The impact of MEIS1 TALE homeodomain transcription factor knockdown on glioma stem cell growth.

Myeloid ecotropic virus insertion site 1 (MEIS1) is a HOX co-factor necessary for organ development and normal hematopoiesis. Recently, MEIS1 has been linked to the development and progression of various cancers. However, its role in gliomagenesis particularly on glioma stem cells (GSCs) remains unclear. Here, we demonstrate that MEIS1 is highly upregulated in GSCs compared to normal, and glioma cells and to its differentiated counterparts. Inhibition of MEIS1 expression by shRNA significantly reduced GSC growth in both in vitro and in vivo experiments. On the other hand, integrated transcriptomics analyses of glioma datasets revealed that MEIS1 expression is correlated to cell cycle-related genes. Clinical data analysis revealed that MEIS1 expression is elevated in high-grade gliomas, and patients with high MEIS1 levels have poorer overall survival outcomes. The findings suggest that MEIS1 is a prognostic biomarker for glioma patients and a possible target for developing novel therapeutic strategies against GBM.

CREB5 promotes the proliferation and self-renewal ability of glioma stem cells.

Glioblastoma multiforme (GBM) is the most fatal form of brain cancer in humans, with a dismal prognosis and a median overall survival rate of less than 15 months upon diagnosis. Glioma stem cells (GSCs), have recently been identified as key contributors in both tumor initiation and therapeutic resistance in GBM. Both public dataset analysis and direct differentiation experiments on GSCs have demonstrated that CREB5 is more highly expressed in undifferentiated GSCs than in differentiated GSCs. Additionally, gene silencing by short hairpin RNA (shRNA) of CREB5 has prevented the proliferation and self-renewal ability of GSCs in vitro and decreased their tumor forming ability in vivo. Meanwhile, RNA-sequencing, luciferase reporter assay, and ChIP assay have all demonstrated the closely association between CREB5 and OLIG2. These findings suggest that targeting CREB5 could be an effective approach to overcoming GSCs.

Targeting the multidrug and toxin extrusion 1 gene (SLC47A1) sensitizes glioma stem cells to temozolomide.

Glioblastoma multiforme (GBM) is the most aggressive type of brain tumor, with an extremely poor prognosis due to resistance to standard-of-care treatments. Strong evidence suggests that the small population of glioma stem cells (GSCs) contributes to the aggressiveness of GBM. One of the mechanisms that promote GSC progression is the dysregulation of membrane transporters, which mediate the influx and efflux of substances to maintain cellular homeostasis. Here, we investigated the role of multidrug and toxin extrusion transporter gene SLC47A1 in GSCs. Results show that SLC47A1 is highly expressed in GSCs compared to non-stem cell glioma cells, and non-tumor cells. Additionally, in-silico analysis of public datasets showed that high SLC47A1 expression is linked to malignancy and a poor prognosis in glioma patients. Further, SLC47A1 expression is correlated with important biological processes and signaling pathways that support tumor growth. Meanwhile, silencing SLC47A1 by short-hairpin RNA (shRNA) influenced cell viability and self-renewal activity in GSCs. Interestingly, SLC47A1 shRNA knockdown or pharmacological inhibition potentiates the effect of temozolomide (TMZ) in GSC cells. The findings suggest that SLC47A1 could serve as a useful therapeutic target for gliomas.

Downregulation of ADAMTS3 Suppresses Stemness and Tumorigenicity in Glioma Stem Cell.

AIMS: Glioblastoma multiforme (GBM) is the most aggressive type of human brain tumor, with a poor prognosis and a median overall survival of fewer than 15 months. Glioma stem cells (GSCs) have recently been identified as a key player in tumor initiation and therapeutic resistance in GBM. ADAMTS family of metalloproteinases is known to cleave a wide range of extracellular matrix substrates and has been linked to tissue remodeling events in tumor development. Here, we investigate that ADAMTS3 regulates GSC proliferation and self-renewal activities, and tumorigenesis in orthotopic xenograft models. METHODS: ADAMTS3 mRNA expression levels in normal human astrocyte (NHA), glioma, and GSCs cell lines were compared. After knockdown of ADAMTS3, alamarBlue assay, in vitro limiting dilution, and orthotopic xenograft assays were performed. To investigate the tumor-associated roles of ADAMTS3, several statistical assays were conducted using publicly available datasets. RESULTS: ADAMTS3 level was remarkably higher in GSCs than in NHA, glioma cell lines, and their matched differentiated tumor cells. Interestingly, knockdown of ADAMTS3 disrupted GSC's proliferation, self-renewal activity, and tumor formation in vivo. Furthermore, ADAMTS3 could be used as an independent predictor of malignancy progression in GBM. CONCLUSION: We identified ADAMTS3 as a potential therapeutic target for GBM.

Sprouty 1 is associated with stemness and cancer progression in glioblastoma.

Glioblastoma multiforme (GBM) is the most severe type of human brain tumor, with a poor prognosis and a low survival rate. GBM is composed of a variety of cell types, including glioma stem-like cells (GSCs), which attribute to its therapeutic resistance (Boyd et al., 2020). Sprouty1 (SPRY1) was first identified as a receptor tyrosine kinases (RTK) signaling mediator in a mammalian cell (Christofori, 2003), however, its role in GBM is unknown. Therefore, the goal of this study was to investigate the role of SPRY1 in the stemness and aggressiveness of GSCs. The mRNA expression levels of SPRY1 were confirmed using quantitative reverse transcription PCR (RT-qPCR) in normal human astrocytes (NHA), glioma cells, and glioma stem cells. SPRY1 expression was inhibited in glioma stem cells using small interference RNA (siRNAs) to examine its role in cell proliferation and tumorsphere formation. Bioinformatics analyses were also employed to investigate the association of SPRY1 expression with patient survival, tumor grade, and subtypes publicly available datasets. We demonstrated that SPRY1 is highly expressed in glioma stem cells than in NHA, glioma cells, and differentiated glioma stem cells. siRNA-mediated downregulation of SPRY1 expression decreased the stemness and self-renewal ability in GSC11. Bioinformatics results showed that high SPRY1 expression correlates with poor overall survival in glioma patients. Our findings suggest that SPRY1 contributes to the stemness and aggressiveness of GBM.

Shinorine and porphyra-334 isolated from laver (Porphyra dentata) inhibit adipogenesis in 3T3-L1 cells.

Mycosporine-like amino acids (MAAs) such as shinorine and porphyra-334 from Porphyra spp. are bioactive compounds with strong photoprotective and antioxidant properties. In this study, the anti-adipogenic effect of shinorine and porphyra-334 was examined in vitro utilizing 3T3-L1 preadipocytes. Shinorine and porphyra-334 were extracted from laver (Porphyra dentata) 50% methanolic (MeOH) extract of and their structures were elucidated by MS and NMR spectroscopy. Both compounds had no cytotoxic effect in 3T3-L1 cells (< 200 µg/mL) and inhibited the accumulation of lipid droplets in 3T3-L1 mature adipocytes in a dose-dependent manner (0.1 and 1.0 µM). Interestingly, both compounds had also significantly reduced the expression of adipogenic-related genes such as peroxisome proliferator-activated receptor γ2 (PPARγ2), CCAAT/enhancer-binding protein α (C/EBPα), adiponectin, and leptin in 3T3-L1 cells. The findings suggest that shinorine and porphyra-334 have the potential to inhibit adipogenesis in 3T3-L1 preadipocytes.

Friend or Foe: Paradoxical Roles of Autophagy in Gliomagenesis.

Glioblastoma multiforme (GBM) is the most common and aggressive type of primary brain tumor in adults, with a poor median survival of approximately 15 months after diagnosis. Despite several decades of intensive research on its cancer biology, treatment for GBM remains a challenge. Autophagy, a fundamental homeostatic mechanism, is responsible for degrading and recycling damaged or defective cellular components. It plays a paradoxical role in GBM by either promoting or suppressing tumor growth depending on the cellular context. A thorough understanding of autophagy's pleiotropic roles is needed to develop potential therapeutic strategies for GBM. In this paper, we discussed molecular mechanisms and biphasic functions of autophagy in gliomagenesis. We also provided a summary of treatments for GBM, emphasizing the importance of autophagy as a promising molecular target for treating GBM.