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The incidence of glioma in men is higher than that in women; however, little is known about the expression and basic function of the androgen receptor (AR) in gliomas. AR inhibited the small VCP/p97-interacting protein (SVIP) on the transcriptional level was previously reported. The present study shows that the protein level of AR is highly expressed in cell lines of the nervous system. Moreover, the AR expression is increased while SVIP expression is decreased in tumor tissue of glioma patients, which is in agreement with the progressing WHO grades. A statistically significant increase in serum testosterone level of glioma patients compared with that of non-cancer patients was also detected. Furthermore, it has been proved that SVIP is down-regulated as well as AR is up-regulated in glioma cell lines with R1881 treatment. Interestingly, the depletion of SVIP using siRNA facilitated cell proliferation and decreased p53 expression. In addition, overexpression of SVIP increased cell death only in p53wt cell lines. Moreover, U87MG cells, p53wt cell line was susceptible to AR antagonists in vitro and in vivo. The current study provides insight into the biological role of AR in suppressing SVIP and p53 and promoting the progression of glioma as well as the clinical treatment of glioma patients.

The colorectal neoplasia differentially expressed (CRNDE) gene encodes a long non-coding RNA (lncRNA) that is the most unregulated among 129 lncRNAs differentially expressed in gliomas. In this study, we confirmed high CRNDE expression in clinical glioma specimens and observed through experiments in human glioma cell lines a novel molecular mechanism by which CRNDE may contribute to glioma pathogenesis. By inducing or silencing CRNDE expression, we detected a positive correlation between CRNDE levels and the proliferative, migratory, and invasive capacities of glioma cells, which were concomitant with a decreased apoptosis rate. Our experiments also suggest that these effects are mediated by downregulation of miR-136-5p, which correlated with the glioma WHO grade. Based on predicted CRNDE/miR-136-5p/mRNA interactions, both the mRNA and protein expression analyses suggested that miR-136-5p-mediated repression of Bcl-2 and Wnt2 underlies the pro-tumoral actions of CRNDE. We therefore propose that CRNDE functions as a competing endogenous RNA (ceRNA) that binds to and negatively regulates miR-136-5p, thereby protecting Bcl-2 and Wnt2 from miR-136-5p-mediated inhibition in glioma.

Glioma is the most common malignant tumor in the central nervous system. Altered long noncoding RNAs (lncRNAs) are playing regulatory roles in physiological and pathogenic processes in cancer. Here, we uncovered a differentially expressed lncRNA called brain cytoplasmic RNA 1 (BCYRN1), and elucidated its function and molecular mechanism in the progression and development of glioma. Three fresh tumor tissues from glioma patients and three normal brain tissues from craniocerebral trauma patients were prepared for high-throughput RNA sequencing. Differential RNA transcripts and BCYRN1 were identified by RT-qPCR in glioma samples and controls. CCK-8, colony formation assays, flow cytometry, TUNEL assays, cell migration assays, wound-healing assays, and xenograft model were established to investigate the biological function of BCYRN1 both in vitro and in vivo. Various bioinformatics analysis, dual-luciferase reporter assays, biotinylated RNA pulldown assays, and rescue experiments were conducted to reveal the underlying mechanisms of competitive endogenous RNAs (ceRNAs). 183 lncRNAs were identified with significant dysregulation in glioma and randomly selected differential RNAs were further confirmed by RT-qPCR. Among them, BCYRN1 was the most downregulated lncRNA, and its low expression positively correlated with glioma progression. Functionally, BCYRN1 overexpression inhibited cell proliferation, migration in glioma cell lines, whereas BCYRN1 depletion resulted in the opposite way. MiR-619-5p was further confirmed as the direct target of BCYRN1. Mechanistically, miR-619-5p specifically targeted the CUE domain containing protein 2 (CUEDC2), and BCYRN1/miR-619-5p suppressed glioma tumorigenesis by inactivating PTEN/AKT/p21 pathway in a CUEDC2-dependent manner. Overall, our data presented that the reduced expression of BCYRN1 was associated with poor patient outcome in glioma. BCYRN1 functioned as a ceRNA to inhibit glioma progression by sponging miR-619-5p to regulate CUEDC2 expression and PTEN/AKT/p21 pathway. Our results indicated that BCYRN1 exerted tumor suppressor potential and might be a candidate in the diagnosis and treatment of glioma.

Abstract. stemness genes, including nAnog, which have been reported to play a significant role in embryonic stem cells (ESCs), are purported to be expressed in specific human tumor types. In the present study, we explored the expression of nAnog in gliomas to demonstrate its key roles in maintaining the undifferentiated state of glioma cells. Brain tumor stem cells (Btscs) were isolated from the human glioma cell line U87 and cultured in simplified serum-free medium. Significantly higher NANOG mRNA and protein expression levels were demonstrated in U87 parental attached cells and suspended Btscs as well as in 69 glioma specimens of different pathological grades. the relative levels of nAnog mrnA and protein expression were higher in the Btscs as compared to those in the U87 parental attached cells and were significantly positively correlated with pathological grade. the coexpression and relationship of nAnog, cD133 and gFAp in situ in the cellular levels was determined through double-label immunohistochemical staining in the gliomas. A positive correlation of nAnog and cD133 expression with pathological grade of the samples was noted, while nAnog and gFAp expression correlated negatively with the pathological grade (p<0.01). overexpression of nAnog in gliomas and its close relationship with the undifferentiated state of glioma cells in vivo and in vitro indicated that nAnog may contribute to the existence of Btscs and may be related to tumorigenesis of the cerebrum by maintaining the undifferentiated state of glioma cells, which provides a foundation to further explore its role in the biological behavior of gliomas.

Annexin A3 (ANXA3) is dysregulated and plays an important role in various cancers. However, the role of ANXA3 in breast cancer is still unclear. Here, we observed that the expression level of ANXA3 was significantly upregulated in breast cancer tissues. ANXA3 knockdown inhibited cell invasion but promoted cell proliferation in both in vitro and in vivo assays. Furthermore, we found that ANXA3 knockdown inhibited the NFκB pathway via upregulating IκBα, resulting in mesenchymal–epithelial transition (MET) and a heterogeneity change of breast cancer stem cells (BCSCs). In addition, we demonstrated that ANXA3 knockdown increased the sensitivity of breast cancer cells to doxorubicin by increasing the drug uptake. The combination of ANXA3 knockdown and doxorubicin treatment simultaneously inhibited tumor growth and metastasis in vivo. This study described the role and mechanisms of ANXA3 in regulating BCSCs and breast cancer growth and metastasis, indicating that downregulating ANXA3 together with chemotherapy might be a novel therapeutic strategy for treating breast cancer.

Abstract. The human herpesvirus-associated ubiquitinspecific protease (HAUSP) deubiquitinating enzyme has been shown to regulate many proteins involved in the cell cycle, as well as tumor suppressors and oncogenes. However, the expression pattern of HAUSP in glioma patients is still unclear. The purpose of the present study was to investigate the expression pattern and prognostic significance of HAUSP in patients with glioma. Eighty glioma specimens and 10 normal control samples were obtained. Immunohistochemical assay, quantitative real-time PCR and western blot analysis were carried out to explore the expression of HAUSP. Additionally, the association of HAUSP expression with clinicopathological parameters and the survival of glioma patients were analyzed. Our results showed that HAUSP expression levels were increased from grade I to grade IV in the tumors of the glioma patients. Moreover, the survival rate of patients with HAUSPpositive tumors was lower when compared to that of patients with HAUSP-negative tumors. We further confirmed that high expression of HAUSP was a significant and independent prognostic indicator in glioma by multivariate analysis. Our data provide convincing evidence for the first time that the overexpression of HAUSP at the gene and protein levels is correlated with poor outcome in patients with glioma in China. HAUSP may play an important oncogenic role in glioma progression, and it is a potential diagnostic and therapeutic target. IntroductionGlioma is the most common primary intracranial tumor in both adults and children. The World Health Organization (WHO) classification scheme divides gliomas into grades I through IV, based on increasing levels of malignancy (1). The prognosis of patients with glioma is poor and is closely related to WHO grade. Glioblastoma multiforme (GBM) WHO grade IV is the most malignant variant with a median survival time of 1 year (2). Efforts to better understand the biological basis of glioma progression may yield important, clinically relevant insights into disease management. Many aggressive treatment approaches, such as postoperative chemotherapy and radiation therapy, have been used clinically. Yet, these approaches do not benefit all patients equally. Adverse effects associated with these approaches dramatically deteriorate the quality of life of certain patients. Therefore, individualized therapy should be considered as a valuable approach for patients with highgrade gliomas. Recently, molecular diagnostics has emerged as a powerful tool to discover new biomarkers, network and therapeutic targets, realizing the proof of principle that personalized medicine can increase survival and cure cancer patients. Thus, elucidation of these critical molecular events may improve therapy and individualize therapeutic interventions for patients with gliomas.Deubiquitylating enzymes (DUBs) antagonize the ubiquitylation of substrates by cleaving polyubiquitin and monoubiquitin and thus afford an additional level of protein post-translational regulation (3). Herpesvi...