Functional analysis of HOXD9 in human gliomas and glioma cancer stem cells

<p>Abstract</p> <p>Background</p> <p><it>HOX </it>genes encode a family of homeodomain-containing transcription factors involved in the determination of cell fate and identity during embryonic development. They also behave as oncogenes in some malignancies.</p> <p>Results</p> <p>In this study, we found high expression of the <it>HOXD9 </it>gene transcript in glioma cell lines and human glioma tissues by quantitative real-time PCR. Using immunohistochemistry, we observed HOXD9 protein expression in human brain tumor tissues, including astrocytomas and glioblastomas. To investigate the role of <it>HOXD9 </it>in gliomas, we silenced its expression in the glioma cell line U87 using <it>HOXD9</it>-specific siRNA, and observed decreased cell proliferation, cell cycle arrest, and induction of apoptosis. It was suggested that <it>HOXD9 </it>contributes to both cell proliferation and/or cell survival. The <it>HOXD9 </it>gene was highly expressed in a side population (SP) of SK-MG-1 cells that was previously identified as an enriched-cell fraction of glioma cancer stem-like cells. <it>HOXD9 </it>siRNA treatment of SK-MG-1 SP cells resulted in reduced cell proliferation. Finally, we cultured human glioma cancer stem cells (GCSCs) from patient specimens found with high expression of <it>HOXD9 </it>in GCSCs compared with normal astrocyte cells and neural stem/progenitor cells (NSPCs).</p> <p>Conclusions</p> <p>Our results suggest that <it>HOXD9 </it>may be a novel marker of GCSCs and cell proliferation and/or survival factor in gliomas and glioma cancer stem-like cells, and a potential therapeutic target.</p

RNA-Binding Protein Musashi1 Modulates Glioma Cell Growth through the Post-Transcriptional Regulation of Notch and PI3 Kinase/Akt Signaling Pathways

Musashi1 (MSI1) is an RNA-binding protein that plays critical roles in nervous-system development and stem-cell self-renewal. Here, we examined its role in the progression of glioma. Short hairpin RNA (shRNA)-based MSI1-knock down (KD) in glioblastoma and medulloblastoma cells resulted in a significantly lower number of self renewing colony on day 30 (a 65% reduction), compared with non-silencing shRNA-treated control cells, indicative of an inhibitory effect of MSI1-KD on tumor cell growth and survival. Immunocytochemical staining of the MSI1-KD glioblastoma cells indicated that they ectopically expressed metaphase markers. In addition, a 2.2-fold increase in the number of MSI1-KD cells in the G2/M phase was observed. Thus, MSI1-KD caused the prolongation of mitosis and reduced the cell survival, although the expression of activated Caspase-3 was unaltered. We further showed that MSI1-KD glioblastoma cells xenografted into the brains of NOD/SCID mice formed tumors that were 96.6% smaller, as measured by a bioluminescence imaging system (BLI), than non-KD cells, and the host survival was longer (49.3±6.1 days vs. 33.6±3.6 days; P<0.01). These findings and other cell biological analyses suggested that the reduction of MSI1 in glioma cells prolonged the cell cycle by inducing the accumulation of Cyclin B1. Furthermore, MSI1-KD reduced the activities of the Notch and PI3 kinase-Akt signaling pathways, through the up-regulation of Numb and PTEN, respectively. Exposure of glioma cells to chemical inhibitors of these pathways reduced the number of spheres and living cells, as did MSI1-KD. These results suggest that MSI1 increases the growth and/or survival of certain types of glioma cells by promoting the activation of both Notch and PI3 kinase/Akt signaling

Skull base chordomas: efficacy of surgery followed by carbon ion radiotherapy

Background Skull base chordomas are challenging to treat because of their invasive nature, critical location, and aggressive recurrence. We report the effectiveness of combined radical skull base surgery with carbon ion radiotherapy for treating skull base chordomas. Methods Between November 1996 and August 2007, 32 patients (12 males and 20 females; mean age at initial presentation 41.4 years, range, 10&#8211;75 years) with skull base chordomas underwent 59 operations. Sub-total resection (resection of >90% of the pre-operative tumour volume) was achieved in 24 out of 59 (40.7%) operations. After surgical excision, 9/32 (28.1%) patients underwent adjuvant carbon ion radiotherapy. The patients were followed up for a mean period of 36.3 months (range, 3&#8211;93 months) from the initial presentation. Findings Fifty percent of the patients had to be re-treated due to tumour regrowth during the follow-up period. Thus far, 3 patients have died from the neoplasms. The overall 7 year survival rate of 9 patients who underwent carbon ion radiotherapy was 85.7%. The rate was higher compared to that of others (76.4%). The 3 year recurrence free survival rates of carbon ion therapy treated group was 70.0%, being higher than that of the other groups treated with radiotherapy or untreated (57.1%, and 7.1% respectively). Log-rank analysis showed a significant difference in the recurrence free survival rates between the group treated with adjunctive carbon ion radiotherapy and the untreated group (P&#8201;=&#8201;0.001146). Conclusions Surgical removal of the tumour around the brainstem and the optic nerve combined with post-operative carbon ion radiotherapy will improve the survival rate and quality of life of patients with complicated skull base chordomas

Surface-Modified Ta3N5 Photoanodes for Sunlight-Driven Overall Water Splitting by Photoelectrochemical Cells

The development of visible-light-responsive semiconductor-based photoelectrodes is a prerequisite for the construction of efficient photoelectrochemical (PEC) cells for solar water splitting. Surface modification with an electrocatalyst on the photoelectrode is effective for maximizing the water splitting efficiency of the PEC cell. Herein, we investigate the effects of surface modification of Ta3N5 photoanodes with electrocatalysts consisting of Ni, Fe, and Co oxides, and their mixture, on the PEC oxygen evolution reaction (OER) performance. Among the investigated samples, NiFeOx-modified Ta3N5 (NiFeOx/Ta3N5) photoanodes showed the lowest onset potential for OER. A PEC cell with a parallel configuration consisting of a NiFeOx/Ta3N5 photoanode and an Al-doped La5Ti2Cu0.9Ag0.1S5O7 (LTCA:Al) photocathode exhibited stoichiometric hydrogen and oxygen generation from water splitting, without any external bias voltage. The solar-to-hydrogen energy conversion efficiency (STH) of this cell for water splitting was found to be 0.2% at 1 min after the start of the reaction. In addition, water splitting by a PEC cell with a tandem configuration incorporating a NiFeOx/Ta3N5 transparent photoanode prepared on a quartz insulating substrate as a front-side electrode and a LTCA:Al photocathode as a back side electrode was demonstrated, and the STH was found to be 0.04% at the initial stage of the reaction

Evaluation of Three Cases Using a Novel Titanium Mesh System—Skull-Fit® with Orbital Wall (Skull-Fit WOW®)—For Cranial Base Reconstructions

Cranial base reconstructions associated with tumor resections around the orbital wall often require that both the upper and lateral orbital walls be reconstructed during a single procedure. Previously, we used titanium mesh plates that were preoperatively fabricated based on three-dimensional models. Although these plates are precise and do not increase the probability of infection, we still had to use autologous bones to reconstruct the orbital walls. Recently, we developed a new titanium mesh plate—called Skull-Fit®—with orbital wall (Skull-Fit WOW®), enabling us to reconstruct the cranial base and orbital walls without bone grafts. Here, we report on three reconstruction cases in which the novel titanium mesh-orbital wall system was used. In all three cases, the customized titanium mesh system performed satisfactorily with little, if any, complications