Yong Gu Chung

Direct Transcriptional Activation of Promyelocytic Leukemia Protein by IFN Regulatory Factor 3 Induces the p53-Dependent Growth Inhibition of Cancer Cells

IFN regulatory factor 3 (IRF3) is a transcriptional factor that plays a crucial role in activation of innate immunity and inflammation in response to viral infection, and is also involved in p53-dependent inhibition of cell growth. Although functional activation of IRF3 by viral infection is relatively well documented, the biological role and regulatory mechanism underlying cell growth inhibition by IRF3 are poorly understood. Here, we show a novel regulatory pathway connecting IRF3-promyelocytic leukemia protein (PML)-p53 in primary and cancer cell lines. Overexpression of IRF3 induces p53-dependent cell growth inhibition in cancer cell lines with normal p53 activity. In addition, doxycycline-induced expression of IRF3 in U87MG cells inhibits tumor growth in nude mice in vivo. IRF3 is found to increase expression of PML by a direct transcriptional activation as determined by PML-promoter-luciferase and chromatin immunoprecipitation assays. When PML is depleted by RNA interference-mediated knockdown, IRF3 fails to increase p53 acetylation and its transcriptional activity. Taken together, the results of the present study indicate that direct transcriptional activation of PML by IRF3 results in the p53-dependent growth inhibition of normal and cancer cells in vitro and in vivo, which is suggestive of a novel regulatory network between the innate immune response and tumor suppression.

Selective cell death of oncogenic Akt-transduced brain cancer cells by etoposide through reactive oxygen species–mediated damage

We have established several glioma-relevant oncogene-engineered cancer cells to reevaluate the oncogene-selective cytotoxicity of previously well-characterized anticancer drugs, such as etoposide, doxorubicin, staurosporine, and carmustine. Among several glioma-relevant oncogenes (activated epidermal growth factor receptor, Ras, and Akt, as well as Bcl-2 and p53DD used in the present study), the activated epidermal growth factor receptor, Ras, and Akt exerted oncogenic transformation of Ink4a/Arf−/− murine astrocyte cells. We identified that etoposide, a topoisomerase II inhibitor, caused selective killing of myristylated Akt (Akt-myr)–transduced Ink4a/Arf−/− astrocytes and U87MG cells in a dose- and time-dependent manner. Etoposide-selective cytotoxicity in the Akt-myr–transduced cells was shown to be caused by nonapoptotic cell death and occurred in a p53-independent manner. Etoposide caused severe reactive oxygen species (ROS) accumulation preferentially in the Akt-myr–transduced cells, and elevated ROS rendered these cells highly sensitive to cell death. The etoposide-selective cell death of Akt-myr–transduced cells was attenuated by pepstatin A, a lysosomal protease inhibitor. In the present study, we show that etoposide might possess a novel therapeutic activity for oncogenic Akt-transduced cancer cells to kill preferentially through ROS-mediated damage. [Mol Cancer Ther 2007;6(8):2178–87]

Influence of interleukin-6 on the development of peritumoral brain edema in meningiomas

OBJECTnPeritumoral brain edema (PTBE) is associated with perioperative neurological deficits in patients with meningiomas. However, the pathogenesis of meningioma-associated edema remains unclear. In the present study, the authors investigated the expression of interleukin-6 (IL-6) and its relationship with PTBE in resected meningiomas.nnnMETHODSnThirty-six benign meningiomas obtained in 36 patients were studied retrospectively. Edema volume was assessed on MR images, and an edema index (EI) was calculated. Interleukin-6 mRNA and protein expression were examined by real-time reverse transcriptase polymerase chain reaction and immunohistochemical staining.nnnRESULTSnPeritumoral brain edema was found in 16 patients (44%). Neither age, sex, histological subtype, nor tumor location were related to PTBE. The level of IL-6 mRNA was 7.72 times greater in the edema group (EI > 0.2) than in the nonedema group (EI < 0.2; p = 0.011). On immunohistochemical analysis, IL-6 protein was found localized in the cytoplasm of the tumor cells, and was detected in 12 (75%) of 16 cases of edematous meningiomas, but in only 6 (30%) of 20 nonedematous cases. There was a significant correlation between the severity of PTBE and IL-6 expression (p = 0.004).nnnCONCLUSIONSnThe authors results in this study indicate that IL-6 expression may contribute to the development of brain edema associated with meningiomas.

Phase III randomized trial of autologous cytokine-induced killer cell immunotherapy for newly diagnosed glioblastoma in korea.

Purpose Adoptive cell immunotherapy involves an ex vivo expansion of autologous cytokine-induced killer (CIK) cells before their reinfusion into the host. We evaluated the efficacy and safety of CIK cell immunotherapy with radiotherapy-temozolomide (TMZ) for the treatment of newly diagnosed glioblastomas. Experimental design In this multi-center, open-label, phase 3 study, we randomly assigned patients with newly diagnosed glioblastoma to receive CIK cell immunotherapy combined with standard TMZ chemoradiotherapy (CIK immunotherapy group) or standard TMZ chemoradiotherapy alone (control group). The efficacy endpoints were analyzed in the intention-to-treat set and in the per protocol set. Results Between December 2008 and October 2012, a total of 180 patients were randomly assigned to the CIK immunotherapy (n = 91) or control group (n = 89. In the intention-to-treat analysis set, median PFS was 8.1 months (95% confidence interval (CI), 5.8 to 8.5 months) in the CIK immunotherapy group, as compared to 5.4 months (95% CI, 3.3 to 7.9 months) in the control group (one-sided log-rank, p = 0.0401). Overall survival did not differ significantly between two groups. Grade 3 or higher adverse events, health-related quality of life and performance status between two groups did not show a significant difference. Conclusions The addition of CIK cells immunotherapy to standard chemoradiotherapy with TMZ improved PFS. However, the CIK immunotherapy group did not show evidence of a beneficial effect on overall survival.

Reactive oxygen species production has a critical role in hypoxia-induced Stat3 activation and angiogenesis in human glioblastoma

Glioblastoma is the most aggressive primary brain tumor with hypoxia-associated morphologic features including pseudopalisading necrosis and endothelial hyperplasia. It has been known that hypoxia can activate signal transducer and activator of transcription 3 (Stat3) and subsequently induce angiogenesis. However, the molecular mechanism underlying hypoxia-induced Stat3 activation has not been defined. In this study, we explored the possible implication of reactive oxygen species (ROS) in hypoxia-driven Stat3 activation in human glioblastoma. We found that hypoxic stress increased ROS production as well as Stat3 activation and that ROS inhibitors (diphenyleneiodonium, rotenone and myxothiazol) and an antioxidant (N-acetyl-l-cysteine) blocked Stat3 activation under hypoxic conditions. To determine a major route of ROS production, we tested whether nicotinamide adenine dinucleotide phosphate oxidase 4 (Nox4) is involved in hypoxia-induced ROS production. Nox4 expression was found to be increased at both mRNA and protein levels in hypoxic glioblastoma cells. In addition, siRNA-mediated knockdown of Nox4 expression abolished hypoxia induced Stat3 activation and vascular endothelial growth factor expression, which is associated with tumor cells’ ability to trigger tube formation of endothelial cells in vitro. Our findings indicate that elevated ROS production plays a crucial role for Stat3 activation and angiogenesis in hypoxic glioblastoma cells.

Supratentorial Arachnoid Cyst Located in the Brain Parenchyma: Case Report

BACKGROUND AND IMPORTANCE:Arachnoid cysts have not been reported to be located within the brain parenchyma. We present a case of an arachnoid cyst that was contained entirely within the right frontal lobe devoid of communication with the subarachnoid space and ventricle. CLINICAL PRESENTATION:A 65-year-old woman presented with a 1-year history of progressive headache and nausea. Computed tomographic and magnetic resonance imagining scans showed a well-defined, nonenhancing mass measuring 5 × 5 × 3.5 cm in the right frontal lobe. The mass appeared to be contained entirely within the brain parenchyma. The patient underwent a right frontal craniotomy, at which time the cystic mass was identified in the brain parenchyma without any communication with the arachnoid space. The cyst contained a clear fluid, and its wall was excised. The fluid contents demonstrated a composition similar to that of normal cerebrospinal fluid. Histological and immunohistochemical examinations of the cyst wall were compatible with the diagnosis of an arachnoid cyst. Postoperatively, the symptoms of the patient resolved, and no recurrence was observed up to 6 months after removal. CONCLUSION:The present case showed an intraparenchymal arachnoid cyst arising in the frontal lobe. Although the etiology is not known, an arachnoid cyst should be included in the differential diagnosis of primary intracerebral cysts.

Intrathecal transplantation of autologous adipose-derived mesenchymal stem cells for treating spinal cord injury: A human trial

Context: Spinal cord injury (SCI) can cause irreversible damage to neural tissues. However, there is currently no effective treatment for SCI. The therapeutic potential of adipose-derived mesenchymal stem cells (ADMSCs) has been emerged. Objective: We evaluated the effects and safety of the intrathecal transplantation of autologous ADMSCs in patients with SCI. Participants/Interventions: Fourteen patients with SCI were enrolled (12 for ASIA A, 1 for B, and 1 for D; duration of impairments 3–28 months). Six patients were injured at cervical, 1 at cervico-thoracic, 6 at thoracic, and 1 at lumbar level. Autologous ADMSCs were isolated from lipoaspirates of patients’ subcutaneous fat tissue and 9u2009×u2009107 ADMSCs per patient were administered intrathecally through lumbar tapping. MRI, hematological parameters, electrophysiology studies, and ASIA motor/sensory scores were assessed before and after transplantation. Results: ASIA motor scores were improved in 5 patients at 8 months follow-up (1–2 grades at some myotomes). Voluntary anal contraction improvement was seen in 2 patients. ASIA sensory score recovery was seen in 10, although degeneration was seen in 1. In somatosensory evoked potential test, one patient showed median nerve improvement. There was no interval change of MRI between baseline and 8 months post-transplantation. Four adverse events were observed in three patients: urinary tract infection, headache, nausea, and vomiting. Conclusions: Over the 8 months of follow-up, intrathecal transplantation of autologous ADMSCs for SCI was free of serious adverse events, and several patients showed mild improvements in neurological function. Patient selection, dosage, and delivery method of ADMSCs should be investigated further.

Expression of astrocyte elevated gene-1 (AEG-1) in human meningiomas and its roles in cell proliferation and survival

Astrocyte elevated gene-1 (AEG-1) has recently been proposed to be involved in tumor development, invasion, and metastasis in several human cancers. However, the functional importance of AEG-1 expression in human meningioma has not been determined. We investigate the level of AEG-1 expression by quantitative reverse transcription PCR, immunohistochemistry analysis, and western blotting in various human meningioma tissues and cells. To determine the suppressive effect of AEG-1 on meningioma progression, we inhibited AEG-1 expression using small interfering RNA and examined cell proliferation, apoptosis, colony formation and tumorigenicity in a mouse xenograft model. AEG-1 expression was frequently elevated at both mRNA and protein levels in meningioma tumor tissues and in meningioma-derived cells as well. This elevation was more commonly observed in high-grade tumors than in benign ones. The knockdown of AEG-1 led to a decrease in overall cell proliferation, as well as anchorage-independent growth of malignant meningioma. In addition, apoptotic cell death occurred in AEG-1 depleted meningioma cells through p-Akt and Bcl-2 suppression. Furthermore, a mouse xenograft meningioma model showed that inhibition of AEG-1 expression significantly decreased tumor growth. Altogether, these data show that the elevation of AEG-1 contributes to the malignant progression of meningiomas, suggesting that AEG-1 could be a novel therapeutic target against human meningiomas.

Multiple Intracranial Aneurysms with Intraventricular Hemorrhage in a Child with Unilateral Fibromuscular Dysplasia of the Renal Artery

A rare case involving multiple intracranial aneurysms with intraventricular hemorrhage (IVH) in a child, accompanied by unilateral fibromuscular dysplasia (FMD) of the renal artery, is reported. A 12-year-old girl presented with secondary hypertension and fourth-ventricle IVH. Cerebral angiography showed multiple aneurysms in the anterior communicating artery, right posterior cerebral artery, and right superior cerebellar artery. Abdominal angiography revealed marked stenosis and dilatation of the left renal artery. Coil embolization of the intracranial aneurysms was successfully performed. Then, a left nephrectomy and autotransplantation were performed. At the time of discharge, she was in an almost normal neurological condition. The association between renal artery FMD and aneurysmal rupture is extremely rare. This case is the first report of multiple intracranial aneurysms with IVH treated successfully with coils in a child concomitant with FMD of the renal artery.

Romo1 is associated with ROS production and cellular growth in human gliomas.

Romo1 is a mitochondrial protein whose elevated expression is commonly observed in various types of human cancers. However, the expression status of Romo1 and its implication in the pathogenesis of human glioblastoma (GBM) remain largely undefined. To understand the role of Romo1 in the progression of GBM, we explored its expression in a series of GBM tissues and cell lines and determined its effect on ROS production, cell proliferation, and tumor growth. Romo1 was frequently overexpressed at the mRNA level in both primary tumors and cell lines and its elevation was more commonly observed in high grade tumors versus low grade tumors. Romo1 expression was associated with ROS production and its knockdown led to a marked reduction of in vitro cellular growth and anchorage-independent growth of GBM. Consistently, Romo1 depletion induced a G2/M arrest of the cell cycle that was accompanied with accumulation of phospho-cdc2. Furthermore, a mouse xenograft assay revealed that Romo1 depletion significantly decreased tumor formation and growth. Therefore, our data demonstrate that Romo1 upregulation is a common event in human GBMs and contributes to the malignant tumor progression, suggesting that Romo1 could be a new therapeutic target for human GBM.