Glioblastoma multiforme (GBM), a lethal brain tumor developing in the white matter of the adult brain, contains a small population of GBM stem cells (GSCs), which potentially cause chemotherapeutic resistance and tumor recurrence. However, the mechanisms underlying the pathogenesis and maintenance of GSCs remain largely unknown. A recent study reported that incorporation of ribosomes and ribosomal proteins into somatic cells promoted lineage trans‐differentiation toward multipotency. This study aimed to investigate the mechanism underlying stemness acquisition in GBM cells by focusing on 40S ribosomal protein S6 (RPS6). RPS6 was significantly upregulated in high‐grade glioma and localized at perivascular, perinecrotic, and border niches in GBM tissues. siRNA‐mediated RPS6 knock‐down significantly suppressed the characteristics of GSCs, including their tumorsphere potential and GSC marker expression; STAT3 was downregulated in GBM cells. RPS6 overexpression enhanced the tumorsphere potential of GSCs and these effects were attenuated by STAT3 inhibitor (AG490). Moreover, RPS6 expression was significantly correlated with SOX2 expression in different glioma grades. Immunohistochemistry data herein indicated that RPS6 was predominant in GSC niches, concurrent with the data from IVY GAP databases. Furthermore, RPS6 and other ribosomal proteins were upregulated in GSC‐predominant areas in this database. The present results indicate that, in GSC niches, ribosomal proteins play crucial roles in the development and maintenance of GSCs and are clinically associated with chemoradioresistance and GBM recurrence.
Although glioblastoma (GBM) stem-like cells (GSCs), which retain chemo-radio resistance and recurrence, are key prognostic factors in GBM patients, the molecular mechanisms of GSC development are largely unknown. Recently, several studies revealed that extrinsic ribosome incorporation into somatic cells resulted in stem cell properties and served as a key trigger and factor for the cell reprogramming process. In this study, we aimed to investigate the mechanisms underlying GSCs development by focusing on extrinsic ribosome incorporation into GBM cells. Ribosome-induced cancer cell spheroid (RICCS) formation was significantly upregulated by ribosome incorporation. RICCS showed the stem-like cell characters (number of cell spheroid, stem cell markers, and ability for trans differentiation towards adipocytes and osteocytes). In RICCS, the phosphorylation and protein expression of ribosomal protein S6 (RPS6), an intrinsic ribosomal protein, and STAT3 phosphorylation were upregulated, and involved in the regulation of cell spheroid formation. Consistent with those results, glioma-derived extrinsic ribosome also promoted GBM-RICCS formation through intrinsic RPS6 phosphorylation. Moreover, in glioma patients, RPS6 phosphorylation was dominantly observed in high-grade glioma tissues, and predominantly upregulated in GSCs niches, such as the perinecrosis niche and perivascular niche. Those results indicate the potential biological and clinical significance of extrinsic ribosomal proteins in GSC development.
Introduction: Cylindromatosis (CYLD) regulates various cell signaling pathways by acting as a deubiquitinating enzyme. Although it was shown that loss of CYLD expression was associated with poor prognosis in glioblastoma multiforme (GBM), the biological roles of CYLD in GBM remain unknown. Here, we elucidated the biological significance of CYLD in the malignant characteristics of GBM. Methods: To assess the biological significance of CYLD in GBM cell line (U251MG), we performed CYLD knockeddown by CYLD-specific siRNA and CYLD overexpression by wild-type CYLD plasmid. Next, we evaluated cell migration by cell migration assay, cell morphological change by endothelial tube formation assay, and cancer stem-like characters by sphere formation assay. Results: In U251MG, CYLD knocked-down significantly promoted cell migration, while CYLD overexpression suppressed it. CYLD knocked-down also induced cell morphological change like vascular mimicry (VM), whereas CYLD overexpression inhibited it. Moreover, CYLD knocked-down promoted cancer stem-like characters, while CYLD overexpression suppressed it. Conclusion: Loss of CYLD expression may be associated with the malignant characters, such as, invasion, VM, and cancer stem-like characters of GBM.
Nalfura ne is a pharmaceutical agent used in the treatment of cutaneous pruritus. Although its orally disintegrating (OD) lm agent is approved, noninferiority of its disintegration and elution to various OD tablet agents has yet to be demonstrated. This study aimed to evaluate the pharmaceutical characteristics of the nalfura ne OD lm agent. Disintegration and elution performance were tested for 4 different types of nalfura ne OD pharmaceutical agents including 1 lm agent and 3 tablet agents. Visual evaluation was employed for the disintegration test, while measurement of concentration using high performance liquid chromatography with ultraviolet was employed for the elution test. As a result of disintegration evaluation (n = 3), the OD lm agent repeatedly exhibited the same complete disintegration time (60 s), while the other three OD tablet agents showed the time variability (120 s -30 min). After the test start, the OD lm agents began disintegration at 20 s while the OD tablet agents began disintegration immediately. As a result of elution evaluation (n = 6), after the test start, the OD lm agent was eluted 100.6% in 5 min, while the OD tablet agents were eluted 95.8%, 75.8% and 80.5%, respectively. In conclusion, this study indicates that the nalfura ne OD lm agent was not inferior to the OD tablet agents in terms of disintegration and elution.
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