[Retracted] miR­218 inhibits the migration and invasion of glioma U87 cells through the Slit2­Robo1 pathway.

[This retracts the article DOI: 10.3892/ol.2015.2904.].

Breaking down barriers: The potential of smarter CAR-engineered NK cells against solid tumors.

Natural killer (NK) cells are considered to be the foremost fighters of our innate immune system against foreign invaders and thus tend to promptly latch onto the virus-infected and tumor/cancerous cells, killing them through phagocytosis. At present, the application of genetically engineered Chimeric antigen receptor (CAR) receptors ensures a guaranteed optimistic response with NK cells and would not allow the affected cells to dodge or escape unchecked. Hence the specificity and uniqueness of CAR-NK cells over CAR-T therapy make them a better immunotherapeutic choice to reduce the load of trafficking of numerous tumor cells near the healthy cell populations in a more intact way than offered by CAR-T immunotherapy. Our review mainly focuses on the preclinical, clinical, and recent advances in clinical research trials and further strategies to achieve an augmented and efficient cure against solid tumors.

Glioma stem cell-derived exosomal miR-944 reduces glioma growth and angiogenesis by inhibiting AKT/ERK signaling.

In this study, we investigated the regulatory role of exosomal microRNA-944 (miR-944) derived from glioma stem cells (GSCs) in glioma progression and angiogenesis. Bioinformatics analysis showed that miR-944 levels were significantly lower in high-grade gliomas (HGGs) than low-grade gliomas in the Chinese Glioma Genome Atlas and The Cancer Genome Atlas datasets. The overall survival rates were significantly shorter for glioma patients expressing low miR-944 levels than high miR-944 levels. GSC-derived exosomal miR-944 significantly decreased in vitro proliferation, migration, and tube formation by human umbilical vein endothelial cells (HUVECs). Targetscan and dual luciferase reporter assays demonstrated that miR-944 directly targets the 3'UTR of VEGFC. In vivo mouse studies demonstrated that injection of agomiR-944 directly into tumors 3 weeks after xenografting glioma cells significantly reduced tumor growth and angiogenesis. GSC-derived exosomal miR-944 significantly reduced VEGFC levels and suppressed activation of AKT/ERK signaling pathways in HUVECs and xenograft glioma cell tumors. These findings demonstrate that GSC-derived exosomal miR-944 inhibits glioma growth, progression, and angiogenesis by suppressing VEGFC expression and inhibiting the AKT/ERK signaling pathway.

Silencing of PRDM5 increases cell proliferation and inhibits cell apoptosis in glioma.

AIM: PR-domain-containing 5 (PRDM5), a family member of PR-domain-containing zinc finger genes, has been reported to participate in modulate cellular processes, including cell growth, differentiation and apoptosis. It has also been found to function as a putative tumor suppressor in different types of cancer. The present study is the first, to the best of our knowledge, to report on the clinical significance of the expression of PRDM5 in glioma cell line. MATERIALS AND METHODS: Western blot analyse the expression of PRDM5 in glioma tissues and cells. 80 tissues microarray samples from patients with glioma were examined using immunohistochemical analysis. Glioblastoma U251 cells were transfected with PRDM5-siRNA and control-siRNA. U251cell proliferation was measured by flow cytometric analysis and plate colony formation assay. Cell apoptosis were detected using flow cytometric analysis. RESULTS: The results of western blot analysis and immunohistochemistry showed that the expression of PRDM5 was decreased in fresh glioma tissues, compared with that in normal brain tissues. Kaplan-Meier postoperative survival curves demonstrated that the low expression of PRDM5 was associated with poor prognosis in patients with glioma. In addition, suppression of PRDM5 promoted cell proliferation via regulating cell cycle progression. Finally, knocking down PRDM5 using small interfering RNA decreased the apoptosis of glioma cells. CONCLUSION: Taken together, these findings suggested that PRDM5 may be a novel therapeutic target of glioma.

Silencing of lncRNA HOXA11-AS inhibits cell migration, invasion, proliferation, and promotes apoptosis in human glioma cells via upregulating microRNA-125a: in vitro and in vivo studies.

Glioma is an aggressive nervous system tumor with poor prognosis. Although the therapeutic strategies to overcome glioma have been improved largely recent years, the potential mechanism of its carcinogenesis remains largely unclear. The present study aimed to investigate the role of long non-coding RNA HOMEOBOX A11 antisense RNA (lncRNA HOXA11-AS) in glioma, and further to explore the underlying mechanism. We forst detected the level of lncRNA HOXA11-AS and microRNA-125a (miR-125a) in glioma tissues and human glioma U251 cells using quantitative real time polymerase chain reaction (qRT-PCR). Then, effect of lncRNA HOXA11-AS silencing on U251 cell migration, invasion, proliferation, and apoptosis was determined. Meanwhile, the expression of caspase-3/8/9 and several tumor-related genes was measured by Western blotting and qRT-PCR. Dual luciferase activity assay was used to confirm the targeting relationship between lncRNA HOXA11-AS and miR-125a. Results indicated that lncRNA HOXA11-AS was significantly increased in U251 cells and positively correlated with glioma World Health Organization (WHO) grade in glioma tissues. lncRNA HOXA11-AS silencing could inhibit cell migration, invasion, proliferation, and promote apoptosis, while up-regulate the expression of caspase-3/8/9 and Bax, inhibit the expression of Bcl-2 and gab2 in U251 cells. miR-125a inhibitor could partially reverse these effects of lncRNA HOXA11-AS silencing on U251 cells. In vivo assays also indicated that lncRNA HOXA11-AS inhibitor could inhibit glioma growth in vivo by regulating the expression of miR-125a. In conclusion, we revealed that lncRNA HOXA11-AS acted as an oncogene in glioma via interacting with miR-125a and considered that lncRNA HOXA11-AS was a potential therapeutic target for glioma.

Protective Effect of Mitogen- and Stress-Activated Protein Kinase on the Rats with Focal Ischemia-Reperfusion Injury.

Mitogen- and stress-activated protein kinase (MSK) is a recently identified nuclear cAMP-regulated enhancer B (CREB) and histone H3 kinase that responds to both mitogen- and stress-activated protein kinases. This study was designed to investigate the protective effect of MSK on the rats with focal ischemia-reperfusion injury. The rat model was established by inserting thread into the middle cerebral artery. The protein expression was measured by immunoblotting. The localization of MSK was measured by immunofluorescence assay. Highly-differentiated pheochromocytoma 12 (PC12) is used as a sympathetic neuron-like cell line and treated with glutamate to induce neurotoxicity. MSK was knocked down and overexpressed by siRNA and MSK over-expressing vector, respectively. The cell viability was measured by cell counting kit (CCK-8) assay. The coronal sections were isolated and stained with 2, 3, 5-triphenyltetrazolium chloride (TTC) to determine infarct volume. Finally, astrocytes were separated from cerebral cortexes of normal rats to analyze the effects of MSK on inflammatory response. In the rats with focal ischemia-reperfusion injury, the expression of MSK was reduced, reaching the lowest level at 3 d after ischemia-reperfusion, and then recovered gradually. MSK was found mainly localized in neurons and astrocytes. The expression levels of caspase-3, caspase-8, caspase-9, and INOS showed the opposite trend with respect to MSK. Further analysis showed that overexpression of MSK exerted a protective effect on glutamate-induced neurotoxicity through inhibiting apoptosis of PC12 cells, as well as decreased the infarct size in rat with focal ischemia-reperfusion injury. On the contrary, knockdown of MSK showed opposite results. Finally, MSK suppressed LPS-induced inflammatory response by decreasing the expression of inducible nitric oxide synthase (INOS) and increasing the expression of interleukin-10 (IL-10) in astrocytes from cerebral cortexes of normal rats. In conclusion, MSK exerted a protective effect on rat with focal ischemia-reperfusion injury through its anti-apoptotic effect on neurons and anti-inflammatory effect on astrocytes.

Cotton-Assisted Surgical Clipping of Very Small Aneurysms: A Two-Center Study.

OBJECTIVE: Very small intracranial aneurysms (VSIAs) are challenging to treat because aneurysm tearing and clip slippage can occur during neurosurgical clipping. In this study, we introduce and share our experience with cotton-assisted clipping of VSIAs. METHODS: We retrospectively analyzed the data of 20 patients with 24 VSIAs treated with cotton-assisted clipping between February 2008 and December 2014 in the Neurosurgery Departments of the First Affiliated Hospital, Soochow University and Taizhou People's Hospital. During surgery, 2 aneurysm necks were torn. To treat the tears, we wrapped rectangular cotton pads around the parental arteries at the site of rupture. The remaining 22 aneurysms were clipped after being wrapped in cotton pads. RESULTS: The 2 aneurysm ruptures were successfully repaired with cotton-assisted clipping. In the remaining 22 aneurysms, no cases of aneurysm clip slippage or aneurysm rupture occurred. Patients were followed up on average for 59.0 months (range, 30-113 months). Of the 20 patients, the 16 patients with preoperative Hunt-Hess grades of 1-3 recovered well after the surgery (Glasgow Outcome Scale [GOS] score, 5). Of the 4 patients with Hunt-Hess grades of 4-5, 3 had a good recovery (GOS scores, 4-5), and 1 patient died of heart disease 6 months after being discharged from the hospital; this patient had a GOS score of 4 at the time of discharge. CONCLUSIONS: Cotton-assisted clipping could prevent aneurysm clip slipping and aneurysm rupture and facilitate the repair of aneurysm neck tears. This technique is a useful alternative therapy for VSIAs.

Endoscopic third ventriculostomy and ventriculoperitoneal shunt for patients with noncommunicating hydrocephalus: A PRISMA-compliant meta-analysis.

BACKGROUND: The surgical methods of endoscopic third ventriculostomy (ETV) and ventriculoperitoneal shunt (VS) for patients with noncommunicating hydrocephalus have rapidly increased in the past 2 decades. However, there is controversy regarding the efficacy and safety of these 2 surgical methods for noncommunicating hydrocephalus. The purpose of this study was to identify whether ETV is safer and more efficacious than VS for patients with noncommunicating hydrocephalus. METHODS: We performed electronic searches in PubMed, Embase, China National Knowledge Internet, and the Cochrane Library to identify studies published up to February 03, 2018. The study summary results included improvement of symptoms, major complications, hematoma, infection, reoperation, mortality, duration of surgery, and hospital stay. Odds ratios (ORs) or standard mean differences (SMDs) with 95% confidence intervals (CIs) were calculated using random-effects models. RESULTS: We identified 10 observational studies (4 prospective and 6 retrospective studies) with data collected from 2017 patients with noncommunicating hydrocephalus. First, there was no significant difference between ETV and VS for symptom improvement (OR: 0.83; 95%CI: 0.46-1.50; P = .534). Second, ETV was associated with lower incidence of major complications when compared with VS (OR: 0.31; 95%CI: 0.17-0.56; P < .001). Third, ETV has little or no significant effect on hematoma (OR: 0.65; 95%CI: 0.22-1.92; P = .433) and mortality (OR: 0.90; 95%CI: 0.11-7.72; P = .926). Fourth, ETV were associated with lower incidence of infection (OR: 0.20; 95%CI: 0.06-0.69; P = .010) and reoperation (OR: 0.22; 95%CI: 0.08-0.56; P = .002). Finally, patients who received ETV had shorter duration of surgery (SMD: -1.71; 95%CI: -3.16 to -0.27; P = .020) and hospital stay (SMD: -0.91; 95%CI: -1.45 to -0.38; P = .001). CONCLUSIONS: This meta-analysis provides robust evidence that ETV has greater benefits in terms of major complications, infection, reoperation, duration of surgery, and hospital stay than VS for patients with noncommunicating hydrocephalus.

MiR-218 inhibits the tumorgenesis and proliferation of glioma cells by targeting Robo1.

BACKGROUND: Malignant glioma is the most common primary brain tumors directly correlated with the high mortality and poor prognosis in clinical practice. MicroRNAs (miRNAs or miRs) influence numerous cancer-relevant processes including cell proliferation, differentiation and metabolism. However, the role of microRNA in malignant glioma is largely unknown. This study aimed to study the role of miR-218, a tumor-suppressive microRNA, in glioma development both in vivo and in vitro. METHODS: The expression level of miR-218, Slit2 and Robo1 was examined by either quantitative (polymerase chain reaction) or western-blotting from both human glioma tissue and glioma cell lines. U87 cells were transfected with miR-218 and then the expression levels of Slit2 and Robo1 were quantified. Cell proliferation was measured both by the in vitro proliferation assay and in vivo graft studies. The luciferase reporter assay was employed to validate the downstream target of miR-218. RESULTS: The expression of miR-218 was lower in glioma cell lines and glioma tissues from the patients with decreased Slit2 and increased Robo1 protein levels. The over-expression of miR-218 inhibited the tumorgenesis and proliferation of glioma cells remarkably. Furthermore, the over-expressing miR-218 in glioma cells results in the downregulation of Robo1 and upregulation of Slit2. Using luciferase reporter assays, we found that Robo1 was a direct downstream target of miR-218. CONCLUSION: Over-expression of miR-218 in glioma cells may inhibit the proliferation and tumorigenicity through targeting Robo1, suggesting that miR-218 could be a potential target for developing therapies in treating glioma.

miR-218 inhibits the migration and invasion of glioma U87 cells through the Slit2-Robo1 pathway.

Malignant gliomas are the most common primary brain tumors in adults and are associated with the highest mortality rate. Glioma invasion is one of the most notable causes of the poor prognosis of this cancer. Preventing the invasive behavior of malignant glioma cells by altering effector molecules can significantly improve the prognosis of a patient. microRNAs (miRNAs) are small noncoding RNAs, ~22 nucleotides in length, that are able to function as oncogenes or tumor suppressors in human cancer. In the present study, the expression level of miRNA 218 (miR-218) was found to be markedly downregulated in glioma cell lines and human primary glioma tissues. miR-218 upregulation was found to dramatically reduce the migratory speed and invasive ability of glioma cells. Furthermore, it was demonstrated that ectopic expression of miR-218 in glioma cells resulted in the downregulation of roundabout, axon guidance receptor, homolog 1 (Robo1), upregulation of Slit homolog 2 (Slit2) and the expression of associated proteins following Robo1 knockdown by small interfering RNA. In addition, it was demonstrated that miR-218 inactivated the Slit2-Robo1 pathway through downregulating Robo1 expression by directly targeting the 3'-untranslated region (3'-UTR) of Robo1. The present results indicate that miR-218 plays important roles in preventing the invasiveness of glioma cells, and reveals a novel mechanism of miRNA-mediated direct suppression of the Slit2-Robo1 pathway in glioma.

Decreased expression of miR-218 is associated with poor prognosis in patients with colorectal cancer.

The identification of biomarkers in colorectal cancer (CRC) diagnosis and therapy is important in achieving early cancer diagnosis and improving patient outcomes. The aim of this study was to examine clinical significance of miR-218 expression in sera and tissues from CRC patients. A total of 189 cases and 30 healthy subjects were included. The expression levels of miR-218, SLIT2 and SLIT3 were measured by quantitative reverse transcription PCR (qRT-PCR). The relationship between miR-218 expression and clinicopathological characteristics was investigated. The expression levels of miR-218, SLIT2 and SLIT3 in CRC tissues were decreased than those in adjacent normal tissues (all P < 0.05). miR-218 expression was significantly associated with TNM stage, lymph node metastasis (LNM) and differentiation (all P < 0.05). Patients with low miR-218 expression had shorter survival time than those with high miR-218 expression (P = 0.036). Furthermore, the expression levels of serum miR-218 in CRC patients were lower than those in controls (P = 0.005). An increased level of serum miR-218 was found 1 month after surgery (P = 0.026). In conclusion, the miR-218 may has important roles in the development and progression of CRC and be a potential diagnostic and prognostic biomarker of CRC.