Background Aberrant EGFR activation is observed in over 50% of cases of adult glioblastoma (GBM). Nevertheless, EGFR antibodies are ineffective in clinical GBM treatment, suggesting the existence of redundant EGFR activation mechanisms. Whether circular RNA (circRNA) encodes a protein involved in EGFR-driven GBM remains unclear. We reported an unexpected mechanism in which circular EGFR RNA (circ-EGFR) encodes a novel EGFR variant to sustained EGFR activation. Method We used RNA-seq, Northern blot and Sanger sequencing to confirm the existence of circ-EGFR. Antibodies and a liquid chromatograph tandem mass spectrometer were used to identify circ-EGFR protein products. Lentivirus-transfected stable cell lines were used to assess the biological functions of the novel protein in vitro and in vivo. Clinical implications of circ-EGFR were assessed using 97 pathologically diagnosed GBM patient samples. Results The infinite open reading frame (iORF) in circ-EGFR translated repeating amino acid sequences via rolling translation and programmed -1 ribosomal frameshifting (-1PRF) induced out-of-frame stop codon (OSC), forming a polymetric novel protein-complex, which we termed rolling-translated EGFR (rtEGFR). rtEGFR directly interacted with EGFR, maintained EGFR membrane localization and attenuated EGFR endocytosis and degradation. Importantly, circ-EGFR levels correlated with the EGFR signature and predicted the poor prognosis of GBM patients. Deprivation of rtEGFR in brain tumor-initiating cells (BTICs) attenuated tumorigenicity and enhanced the anti-GBM effect. Conclusion Our findings identified the endogenous rolling-translated protein and provided strong clinical evidence that targeting rtEGFR could improve the efficiency of EGFR-targeting therapies in GBM.

Glioma-initiating cells (GIC), which are characterized by their self-renewal capacity and tumorigenicity, were recently identified as a highly tumorigenic subpopulation of glioblastoma multiforme and are considered responsible for glioblastoma recurrence and chemo/radiation resistance. Previously, it was revealed that Wnt signaling activation is critical to the self-renewal of GICs. However, the molecular mechanism underlying the high expression of b-catenin, the key transcription factor of the Wnt signaling pathway, remains elusive. In this investigation, it was determined that aurora kinase A (AURKA) regulates the self-renewal and tumorigenicity of GICs by stabilizing b-catenin. In GICs, AURKA directly interacts with AXIN and disrupts the AXIN/GSK3b/ b-catenin destruction complex and stabilizes b-catenin, thereby activating Wnt signaling to promote selfrenewal. Stable knockdown of AURKA destabilizes b-catenin by increasing phosphorylated b-catenin bound to AXIN and suppresses Wnt signaling, which inhibits the ability of GICs to self-renew. This effect is rescued by expression of an AURKA kinase dead mutant, D274A, which lacks the ability to phosphorylate GSK3b, indicating that stabilization of b-catenin by AURKA in GICs is independent from phosphorylation of GSK3b. Functional experiments confirm that inhibition of AUKRA in GICs could suppress their "stemness," selfrenewal ability, and tumorigenicity both in vitro and in vivo, and these effects could be rescued by stabilized b-catenin mutant. These findings indicate that AURKA competes away the binding of AXIN from b-catenin, induces b-catenin stabilization, and activates Wnt signaling in GICs.

Ubiquitin-conjugating enzyme E2C (UBE2C) is characterized as a crucial molecule in cancer cell growth that plays an essential role in the development of gliomas, but the detailed mechanisms have not been fully elucidated. In this study, we found that Forkhead box transcription factor M1 (FoxM1) overexpression increased UBE2C expression, whereas FoxM1 suppression inhibited UBE2C expression in glioma cells. In addition, high FoxM1/UBE2C expression was significantly correlated with poor prognosis in glioma. We subsequently demonstrated that UBE2C was a direct transcriptional target of FoxM1, and site-directed mutations markedly down-regulated UBE2C promoter activity. Moreover, UBE2C siRNA (si-UBE2C) significantly induced glioma cell autophagy and increased both mCherry-LC3 punctate fluorescence and LC3B-II/LC3-I expression. Notably, the si-UBE2C-induced decrease in cell viability was markedly inhibited by the autophagy inhibitor bafilomycin A1. The silencing of UBE2C resulted in a distinct inhibition of the PI3K-Akt-mTOR pathway, which functions in the negative modulation of autophagy. Collectively, our findings provide clinical and molecular evidence that FoxM1 promotes glioma progression by enhancing UBE2C transcription and that the inhibition of UBE2C partially induces autophagic glioma cell death. Thus, targeting the FoxM1-UBE2C axis has therapeutic potential in the treatment of gliomas.

Midkine (MDK) expression is associated with the proliferation of many cancers, including glioma. SP1 directly up-regulates the expression of MDK, and the SP1-MDK axis cooperates in glioma tumorigenesis.

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The combination of HSV-tk/GCV system with wt-p53 gene transduction is optimal for clinical therapeutic trials of suicide gene therapy for malignant gliomas.

BACKGROUND AND PURPOSE: Previous studies have suggested that increased mortality and disability in patients with brain tumor are associated with peritumoral brain edema. However, the mechanism of peritumoral brain edema in brain tumors is unknown. This study aimed to investigate the effect of Piezo1 overexpression on peritumoral brain edema in glioblastomas. MATERIALS AND METHODS: The Piezo1 expression in cell lines and paired samples was detected by quantitative reverse transcription polymerase chain reaction, Western blot, and immunohistochemistry. Sixty-four patients with glioblastomas were analyzed retrospectively. The Piezo1 expression of tumor tissue was detected by immunohistochemistry. The diameters of tumor and edema were measured by preoperative MR imaging, and the edema index value was calculated. RESULTS: Western blot and quantitative reverse transcription polymerase chain reaction showed that Piezo1 expression was higher in 6 glioma cell lines than in the normal astrocyte cell line. Compared with peritumoral tissues, Piezo1 was up-regulated in tumor tissues. Sixty-four patients with glioblastomas were enrolled in further study. Piezo1 was higher in the moderate edema group than in the mild edema group (P , .001), higher in the severe edema group than in the moderate edema group (P , .001), and correlated with the edema index (r ¼ 0.73; P , .001). Receiver operating characteristic curve analysis showed that the edema index yielded an area under the curve of 0.867 (95% CI, 0.76-0.97; P , .001), with a sensitivity of 100% and a specificity of 70%. CONCLUSIONS: Piezo1 overexpression is positively correlated with the degree of peritumoral brain edema in glioblastomas. Predicting high Piezo1 expression in tumor tissues based on the edema extent shows good sensitivity and specificity. ABBREVIATIONS: EI ¼ edema index; GBM ¼ glioblastoma; IHC ¼ immunohistochemistry; IRS ¼ immunoreactivity score; PTBE ¼ peritumoral brain edema; qRT-PCR ¼ quantitative reverse transcription polymerase chain reaction; ROC ¼ receiver operating characteristic; WHO ¼ World Health Organization