p to upregulate SERPINE1 in GBM cells. Also, we validated that knock-down of circZNF652 regulated the miR-486-5p/SERPINE1 axis to reverse the malignant phenotypes in GBM cells. Interestingly, we noticed that GBM cells derived exosomes were characterized by high-expressed CircZNF652. Collectively, we concluded that targeting the circular RNA circZNF652/miR-486-5p/SERPINE1 axis was a novel and effective strategy to suppress cancer progression in GBM.

Circ_0007534 Silencing Inhibits the Proliferation, Migration and Invasion and Induces the Apoptosis of Glioma Cells Partly Through Down-Regulating PROX1 Via Elevating miR-22-3p Level.

Glioma is a common malignant brain neoplasm. The role and mechanism of circular RNA 0,007,534 (circ_0007534) in glioma progression were investigated in this study. The expression of circ_0007534, microRNA-22-3p (miR-22-3p) and prospero homeobox protein 1 (PROX1) messenger RNA (mRNA) was determined by quantitative real-time polymerase chain reaction (qRT-PCR). The proliferation, migration and invasion abilities were analyzed by colony formation assay, transwell migration assay and transwell invasion assay. Cell apoptosis was assessed through measuring the activity of Caspase-3 using the Caspase-3 kit and the apoptosis rate using flow cytometry. Dual-luciferase reporter assay was used to confirm the target interaction between miR-22-3p and circ_0007534 or PROX1. The protein level of PROX1 was examined by Western blot assay. Animal studies were conducted to analyze the influence of circ_0007534 interference on xenograft tumor growth in vivo. Circ_0007534 was highly expressed in glioma tissues and cell lines relative to that in normal tissues and NHA cell line. Circ_0007534 knockdown suppressed the proliferation and motility while induced the apoptosis of glioma cells. Circ_0007534 negatively regulated miR-22-3p level through targeting it in glioma cells. Circ_0007534 interference-induced influences in glioma cells were partly overturned by the silencing of miR-22-3p. PROX1 was a target of miR-22-3p, and circ_0007534 interference-mediated effects in glioma cells were largely diminished by the overexpression of PROX1. Circ_0007534 interference restrained glioma development in vivo. Circ_0007534 aggravated glioma progression through elevating PROX1 expression via targeting miR-22-3p, which provided new targets for the diagnosis and treatment of glioma.

Glioblastoma stem cell (GSC)-derived PD-L1-containing exosomes activates AMPK/ULK1 pathway mediated autophagy to increase temozolomide-resistance in glioblastoma.

Temozolomide (TMZ)-resistance hampers the therapeutic efficacy of this drug for glioblastoma (GBM) treatment in clinic, and emerging evidences suggested that exosomes from GBM-derived stem cells (GSCs) contributed to this process, but the detailed mechanisms are still largely unknown. In the present study, we reported that GSCs derived programmed death-ligand 1 (PD-L1) containing exosomes activated AMPK/ULK1 pathway mediated protective autophagy enhanced TMZ-resistance in GBM in vitro and in vivo. Specifically, we noticed that continuous low-dose TMZ stimulation promoted GSCs generation and PD-L1 containing exosomes (PD-L1-ex) secretion in GBM cells, and that PD-L1-ex inhibited cell apoptosis and promoted cell autophagy to increased TMZ-resistance in GBM cells, which were reversed by co-treating cells with the autophagy inhibitor 3-methyladenine (3-MA). Consistently, upregulation of PD-L1 also increased TMZ-resistance in TS-GBM cells, and silencing of PD-L1 sensitized TR-GBM cells to TMZ. In addition, PD-L1-ex activated AMPK/ULK1 pathway to induce autophagy in TMZ treated GBM cells, and the inhibitors for AMPK (compound C) and ULK1 (SBI-0206965) promoted cell apoptosis in GBM cells co-treated with PD-L1-ex and high-dose TMZ. Finally, we evidenced that PD-L1-ex promoted tumor growth and Ki67 protein expressions to increase TMZ-resistance in GBM in vivo. Collectively, we concluded that GSCs-derived PD-L1-ex activated AMPK1/ULK1 signaling cascade mediated autophagy to increase TMZ-resistance in GBM, and this study provided potential strategies to improve the therapeutic efficacy of TMZ in GBM.

Surgical management of growth hormone-secreting pituitary adenomas: A retrospective analysis of 33 patients.

The endoscopic endonasal transsphenoidal approach (EETA) is the primary treatment for growth hormone (GH) adenoma. This study aimed to investigate the outcomes of EETA in 33 patients with GH-secreting pituitary adenoma (PA).Thirty-three patients who underwent EETA in Eighth People's Hospital of Shenzhen between January 2013 and December 2017 were included in the comprehensive analysis. Factors affecting the extent of resection and postoperative remission rates were also reviewed.The total cut rate was 63.6% (21), and the total remission rate was 66.7% (22) in all patients after surgery. The cure rate was 60.6% (20) for 33 patients. The total removal rate and remission rate were significantly different (P = .01, P = .007) for microadenomas, macroadenomas, and giant adenomas. In addition, the total removal rate and remission rate were significantly different (P = .004, P = .007) for patients with noninvasive and invasive GH-secreting PAs. Furthermore, there were significant differences (P = .003, P = .005) in the total removal rate and remission rate of patients with different preoperative GH levels. All patients with hypertension and diabetes mellitus were normalized. Three patients exhibited recurrence after surgery. Several patients suffered from postoperative complications, including transient diabetes insipidus in 3 (9.1%) patients and postoperative transient cerebrospinal fluid leakage in 2 (6.1%) patients.EETA is an effective therapeutic approach for treating patients with GH-secreting PA with high remission and low complication rates. Therefore, EETA should be considered a primary treatment for patients with GH-secreting PA.