Integrated analysis based on vesicle trafficking-related genes identifying CNIH4 as a novel therapeutic target for glioma.

BACKGROUND: Vesicle trafficking is a highly important process in numerous human diseases, especially in the central nervous system dysfunctions. However, as a key component of vesicle trafficking-related genes (VRGs), Cornichon family AMPA receptor auxiliary protein 4 (CNIH4) has not been systematically elucidated in glioma so far. METHODS: Differentially expressed VRGs were selected using molecular signatures database (MSigDB), The Cancer Genome Atlas (TCGA), and Genotype-Tissue Expression (GTEx) mRNA expression profiles. Further exploration of CNIH4 was determined using LASSO-Cox regression algorithms. Then Kaplan-Meier (K-M) plotter, receiver operating characteristic (ROC) curves, and multivariate Cox regression analyses were utilized to assess the independent significance of CNIH4 in the CGGA validation cohort. Functional exploration was performed with Gene Set Enrichment Analysis (GSEA) and then verified using a series of functional experiments in glioma cells. Finally, the consensus clustering algorithm was applied to identify clusters in glioma samples. After that, differences in prognosis, the tumor immune microenvironment (TIME), and therapy response were evaluated between clusters. RESULTS: CNIH4 was shown to be overexpressed in malignant glioma variants and was frequently observed in GCSs and TMZ-resistant cell lines. Higher CNIH4 levels were significantly related to poor outcomes and positively correlated with adverse clinicopathological characteristics. Survival analyses revealed CNIH4 as an independent risk factor that outperformed traditional measures. Enrichment analysis indicated that overactive CNIH4 significantly gathered in stem cell processes. Furthermore, functional assays of silencing CNIH4 expression suppressed stem cell-like properties in vitro and inhibited tumorigenicity in vivo. Finally, the CNIH4-enriched subgroup negatively modulated immunotherapeutic response and reflected lower chemotherapy sensitivity for glioma patients. CONCLUSION: Our study identified CNIH4 as a potential VRG that regulates tumor stemness, microenvironment immunity, and chemotherapy sensitivity. It may serve as a novel prognostic factor and a promising target against glioma therapy.

Contribution of Oxidative Stress Induced by Sonodynamic Therapy to the Calcium Homeostasis Imbalance Enhances Macrophage Infiltration in Glioma Cells.

BACKGROUND: To better understand the Ca2+ overload mechanism of SDT killing gliomas, we examined the hypothesis that the early application of the mechanosensitive Ca2+ channel Piezo1 antagonist (GsMTx4) could have a better anti-tumor effect. METHODS: The in vitro effect of low-energy SDT combined with GsMTx4 or agonist Yoda 1 on both the ROS-induced distribution of Ca2+ as well as on the opening of Piezo1 and the dissociation and polymerization of the Ca2+ lipid complex were assessed. The same groups were also studied to determine their effects on both tumor-bearing BALB/c-nude and C57BL/6 intracranial tumors, and their effects on the tumor-infiltrating macrophages were studied as well. RESULTS: It was determined that ultrasound-activated Piezo1 contributes to the course of intracellular Ca2+ overload, which mediates macrophages (M1 and M2) infiltrating under the oxidative stress caused by SDT. Moreover, we explored the effects of SDT based on the dissociation of the Ca2+ lipid complex by inhibiting the expression of fatty acid binding protein 4 (FABP4). The Piezo1 channel was blocked early and combined with SDT treatment, recruited macrophages in the orthotopic transplantation glioma model. CONCLUSIONS: SDT regulates intracellular Ca2+ signals by upregulating Piezo1 leading to the inhibition of the energy supply from lipid and recruitment of macrophages. Therefore, intervening with the function of the Ca2+ channel on the glioma cell membrane in advance is likely to be the key factor to obtain a better effect combined with SDT treatment.

Long Non-Coding RNA AGAP2-AS1/miR-628-5p/PTN Axis Modulates Proliferation, Migration, Invasion, and Apoptosis of Glioma Cells.

PURPOSE: Long non-coding RNAs (lncRNAs) have been reported to be involved in a variety of cancers, including glioma. However, the exact role and underlying mechanism of lncRNA AGAP2 antisense RNA 1 (AGAP2-AS1) in glioma have not yet been fully elucidated. METHODS: The expression levels of AGAP2-AS1, microRNA-628-5p (miR-628-5p) and pleiotrophin (PTN) were measured by quantitative real-time polymerase chain reaction (qRT-PCR). Cell proliferation, apoptosis, migration and invasion were detected by Cell Counting Kit-8 (CCK-8) assay, flow cytometry, transwell assay, respectively. Western blot assay was used to detect the protein level of PTN. The interaction between miR-628-5p and AGAP2-AS1 or PTN was predicted by bioinformatics software and confirmed by the dual-luciferase reporter and RNA Immunoprecipitation (RIP) assays. Murine xenograft model was established to confirm the role of AGAP2-AS1 in glioma progression in vivo. RESULTS: AGAP2-AS1 expression was upregulated in glioma tissues and cells. Knockdown of AGAP2-AS1 inhibited the proliferation, migration and invasion, but facilitated apoptosis in glioma cells. Moreover, AGAP2-AS1 could directly bind to miR-628-5p and its overexpression reversed the anti-tumor effect of miR-628-5p restoration on the progression of glioma cells. In addition, miR-628-5p directly targeted PTN and its inhibition abolished the inhibitory effect of PTN knockdown on the progression of glioma cells. Furthermore, AGAP2-AS1 functioned as a competing endogenous RNA (ceRNA) by sponging miR-628-5p to modulate PTN expression. Besides, AGAP2-AS1 depletion reduced tumor growth by upregulating miR-628-5p and downregulating PTN. CONCLUSION: AGAP2-AS1 knockdown suppressed cell proliferation, migration and invasion but promoted cell apoptosis in glioma cells by regulating miR-628-5p/PTN axis, providing novel avenues for treatment of glioma.

Retracted: LncRNA SNHG16 Promotes Proliferation, Migration, and Invasion of Glioma Cells Through Regulating the miR-490/PCBP2 Axis.

Cancer Biotherapy and Radiopharmaceuticals officially retracts the paper entitled, "LncRNA SNHG16 Promotes Proliferation, Migration, and Invasion of Glioma Cells Through Regulating the miR-490/PCBP2 Axis," by Fangen Kong, Yang Yan, Jinfeng Deng, Yaoli Zhu, Yingqin Li, Huiqing Li, and Yiping Wang (Cancer Biother Radiopharm. E-pub ahead of print 23 Jul 2020; doi: 10.1089/cbr.2019.3535) at the authors' request: "We apologized that we have found a serious problem in our paper. In fact, the Western blot experiment in our study was commissioned a third-party company for testing. In present, some peers have found that the company has forged experimental reports. After contacting the company, they were unable to provide the original images. We have checked and confirmed that the authenticity of the data provided by the company is problematic. In view of the problems in this paper, all the authors have discussed and agreed to withdraw the paper." [sic] The journal publisher requested the name of the "third-party company," to which the authors replied: "We apologize for our mistakes. Our so-called "the third party company", after further investigation, is actually not a company but an individual person. Due to the personal reasons, the previous experimental data were lost and the original raw data could not be provided. So we can not guarantee the authenticity of those data provided by that person. Some members are considering to repeat the experiment again, but we have no way to raise enough fund to repeat it. Hence after serious discussion, we decided to withdraw the manuscript. Again we apologize sincerely for your inconvenience." [sic] Submissions from a third party are a violation of the journal's standard protocols and is considered an infraction against the rigorous standards of scientific publishing. The Editor and Publisher of Cancer Biotherapy and Radiopharmaceuticals are committed to preserving the scientific literature and the community it serves and does not tolerate any violations of scientific misconduct. Therefore, the publisher officially retracts the article.

Erratum: microRNA-34a overexpression inhibits cell migration and invasion via regulating SIRT1 in hepatocellular carcinoma.

[This corrects the article DOI: 10.3892/ol.2017.7090.].

Knockdown of Urothelial Carcinoma-Associated 1 Suppressed Cell Growth and Migration Through Regulating miR-301a and CXCR4 in Osteosarcoma MHCC97 Cells.

Liver cancer is one of the most common malignancies in the world and a leading cause of cancer-related mortality. Accumulating evidence has highlighted the critical role of long noncoding RNAs (lncRNAs) in various cancers. The present study aimed to explore the role of lncRNA urothelial carcinoma-associated 1 (UCA1) in cell growth and migration in MHCC97 cells and its underlying mechanism. First, we assessed the expression of UCA1 in MHCC97 and three other cell lines by RT-qPCR. Then the expression of UCA1, miR-301a, and CXCR4 in MHCC97 cells was altered by transient transfection. The effects of UCA1 and miR-301 on cell viability, migration, invasion, and apoptosis were assessed. The results revealed that UCA1 expression was relatively higher in MHCC97 cells than in MG63, hFOB1.19, and OS-732 cells. Knockdown of UCA1 reduced cell viability, inhibited migration and invasion, and promoted cell apoptosis. However, the effect of UCA1 knockdown on cell growth and migration was blocked by miR-301a overexpression, whose expression was regulated by UCA1. We also found that miR-301a positively regulated CXCR4 expression. CXCR4 inhibition reversed the effect of miR-301a overexpression on cell growth and migration. Moreover, miR-301a activated the Wnt/ß-catenin and NF-κB pathways via regulating CXCR4. The present study demonstrated that UCA1 inhibition exerted an antigrowth and antimigration role in MHCC97 cells through regulating miR-301a and CXCR4 expression.

Protective role of microRNA-126 in intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) is a disease associated with high mortality and morbidity. MicroRNAs (miRNAs) are important regulators of translation and have been reported to be associated with the pathogenesis of numerous cerebrovascular diseases, including ICH. The present study explored the role of miRNA (miR)­126 in ICH. Adult male Wistar rats were randomly assigned to ICH model and sham groups. ICH was induced by intracerebral injection of collagenase. The mRNA expression levels of miR­126 in the two groups were determined. The miR­126 lentivirus expression vector pWPXL­miR­126 or negative control vector was then constructed and delivered via intraparenchymal injection. Following transduction, behavioral testing (rotarod and limb placement tests), relative hemorrhagic lesion size, apoptotic cells and protein levels of vascular endothelial growth factor (VEGF)­A and caspase­3 were determined. The relative expression levels of miR­126 were significantly decreased in the ICH group compared to the sham group (P=0.026). Overexpression of miR­126 significantly improved the relative duration of stay on the rotarod at day 2 (P=0.029) and 3 (P=0.033), and statistically reduced the deficit score (P=0.036), the relative size of hemorrhagic lesion (P=0.019) and the number of apoptotic cortical neurons (P=0.024) compared with the sham group. Additionally, the protein levels of VEGF­A were significantly elevated, however levels of caspase­3 were downregulated by overexpression of miR­126 compared with the negative control group. MiR­126 therefore exhibits a protective role in ICH. Overexpression of miR­126 protects against ICH, and may be involved in the process of angiogenesis and exhibit an anti-apoptotic effect.

microRNA-34a overexpression inhibits cell migration and invasion via regulating SIRT1 in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) remains one of the most common types of malignancy with high mortality and morbidity rates. Previous studies have suggested that microRNAs (miRs) serve pivotal functions in various types of tumor. The aim of the present study was to assess the association between miR-34a expression and HCC cell migration and invasion, and the potential underlying mechanisms. The miR-34a overexpression vector or scramble control was transfected into human Hep3B and Huh7 cell lines. Transwell assays, and Matrigel and wound healing assays were used to detect the effects of miR-34a expression on HCC cell invasion and migration, respectively. The expression of miR-34a and the mRNA expression of other associated proteins were detected using quantitative reverse transcription polymerase chain reaction, and protein levels were measured using western blot analysis. Compared with the control, miR-34a expression was significantly downregulated in Hep3B and Huh7 cells, but this was reversed by the transfection with exogenous miR-34a (P<0.01). The number of migrated or invaded cells was significantly reduced by the overexpression of miR-34a in Hep3B or Huh7 cells (P<0.01). The expression of sirtuin 1 was upregulated, while the level of acetylate-p53 was downregulated by overexpression of miR-34a. Taken together, the results of the present study suggested that the overexpression of miR-34a may have suppressed HCC metastasis via inhibited cell migration and invasion.