Function of a complex of p-Y42 RhoA GTPase and pyruvate kinase M2 in EGF signaling pathway in glioma cells.

Epidermal growth factor (EGF) is known to be a critical stimulant for inducing the proliferation of glioma cancer cells. In our study, we observed that GST-RhoA binds to pyruvate kinase M2 (PKM2) in vitro. While EGF reduced the levels of RhoA protein, it significantly increased p-Y42 RhoA, as well as PKM1 and PKM2 in LN18 glioma cell line. We determined that RhoA undergoes degradation through ubiquitination involving SCF1 and Smurf1. Interestingly, we observed that p-Y42 RhoA binds to PKM2, while the dephosphomimetic form, RhoA Y42F, did not. Additionally, our observation revealed that PKM2 stabilized both RhoA and p-Y42 RhoA. Importantly, RhoA, p-Y42 RhoA, and PKM2, but not RhoA-GTP, were localized in the nucleus upon EGF stimulation. Knockdown of RhoA with siRNA resulted in the reduced levels of phosphoglycerate kinase1 (PGK1) and microtubule affinity-regulating kinase 4 (MARK). Furthermore, we found that the promoter of PGK1 was associated with ß-catenin and YAP. Notably, p-Y42 RhoA and PKM2 co-immunoprecipitated with ß-catenin and YAP. Based on these findings, we proposed a novel mechanism by which p-Y42 RhoA and PKM2, in conjunction with ß-catenin and YAP, regulate PGK1 expression, contributing to the progression of glioma upon EGF.

Annexin A2 Stabilizes Oncogenic JAG1 Intracellular Domain by Inhibiting Proteasomal Degradation in Glioblastoma Cells.

Glioblastoma (GBM) is the most lethal brain cancer, causing inevitable deaths of patients owing to frequent relapses of cancer stem cells (CSCs). The significance of the NOTCH signaling pathway in CSCs has been well recognized; however, there is no NOTCH-selective treatment applicable to patients with GBM. We recently reported that Jagged1 (JAG1), a NOTCH ligand, drives a NOTCH receptor-independent signaling pathway via JAG1 intracellular domain (JICD1) as a crucial signal that renders CSC properties. Therefore, mechanisms regulating the JICD1 signaling pathway should be elucidated to further develop a selective therapeutic regimen. Here, we identified annexin A2 (ANXA2) as an essential modulator to stabilize intrinsically disordered JICD1. The binding of ANXA2 to JICD1 prevents the proteasomal degradation of JICD1 by heat shock protein-70/90 and carboxy-terminus of Hsc70 interacting protein E3 ligase. Furthermore, JICD1-driven propagation and tumor aggressiveness were inhibited by ANXA2 knockdown. Taken together, our findings show that ANXA2 maintains the function of the NOTCH receptor-independent JICD1 signaling pathway by stabilizing JICD1, and the targeted suppression of JICD1-driven CSC properties can be achieved by blocking its interaction with ANXA2.

FOXO3a Mediates Homologous Recombination Repair (HRR) via Transcriptional Activation of MRE11, BRCA1, BRIP1, and RAD50.

To test whether homologous recombination repair (HRR) depends on FOXO3a, a cellular aging model of human dermal fibroblast (HDF) and tet-on flag-h-FOXO3a transgenic mice were studied. HDF cells transfected with over-expression of wt-h-FOXO3a increased the protein levels of MRE11, BRCA1, BRIP1, and RAD50, while knock-down with siFOXO3a decreased them. The protein levels of MRE11, BRCA1, BRIP1, RAD50, and RAD51 decreased during cellular aging. Chromatin immunoprecipitation (ChIP) assay was performed on FOXO3a binding accessibility to FOXO consensus sites in human MRE11, BRCA1, BRIP1, and RAD50 promoters; the results showed FOXO3a binding decreased during cellular aging. When the tet-on flag-h-FOXO3a mice were administered doxycycline orally, the protein and mRNA levels of flag-h-FOXO3a, MRE11, BRCA1, BRIP1, and RAD50 increased in a doxycycline-dose-dependent manner. In vitro HRR assays were performed by transfection with an HR vector and I-SceI vector. The mRNA levels of the recombined GFP increased after doxycycline treatment in MEF but not in wt-MEF, and increased in young HDF comparing to old HDF, indicating that FOXO3a activates HRR. Overall, these results demonstrate that MRE11, BRCA1, BRIP1, and RAD50 are transcriptional target genes for FOXO3a, and HRR activity is increased via transcriptional activation of MRE11, BRCA1, BRIP1, and RAD50 by FOXO3a.

Comparison of Facial Proportions Between Eastern and Western Attractive Young Women.

The characteristics of what is considered a beautiful face differ between Eastern and Western countries.The authors of this study analyzed beauty pageant contestants using a three-dimensional (3D) photogrammetric analysis tool. All of the 3D photographs were taken between October and November 2016 in Seoul, Korea. The participants were 43 Miss Korea contestants (Group I) and 22 Miss Paraguay contestants (Group II).In absolute length, those in Group I had longer upper and middle faces. In the proportions of volume and length, Group I had larger upper and middle faces than Group II. Widths of the lower face and entire face were also wider in Group I. The lower facial index was larger in Group I. Group I had longer noses and wider intercanthal distance, not only in absolute length but also in proportion to the face. Group II showed thicker lips, longer chins, and wider noses relative to the face. Group II had wide eyes, in the absolute measurement and in proportion to the face. Group I participants appeared to have an increased height of eyes and had wider angles in their faces as well as wider nasofrontal, labiomental, and nasomental angles.The authors objectively established reference data for faces that are considered attractive in the East and the West. The data are expected to contribute to the clinical practice of plastic surgeons.

Correction of Congenital Telecanthus by Extended Medial Epicanthoplasty With Skin Redraping Method.

BACKGROUND: Recently, skin-redraping medial epicanthoplasty has emerged as an extremely effective way to minimize the resultant scar. We found that the novel skin-redraping medial epicanthoplasty technique, which has been applied to aesthetic surgery, could also be suitable for the correction of congenital epicanthus and telecanthus. METHODS: We retrospectively identified patients who had an epicanthoplasty from December 2007 to August 2017. Among 47 patients, we identified 19 cases with congenital pathologies (nonaesthetic cases). Overall, 7 patients with at least 2 anthropometric measurements were selected. RESULTS: There was a mean presurgical intercanthal distance of 35.85 mm (range, 24-52 mm) and a mean intercanthal distance of 26.85 mm (range, 17-36 mm) with a mean difference of 9 mm following postsurgical revision. To better categorize this difference, statistical analysis was conducted using a paired t test, which showed a significant result with P = 0.008. CONCLUSIONS: Our results revealed that the skin-redraping medial epicanthoplasty technique could be a better option even in the reconstruction of congenital telecanthus as well as aesthetic plastic surgery. It could correct mild to severe telecanthus and minimize scar formation.

Impact of Venous Outflow Pattern on Flap Compromise in Head and Neck Reconstruction: Review of 309 Radial Forearm Free Flaps.

There is ongoing controversy regarding the most appropriate venous drainage pattern for anastomosing the radial forearm free flap in head and neck reconstruction. Although the various perforator flaps have been used in our practice, the authors evaluated the impact of venous outflow pattern on the incidence of only the radial forearm free flap compromise for minimizing the bias. The authors retrospectively reviewed 309 radial forearm free flaps used for head and neck reconstruction following cancer ablation (January 2005 to December 2015), and evaluated the association between the incidence of venous insufficiency and the choice of venous system in the flap and at the recipient site, the number of venous anastomoses, and the combination of flap and recipient venous systems. No significant association was found between the incidence of venous insufficiency and the risk factors evaluated. Compared with single or dual anastomosis involving only the vena comitantes, dual anastomosis involving distinct venous systems was associated with lower incidence of venous insufficiency (P = 0.039). The dual anastomosis of separate venous system was correlated with lower incidence of venous insufficiency compared with the single or dual anastomosis of vena comitantes only (P = 0.039).

Comparison Between Intermaxillary Fixation With Screws and an Arch Bar for Mandibular Fracture.

PURPOSE: Intermaxillary fixation (IMF) using the arch bar has been the standard technique for a long time in the management of mandibular fracture. But because of several complications, intermaxillary fixation with screws has been introduced and adopted to use. This investigation compared the outcomes and complications between the traditional IMF and modified intermaxillary fixation with screws techniques in terms of the malocclusion, surgical time, root injury, and screw or arch bar failure. METHODS: This retrospective review included 66 patients who underwent reconstruction of mandibular fractures that uses traditional arch bar or IMF screws as IMF. Preoperative and postoperative facial bone computed tomography, panoramic x-ray were used to evaluate the patients. The complaints and complications were recorded in electric medical record based on patients' consultation during follow-up. RESULTS: The total complication rate was no higher using anchoring screw as an IMF than using arch bar fixation as an IMF. Mean surgical time was significantly shorter in the anchoring screw group than arch bar fixation (111 versus 157 min; P < .05). After compensation of the number of fracture sites, there was a significant difference in operation time (linear regression model, P = .009). CONCLUSION: This investigation revealed that the IMF using IMF screw systems could be a good alternative for the management of mandibular fracture. It could minimize the whole operation time with the similar complication ratio.

Energy Balance in Medium-Scale Methanol, Ethanol, and Acetone Pool Fires.

Several series of measurements were made to characterize medium-scale pool fires steadily burning in a well-ventilated, quiescent, open environment. Time-averaged local measurements of radiative and total heat flux were made in steadily burning methyl alcohol (methanol; CH3OH), ethyl alcohol (ethanol; C2H5OH), and acetone ((CH3)2 CO) pool fires. The fuel lip height in a water-cooled stainless-steel burner was maintained at 10 mm. Schmidt-Boelter heat flux gauges were used to measure the radiative emission to the surroundings. The total heat flux directed towards the pool surface was measured using a Gardon gauge positioned just above the pool surface. A previously developed method was used to calculate the convective heat flux to the pool surface, allowing estimation of the radiative flux, which agreed within experimental uncertainty with a previous measurement in the methanol pool fire. The steady-state mass burning rate was measured using a load cell, and the heat release rate was measured in the exhaust using calorimetry. The energy balance for each of the fires was determined. The results showed that both radiation and convection play significant roles in these pool fires. Radiation was the dominant mechanism of heat feedback to the fuel surface, accounting from 68 % to 88 % of the energy, while enthalpy convected in the plume represented 68 % to 78 % of the fire's total energy, far exceeding radiative emission to the surroundings.

Three-dimensional Photogrammetric Analysis of Facial Soft-to-Hard Tissue Ratios After Bimaxillary Surgery in Facial Asymmetry Patients With and Without Sturge-Weber Syndrome.

Sturge-Weber syndrome (SWS) is a rare neurocutaneous syndrome characterized by facial port-wine stains. Most patients with facial asymmetry due to SWS have soft and/or hard tissue hypertrophy and require both soft tissue correction and bone surgery. In our experience, because SWS patients are more likely than non-SWS patients to be dissatisfied after bone surgery because of limited soft tissue change, we compared soft tissue changes after bimaxillary surgery between facial asymmetry patients with and without SWS.All patients-5 with SWS and 5 without SWS-underwent bimaxillary surgery by a single surgeon. Soft-to-hard ratios were determined using the preoperative and postoperative vertical lengths from the intersection point between the external orbital contour laterally and the oblique orbital line (LO) to the occlusion line (OL) and the LO to the mandible angle (AG) on cephalography and the distances between the lateral canthus (LC) and oral commissure (OC) and between the LC and soft tissue gonion (Go') on 3-dimensional scanned images.The average change in the [LC-OC] to [LO-OL] ratio was 23.03% ± 10.09% in SWS patients and 88.05% ± 10.44% in non-SWS patients (P = 0.008). The average change in the [LC-Go'] to [LO-AG] ratio was 35.54% ± 15.47% in SWS patients and 78.90% ± 47.56% in non-SWS patients (P = 0.032).Soft-to-hard tissue ratios after orthognathic surgery are significantly smaller in SWS patients than in non-SWS patients. This information is important for preoperative patient counseling, managing patient expectations, enhancing results, and planning the second-stage soft tissue surgery.

Three-Dimensional Analysis of Airway Change After LeFort III Midface Advancement With Distraction.

INTRODUCTION: LeFort III midface advancement using the distraction technique became the standard method for the correction of various craniofacial syndromes accompanied by the midface retrusion. Midface hypoplasia is known to be related to the imbalance in facial aesthetics, malocclusion, and the airway problem. This study aimed to evaluate the change in airway volume after performing a LeFort III midface advancement with the distraction techniques. PATIENTS AND METHODS: Between April 2008 and February 2013, 7 patients aged 5 to 7 years underwent standard LeFort III osteotomy, followed by distraction with a rigid external distractor with or without internal distractor. The degree of advancement of the midface and the airway volume were evaluated with 3-dimensional computed tomography scans and the 3-dimensional software. RESULTS: The average latent period was 3.57 days. The average manual distraction distance was 17.55 mm for 3.82 weeks. The consolidation period ranged from 3 to 7 months. Changes between the preoperative and postoperative airway volumes were remarkable. The average preoperative postpharyngeal airway volume was 5649.33 mm compared with an average postoperative airway volume of 7403.44 mm. Therefore, the average postpharyngeal airway space increased by a remarkable 32.78%. CONCLUSIONS: This investigation revealed that the LeFort III midface advancement using distraction could increase postpharyngeal airway space by approximately 33% when the midface is advanced by approximately 18 mm. This method could be used as a future reference for LeFort III midface advancement with distraction.

One-Piece Mandibuloplasty Compared to Conventional Mandibuloplasty With Narrowing Genioplasty.

BACKGROUND: Recently, the mandibular body and chin shape are known to be important issue as well as the mandibular angle. The authors have performed the one-piece mandibuloplasty from the mandibular angle to the most anterior part of chin to achieve the change of the whole mandibular shape as a one-piece. METHODS: All of 14 patients who complaint prominent mandibular angle and chin were randomly allocated into 2 groups. Group I (n = 7) was treated with conventional mandibuloplasty with narrowing genioplasty and Group II (n = 7) was treated with one-piece mandibuloplasty. Pre- and postoperative clinical photography, cephalometry, computed tomography scan, 3-dimensional photography were taken and occurrence of secondary angle, patient's satisfaction, and operative time were evaluated. RESULTS: The mean volume reduction per side was 41.8 cc on one-piece mandibuloplasty and 36.5 cc on conventional mandibuloplasty with narrowing genioplasty. Furthermore, average lower facial decreased from 64.3 to 61.0 after 6 months postoperatively and was maintained until 3 years on average after the operation. In one-piece mandibuloplasty group shows a little higher satisfaction about mandible body, and it was estimated that the presence of secondary angle makes dissatisfaction. The authors' treatment approach resulted in a shorter total surgery time than conventional technique (70.57 versus 105.14 min, P = 0.002). CONCLUSIONS: One-piece mandibuloplasty based on 3-dimensional printing model turned out to be very successful for the natural shaping of the lower jaw in the patients with the prominent mandible in terms of the technical efficiency and the aesthetic point of view.

Positive Effect of Incubated Adipose-Derived Mesenchymal Stem Cells on Microfat Graft Survival.

Autologous fat grafting is commonly used for soft tissue augmentation, but its unpredictably high resorption rate remains a major limitation. Although adipose-derived mesenchymal stem cells (ASCs) are an attractive candidate for enhancing graft retention, their poor posttransplantation viability limits their application. The authors aimed to evaluate the effect of incubated ASCs on microfat graft survival in an immunocompromised mouse model. Lipoaspirates for microfat injection were collected from the wasted lower abdominal adipose tissues of 5 patients who had undergone breast reconstructive surgery with an abdominal flap. Adipose-derived mesenchymal stem cells were also isolated and proliferated from these fat tissues. Sixty athymic mice were randomly allocated to a control group (microfat grafting alone; n = 30) or ASCs group (microfat grafting plus simultaneous human ASCs injection; n = 30). The volume and weight of survived fat were measured at 8 and 16 weeks, and histopathological and immunologic staining was performed at 16 weeks. The survived fat volume of the ASCs group was significantly greater than that of the control group at 8 and 16 weeks, whereas the weight of survived fat tissues did not significantly differ. Histologic evaluation of the harvested fat indicated significantly higher levels of adipocytes, and fewer cysts and fibrosis in the tissues in the ASCs group than in the control group. The ASCs group also exhibited a significantly higher number of capillary vessels than the control group on CD31 and alpha-smooth muscle actin staining. In conclusion, transplanted fat survival is markedly higher when simultaneous microfat graft and ASCs injection were performed, as compared with that in the classical microfat graft alone method in mice; this improvement was primarily attributed to the increased ability to produce blood vessels.

Comparison of Facial Proportions Between Beauty Pageant Contestants and Ordinary Young Women of Korean Ethnicity: A Three-Dimensional Photogrammetric Analysis.

BACKGROUND: Although the harmony of facial proportions is traditionally perceived as an important element of facial attractiveness, there have been few objective studies that have investigated this esthetic balance using three-dimensional photogrammetric analysis. OBJECTIVES: To better understand why some women appear more beautiful, we investigated differences in facial proportions between beauty pageant contestants and ordinary young women of Korean ethnicity using three-dimensional (3D) photogrammetric analyses. METHODS: A total of 43 prize-winning beauty pageant contestants (group I) and 48 ordinary young women (group II) of Korean ethnicity were photographed using 3D photography. Numerous soft tissue landmarks were identified, and 3D photogrammetric analyses were performed to evaluate 13 absolute lengths, 5 angles, 3 volumetric proportions, and 12 length proportions between soft tissue landmarks. RESULTS: Group I had a greater absolute length of the middle face, nose height, and eye height and width; a smaller absolute length of the lower face, intercanthal width, and nasal width; a larger nasolabial angle; a greater proportion of the upper and middle facial volume, nasal height, and eye height and width; and a lower proportion of the lower facial volume, lower face height, intercanthal width, nasal width, and mouth width. All these differences were statistically significant. CONCLUSIONS: These results indicate that there are significant differences between the faces of beauty pageant contestants and ordinary young women, and help elucidate which factors contribute to facial beauty. The group I mean values could be used as reference values for attractive facial profiles. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Comparison of Periorbital Anthropometry Between Beauty Pageant Contestants and Ordinary Young Women with Korean Ethnicity: A Three-Dimensional Photogrammetric Analysis.

BACKGROUND: The purpose of this study is to investigate the differences in the periorbital anthropometry between national Beauty Pageant Contestants and Ordinary Young Women with Korean ethnicity. METHODS: Forty-three Beauty Pageant Contestants who were elected for the national beauty contest and forty-eight Ordinary Young Women underwent 3D photography. The authors analyzed 3D photogrammetric measures regarding periorbital soft tissue. RESULTS: The palpebral fissure width was significantly higher in the Beauty Pageant Contestants than the Ordinary Young Women (27.7 ± 1.2 vs. 26.3 ± 1.6 mm) (p < 0.001). The palpebral fissure height was also significantly higher in the Beauty Pageant Contestants (11.5. ± 1.0 vs. 9.1 ± 1.2 mm) (p < 0.001). The intercanthal width and upper eyelid height were smaller for the Beauty Pageant Contestants (intercanthal width, 34.3 ± 1.86 mm vs. 36.7 ± 3.1 mm; upper eyelid height, 11.5 ± 1.4 mm vs. 13.4 ± 2.3 mm) (p < 0.05). The nasal width and midfacial width were significantly smaller in the Beauty Pageant Contestants (nasal width, 38.0 ± 1.8 vs. 39.5 ± 2.2 mm; midfacial width 144.5 ± 3.9 vs. 146.9 ± 5.2 mm) (p < 0.05). The eyebrow showed significantly different features between the two groups in terms of vertical position in the upper face and the shape of the brow apex. The interpupillary distance, binocular distance, slant of palpebral fissure and width of pretarsal crease showed no significant difference between the two groups. CONCLUSION: Periorbital features in Beauty Pageant Contestants are wide-set eyes, larger palpebral fissure in width and height, relatively small upper eyelid height and intercanthal width, and relatively small nose and facial width compared to normal women. Our anthropometric results can be referable values for Asian eyelid surgery and help surgeons to establish individualized surgical planning. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Bench-Scale Test Facility for Evaluating the Performance of Thermal Imagers for Fire Service Applications.

A bench-scale facility was developed for the evaluation of thermal imaging cameras. Smoke obscuration conditions in the optical smoke cell were characterized by measuring laser light transmittance through the cell. Measurements showed that the laser transmittance along the axial direction of the optical smoke cell was relatively uniform in the upper and lower halves of the cell for various smoke obscuration conditions. The thermal sensitivity of thermal imagers was investigated using the Michelson Contrast (CM) as a performance metric for a bar target viewed through the smoke-filled cell for different background thermal conditions. The results of the study indicate that the optical smoke cell can be utilized as a well-controlled and effective bench-scale test apparatus to evaluate aspects of the performance of thermal imagers for fire service applications.

Characterization of Stovetop Cooking Oil Fires.

A series of cooking fire experiments were conducted by the National Institute of Standards and Technology (NIST) to examine the hazard associated with cooking oil fires. First, a series of twelve experiments were conducted on a free-standing stove situated in the open. The experiments were based on scenarios outlined in the draft UL 300A standard for fire suppression apparatus. Both gas and electric ranges were tested. The amount of oil and types of cooking pans were varied in the experiments. Oil was heated on a cook top burner until autoignition took place. Measurements of oil and pan temperatures, heat release rates, and heat fluxes characterized the hazard of the ensuing fires. Next, two experiments were conducted using a full-scale residential kitchen arrangement to examine the hazard associated with the free burning oil fires situated within a compartment equipped with commercial furnishings, fiberboard cabinets, and countertops. The dimensions of the test room were 3.6 m × 3.4 m × 2.4 m high. Corn oil was heated on a cook top burner until autoignition took place. Measurements of room temperatures, heat fluxes, and heat release rates showed that even small cooktop fires spread and grew ultra-fast within the kitchen compartment.

Wnt3A Induces GSK-3ß Phosphorylation and ß-Catenin Accumulation Through RhoA/ROCK.

In canonical pathway, Wnt3A has been known to stabilize ß-catenin through the dissociation between ß-catenin and glycogen synthase kinase-3ß (GSK-3ß) that suppresses the phosphorylation and degradation of ß-catenin. In non-canonical signaling pathway, Wnt was known to activate Rho GTPases and to induce cell migration. The cross-talk between canonical and non-canonical pathways by Wnt signaling; however, has not been fully elucidated. Here, we revealed that Wnt3A induces not only the phosphorylation of GSK-3ß and accumulation of ß-catenin but also RhoA activation in RAW264.7 and HEK293 cells. Notably, sh-RhoA and Tat-C3 abolished both the phosphorylation of GSK-3ß and accumulation of ß-catenin. Y27632, an inhibitor of Rho-associated coiled coil kinase (ROCK) and si-ROCK inhibited both GSK-3ß phosphorylation and ß-catenin accumulation. Furthermore, active domain of ROCK directly phosphorylated the purified recombinant GSK-3ß in vitro. In addition, Wnt3A-induced cell proliferation and migration, which were inhibited by Tat-C3 and Y27632. Taken together, we propose the cross-talk between canonical and non-canonical signaling pathways of Wnt3A, which induces GSK-3ß phosphorylation and ß-catenin accumulation through RhoA and ROCK activation. J. Cell. Physiol. 232: 1104-1113, 2017. © 2016 Wiley Periodicals, Inc.

A cell-autonomous positive-signaling circuit associated with the PDGF-NO-ID4-regulatory axis in glioblastoma cells.

Most cancer-related signaling pathways sustain their active or inactive status via genetic mutations or various regulatory mechanisms. Previously, we demonstrated that platelet-derived growth factor (PDGF) activates Notch signaling through nitric oxide (NO)-signaling-driven activation of inhibitor of differentiation 4 (ID4) in glioblastoma (GBM) stem cells (GSCs) and endothelial cells in the vascular niche of GBM, leading to maintenance of GSC traits and GBM progression. Here, we determined that the PDGF-NO-ID4-signaling axis is constantly activated through a positive regulatory circuit. ID4 expression significantly increased PDGF subunit B expression in both in vitro cultures and in vivo tumor xenografts and regulated NO synthase 2 (NOS2) expression and NO production by activating PDGF signaling, as well as that of its receptor (PDGFR). Additionally, ectopic expression of PDGFRα, NOS2, or ID4 activated the PDGF-NO-ID4-signaling circuit and enhanced the self-renewal of GBM cell lines. These results suggested that the positive regulatory circuit associated with PDGF-NO-ID4 signaling plays a pivotal role in regulating the self-renewal and tumor-initiating capacity of GSCs and might provide a promising therapeutic target for GBM.

LIM domain only 2 induces glioma invasion via cytosolic p27(KIP1).

High-grade gliomas are considered the most malignant of brain tumors and have a poor prognosis. In a previous study, we showed that LIM domain only 2 (LMO2) regulates glioma stem cell properties and tumor angiogenesis and gave rise to highly invasive glioma xenografts. Glioma invasion in the surrounding parenchymal tissues is a major hurdle with respect to eliminating glioma by surgery. Invasive glioma cells are considered one of the main culprits for the recurrence of tumors after therapies. In the current study, we focused on determining the molecular mechanism(s) by which LMO2 regulates glioma cell migration and invasion. Forced expression of LMO2 in human U87MG glioma cells led to glioma invasion, as determined by in vivo xenograft assays and enhanced in vitro migration and invasion. LMO2 was associated with increased levels of cytosolic p27(Kip1) protein. LMO2 possibly induced the stabilization and augmented interactions between p27(Kip1) and RhoA. We knocked down the expression of p27(Kip1), which led to a decrease in LMO2-driven glioma cell migration and invasion. Taken together, our findings indicate that LMO2 promotes glioma cell migration and invasion by increasing the levels of cytosolic p27(Kip1).

Irradiation induces glioblastoma cell senescence and senescence-associated secretory phenotype.

Glioblastoma multiforme (GBM) is one of the most aggressive and fatal primary brain tumors in humans. The standard therapy for the treatment of GBM is surgical resection, followed by radiotherapy and/or chemotherapy. However, the frequency of tumor recurrence in GBM patients is very high, and the survival rate remains poor. Delineating the mechanisms of GBM recurrence is essential for therapeutic advances. Here, we demonstrate that irradiation rendered 17-20 % of GBM cells dead, but resulted in 60-80 % of GBM cells growth-arrested with increases in senescence markers, such as senescence-associated beta-galactosidase-positive cells, H3K9me3-positive cells, and p53-p21(CIP1)-positive cells. Moreover, irradiation induced expression of senescence-associated secretory phenotype (SASP) mRNAs and NFκB transcriptional activity in GBM cells. Strikingly, compared to injection of non-irradiated GBM cells into immune-deficient mice, the co-injection of irradiated and non-irradiated GBM cells resulted in faster growth of tumors with the histological features of human GBM. Taken together, our findings suggest that the increases in senescent cells and SASP in GBM cells after irradiation is likely one of main reasons for tumor recurrence in post-radiotherapy GBM patients.