Gene Transfer of Pro-opiomelanocortin Prohormone Suppressed the Growth and Metastasis of Melanoma: Involvement of ␣-Melanocyte-Stimulating Hormone-Mediated Inhibition of the Nuclear Factor B/Cyclooxygenase-2 Pathway

ABSTRACT Pro-opiomelanocortin (POMC) is a prohormone of various neuropeptides, including corticotropin, ␣-melanocyte-stimulating hormone (␣-MSH), and ␤-endorphin (␤-EP) . POMC neuropeptides are potent inflammation inhibitors and immunosuppressants and may exert opposite influences during tumorigenesis. However, the role of POMC expression in carcinogenesis remains elusive. We evaluated the antineoplastic potential of POMC gene delivery in a syngenic B16-F10 melanoma model. Adenovirus-mediated POMC gene delivery in B16-F10 cells increased the release of POMC neuropeptides in cultured media, which differentially regulated the secretion of pro-and anti-inflammatory cytokines in lymphocytes. POMC gene transfer significantly reduced the anchorage-independent growth of melanoma cells. Moreover, pre-or post-treatment with POMC gene delivery effectively retarded the melanoma growth in mice. Intravenous injection of POMC-transduced B16-F10 cells resulted in reduced foci formation in lung by 60 to 70% of control. The reduced metastasis of POMC-transduced B16-F10 cells could be attributed to their attenuated migratory and adhesive capabilities. POMC gene delivery reduced the cyclooxygenase-2 (COX-2) expression and prostaglandin (PG) E 2 synthesis in melanoma cells and tumor tissues. In addition, application of NS-398, a selective COX-2 inhibitor, mimicked the antineoplastic functions of POMC gene transfer in melanoma. The POMC-mediated COX-2 down-regulation was correlated with its inhibition of nuclear factor B (NFB) activities. Exogenous supply of ␣-MSH inhibited NFB activities, whereas application of the ␣-MSH antagonist growth hormone-releasing peptide-6 (GHRP-6) abolished the POMC-induced inhibition of NFB activities and melanoma growth in mice. In summary, POMC gene delivery suppresses melanoma via ␣-MSH-induced inhibition of NFB/COX-2 pathway, thereby constituting a novel therapy for melanoma. POMC is a multifunctional polycistronic gene located on human chromosome 2p23.3. POMC is a 31 kDa prohormone that is processed into various neuropeptides, including corticotropin, melanotropins (␣-, ␤-, and ␥-MSH), lipotropins, and ␤-endorphin (␤-EP

Expression of Thyroid Hormone Receptors in Intracranial Meningiomas

Thyroid hormone has a unique function in human organs. Many of its effects occur at the level of gene expression and are mediated by thyroid hormone receptors (TRs). We investigated the relationship between TRs and the prognosis of meningiomas. We investigated TR expression in human intracranial meningiomas using reverse transcription-polymerase chain reaction. Specimens of 25 tumors were obtained by craniotomy from various intracranial meningiomas. We found that the expression of TRs was receptor subtype- and cell type-dependent. Human TRα1 (hTRα1) was expressed in nine cases, hTRα2 was expressed in 14 cases, and both hTR-alpha-1 and hTR-alpha-2 were expressed in five cases; hTRβ1 was expressed in nine cases of recurrent or malignant tumors. The expression of hTRβ1 may be an indicator of recurrent or malignant meningiomas

Sphenoid Ridge Lymphoplasmacyte-rich Meningioma

There are numerous histologic variants of meningioma. Among the more uncommon are intracranial masses composed of meningiomatous and plasma cell-lymphocytic elements. We report a 22-year-old woman with lymphoplasmacyte-rich meningioma who initially presented with dizziness and progressive headache. Neuroradiologic images revealed typical meningiomas of the sphenoid ridge with extensive perifocal edema. Complete macroscopic removal of the tumor was performed. Histologic examination revealed a meningioma with massive infiltrates of plasma cells and lymphocytes. Brain computed tomography on the 6th postoperative day revealed total removal of the tumor with marked reduction of brain edema. Complete resolution of symptoms occurred with no evidence of tumor recurrence during 2 years of follow-up

Differentiation Among Metastatic Brain Tumors, Radiation Necroses, and Brain Abscesses Using Proton Magnetic Resonance Spectroscopy

Magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (MRS) were evaluated for differentiating metastatic brain tumors, radiation necroses, and brain abscesses. Twelve histologically verified lesions in 12 patients were studied using preoperative MRI and proton MRS. The signal intensities of four major metabolites, N-acetyl aspartate (NAA), choline-containing compounds (Cho), creatine and phosphocreatine (Cr), and lactate (Lac), were observed over the region of interest. Metastatic brain tumors showed a decrease in NAA/Cr and an increase in Cho/Cr ratios. Radiation necroses showed a decrease in NAA/Cr and no change in Cho/Cr ratios. Brain abscesses showed an increase in Lac/Cr ratio. Correlation with histopathologic findings showed that a high Cho signal was suggestive of a metastatic brain tumor. Lac signals were observed in brain abscesses, presumably reflecting the anerobic glycolysis of living cells. Although more cases and studies are necessary, metabolic information provided by proton MRS combined with MRI is useful for differentiating among metastatic brain tumors, radiation necroses, and brain abscesses

Serum Concentration of Soluble Decoy Receptor 3 in Glioma Patients Before and After Surgery

The suppression of immune responses in malignant gliomas is thought to be involved in glioma pathogenesis. The newly identified tumor-secreted soluble decoy receptor 3 (DcR3) can bind to the ligands CD95L and LIGHT, thereby neutralizing their pro-apoptotic actions. Little is known of the production of DcR3 by glioma cells. This study investigated the serum concentration of DcR3 in glioma patients before and after tumor removal. Blood samples were taken from 17 glioma patients and 10 control patients. The serum DcR3 concentration was measured using a DcR3 enzyme-linked immunosorbent assay. There was no statistically significant difference between preoperative (0.069 % 0.027 ng/mL) and postoperative DcR3 concentrations (0.068 % 0.022 ng/mL; p = 0.951). Similarly, there was no difference in preoperative DcR3 concentration between glioma patients (0.069 % 0.027 ng/mL) and controls (0.063 % 0.023 ng/mL; p = 0.106). Our study demonstrated no alteration in DcR3 concentration in glioma patients before and after tumor removal

A novel ninein-interaction protein, CGI-99, blocks ninein phosphorylation by GSK3β and is highly expressed in brain tumors

AbstractTo explore more hNinein interacting proteins, the yeast two-hybrid screening using ninein C-terminal domain as bait protein was performed. One novel gene, CGI-99, was demonstrated to associate with hNinein in the yeast two-hybrid method and in vitro GST pull-down assay. Molecular characterization also showed that CGI-99 possessed a transcriptional activity at the N-terminal. In addition, CGI-99 formed a dimer with the C-terminal, which overlapped with hNinein binding site. In kinase assay, CGI-99 binds to hNinein and completely blocks the phosphorylation of hNinein by GSK3β. Moreover, CGI-99 was highly expressed in all brain tumors which is in agreement with the Northern blot analysis. Taken together, we have isolated a novel protein CGI-99, which may be involved in the functional regulation of human ninein in the centrosome structure and may also be important in brain development and tumorigenesis

Effect of Aspirin and Indomethacin on Prostaglandin E2 Synthesis in C6 Glioma Cells

Prostaglandin E2 (PGE2) plays an important role in immunosuppression and tumor growth. PGE2 inhibitors such as aspirin and indomethacin suppress experimental tumor growth. Little is known of the relationship between PGE2 synthesis in brain tumors and the dose of aspirin or indomethacin. The present study was undertaken to evaluate the effect of different doses of aspirin and indomethacin on PGE2 synthesis in C6 glioma cells. C6 glioma cells were incubated with different concentrations (2, 4, and 8 μM) of aspirin and indomethacin for 1, 2, 4, 6, 8, 12, and 24 hours. Intracellular PGE2 concentration was measured by enzyme immunoassay. Each concentration of aspirin and indomethacin effectively inhibited PGE2 synthesis. Concentrations of 2, 4, and 8 μM of aspirin significantly inhibited PGE2 production at 6, 4, and 1 hours, respectively, and the inhibition persisted for more than 24 hours (p 0.05). Indomethacin 8 μM was effective at 1 hour and the inhibition persisted beyond 24 hours (p < 0.05). Our study demonstrates that aspirin and indomethacin inhibit PGE2 synthesis in C6 glioma cells and that low-dose aspirin is as effective as high-dose aspirin. This study may encourage future clinical use of low-dose aspirin in the prevention or treatment of brain tumors