Expression of merlin, NDRG2, ERBB2, and c-MYC in meningiomas: relationship with tumor grade and recurrence

Meningiomas are common, usually benign tumors of the central nervous system that have a high rate of post-surgical recurrence or regrowth. We determined expression of the proteins merlin, NDRG2, ERBB2, and c-MYC in meningiomas using immunohistochemistry and assessed relationships between protein expression and gender, age, tumor grade, and recurrence or regrowth. The study sample comprised 60 patients, (44 women and 16 men) with a mean age of 53.2±12.7 years. Tumors were classified as grade I (n=48) or grades II and III (n=12). Expression of merlin, NDRG2, ERBB2, and c-MYC was not significantly different statistically with relation to gender, age, or meningioma recurrence or regrowth. Merlin was expressed in 100% of the cases. No statistically significant difference between tumor grade and recurrence or regrowth was identified. Statistically significant differences were identified between the mean age of patients with grade I (54.83±11.60) and grades II and III (46.58±15.08) meningiomas (P=0.043), between strong c-MYC expression and grades II and III (P<0.001), and between partial surgical resection and tumor recurrence or regrowth (P<0.001). These findings reveal the lower mean age among grades II and III meningioma patients than grade I patients, the influence of the protein merlin on tumorigenesis, the association of c-MYC with aggressive meningiomas, and that partial surgical resection is associated with tumor recurrence or regrowth.

The Similarities and Differences between Intracranial and Spinal Ependymomas : A Review from a Genetic Research Perspective

Ependymomas occur in both the brain and spine. The prognosis of these tumors sometimes differs for different locations. The genetic landscape of ependymoma is very heterogeneous despite the similarity of histopathologic findings. In this review, we describe the genetic differences between spinal ependymomas and their intracranial counterparts to better understand their prognosis. From the literature review, many studies have reported that spinal cord ependymoma might be associated with NF2 mutation, NEFL overexpression, Merlin loss, and 9q gain. In myxopapillary ependymoma, NEFL and HOXB13 overexpression were reported to be associated. Prior studies have identified HIC-1 methylation, 4.1B deletion, and 4.1R loss as common features in intracranial ependymoma. Supratentorial ependymoma is usually characterized by NOTCH-1 mutation and p75 expression. TNC mutation, no hypermethylation of RASSF1A, and GFAP/NeuN expression may be diagnostic clues of posterior fossa ependymoma. Although MEN1, TP53, and PTEN mutations are rarely reported in ependymoma, they may be related to a poor prognosis, such as recurrence or metastasis. Spinal ependymoma has been found to be quite different from intracranial ependymoma in genetic studies, and the favorable prognosis in spinal ependymoma may be the result of the genetic differences. A more detailed understanding of these various genetic aberrations may enable the identification of more specific prognostic markers as well as the development of customized targeted therapies.

Expression of Ezrin in Vagina Cells of Postmenopausal Rats after Dietary Administration of Omega-3 Fatty Acid Formula

OBJECTIVES: To see the effect of dietary administration of omega 3-fatty acid formula on the vaginal cells of postmenopausal rats. METHODS: Three-week-old female Wistar/ST rats were raised after one week of adjustment period. The rats were then divided into three groups, for three different kinds of diet; general diet, 1% omega-3 fatty acid diet, and 2% omega-3 fatty acid diet. After eight weeks of having assigned diet, after the oophorectomy, with the same diet previously they had Immunohistochemistry, Immunofluorescence, and Western Blot about ezrin, merlin were done. RESULTS: In immunohistochemistry, estrogen injection group revealed thicker and well differentiated features. In Immunofluorescence, Omega-3 fatty acid composition in diet did not effect expression of ezrin and merlin in rat vagina in estrogen injection group, their vaginal epithelium showed full layers (from basal to apical layer). In Western Blot analysis, Omega-3 fatty acid composition in diet did not affect expression of ezrin and merlin in rat vagina estrogen presented significant impact on expression of ezrin and merlin. CONCLUSION: Although omega-3 fatty acid composition changed in diet, vaginal epithelial morphology unchanged. Estrogen did effect on vagina cell, but omega-3 fatty acid did not effect on ezrin and merlin in vagina.

Merlina y nuevos tratamientos de schwannomas vestibulares en pacientes con neurofibromatosis tipo 2 / Merlin and new treatments for vestibular schwannomas in patients with Neurofibromatosis type 2

Los schwannomas vestibulares son tumores benignos que habitualmente se presentan en forma esporádica y unilateral, pero pueden aparecer de manera bilateral en el contexto de una neurofibromatosis tipo 2 (NF2). En aquellos asociados a NF2 se han identificado mutaciones del gen NF2 que codifica para merlina, una proteína citoplasmática que se localiza primariamente en protrusiones celulares ricas en actina, y en sitios de contacto entre células y matriz extracelular. La evidencia sugiere que merlina ejerce un rol como proteína supresora de tumores ya que regula la cascada de activación de diversos tipos de receptores de factores de crecimiento celular De esta manera, el déficit de merlina provoca un patrón de proliferación celular aumentado, alteraciones del citoesqueleto, apoptosis disminuida, y un incremento de la adhesión a la matriz extracelular. Se han desarrollado terapias clínicas para la NF2 con anticuerpos monoclonales e inhibidores dirigidos contra distintas moléculas involucradas en las cascadas de señalización celular moduladas por merlina. En este artículo se revisan y discuten los mecanismos celulares dependientes de merlina y los diversos estudios clínicos y experimentales que se han probado en pacientes con NF2.

Vestibular schwannomas are benign tumors that may occur bilaterally in the context of neurofibromatosis type 2 (NF2). A mutation in the NF2 gene coding for merlin protein has been identified in those cases associated with NF2. Merlin is a cytoplasmic protein localized in actin rich cell protrusions, and near contact sites between cells and extracellular matrix. The evidence suggests that merlin plays a role as tumor suppressor protein, regulating the activation cascade of different types of receptors for cell growth factors. Thus, merlin deficiency causes a pattern of increased cell proliferation, cytoskeletal alterations, decreased apoptosis and increased cell adhesion to the extracellular matrix. Several clinical therapies have been developed for NF2 patients including monoclonal antibodies and inhibitors directed against different molecules involved in cell signaling cascades modulated by merlin. In this article we review and discuss cellular mechanisms dependent of merlin and some clinical and experimental studies that have been studied in patients with NF2.

Expression of Merlin protein in non-small cell lung carcinoma and the clinical significance / 中南大学学报(医学版)

OBJECTIVE@#To determine the expression and clinical significance of Merlin protein in non-small cell lung cancer (NSCLC).@*METHODS@#The expression of Merlin protein in 45 cases of NSCLC and adjacent tissue of NSCLC and normal lung tissue was checked by immunohistochemistry. The relation between the expression of Merlin protein and the multiple factors of pathological type, gender, P-TNM stage, differentiation and lymph node metastasis was analyzed.@*RESULTS@#The expression rates of Merlin protein in NSCLC and normal lung tissue sections were 73.33% and 15.56%, respectively (P0.05).@*CONCLUSION@#Merlin protein might contribute to the initiation of metastasis of NSCLC.

Merlin; NF2 Tumor Suppressor and Regulator of Receptor Distribution/Signaling / 대한이비인후과학회지

Acoustic tumor is the most common tumor originating from cerebellopontine angle. Acoustic tumor is benign and main origin of this tumor is vestibular nerve. This tumor arises in Schwann cell (SC) and is encapsulated. Recently, the tumor is called vestibular schwannoma (VS). VS is classified to two type by epidemiology, sporadic form and neurofibromatosis type 2 (NF2). NF2 is autosomal dominant inherent disorder. This tumor is characterized bilateral VS, brain tumors such as meningioma and ependymoma, and spinal or cranial nerve schwannoma. Genetic studies suggested that NF2 is caused by abnormality or mutation of NF2 gene in chromosome 22q12. Both of them are known to develop the tumor by mutation of NF2 gene. Merlin is the cytoskeletal protein product of the NF2 tumor suppressor gene that mediates cell to cell contact information to regulate SC proliferation and survival. And merlin is highly homologous to ERM proteins. Merlin function is regulated by its conformation, adopting an inactive, growth permissive state following serine 518 (S518) phosphorylation. In NF2 patients, the precise mechanisms of developing the VS are unclear. But, the abnormalities of merlin are confirmed by many studies. And now, a lot of research about merlin function is progressing. In this study, the author would introduce about merlin (structure, function, molecular pathway, tumorigenesis and regulation) which leads to VS and molecular studies about merlin, and suggest the future direction of research.

Mutation analysis of NF2 gene and clinical investigation in a Chinese family with neurofibromatosis type II / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To report a heterozygous RNA-splicing mutation (IVS3+ 3A to C) of NF2 gene in a Chinese family with autosomal dominant neurofibromatosis type II and investigate the relationship between the genotype and phenotype.</p><p><b>METHODS</b>The proband with bilateral vestibular schwannomas underwent gamma knife radiosurgery two years earlier. DNA of blood samples from all affected individuals, suspected individuals and unaffected relatives of the family was extracted and amplified to detect the polymorphisms at loci D22S1150 and D22S268 that are linked with the NF2 gene. Two-point LOD score was calculated. The promoter region, 17 exons and exon/intron boundaries of NF2 gene were amplified and sequenced for the proband. The exon 3/intron 3 boundaries of NF2 gene was amplified and sequenced for the other 3 patients, 1 suspected individual, 9 unaffected members of the family and 150 unrelated controls.</p><p><b>RESULTS</b>The result of two-point linkage analysis suggested that NF2 gene was a candidate gene (Zmax= 2.109, θ = 0.00, locus D22S1150). DNA sequencing revealed a heterozygous splicing mutation in intron 3 (IVS3+ 3A to C) for the proband. Identical mutation was also observed in the other 3 patients and 1 suspected individual. No mutation was found in the 9 normal family members and 150 unrelated controls, which was consistent with the clinical diagnosis.</p><p><b>CONCLUSION</b>This is the first report of familial neurofibromatosis type II with a splicing mutation of IVS3+ 3A to C of the NF2 gene. The mutation might be responsible for the neurofibromatosis type II in the family.</p>

Expression of S518 phosphorylated Merlin and its interaction with CD44 in vestibular schwannoma / 中华耳鼻咽喉头颈外科杂志

<p><b>OBJECTIVE</b>To investigate the impact of S518 phosphorylation in Merlin on the interaction with CD44 in vestibular schwannoma and the tumor growth.</p><p><b>METHODS</b>Thirty-five samples of vestibular schwannoma were identified by pathology. Immunohistopathology and western blot were employed to analyze the expression and localization of S518 phosphorylated Merlin in the tumor tissues. Nerve tissues that were collected during other surgical operation were used as control. The expression level of S518 phosphorylated Merlin was compared with clinical stages, tumor size, clinical course and cystic degeneration. Immunoprecipitation was used to evaluate the impact of S518 phosphorylation in Merlin on the interaction with CD44.</p><p><b>RESULTS</b>In vestibular schwannoma, Merlin was phosphorylated at S518 and demonstrated perinuclear localization. The S518 phosphorylation level was much lower in the normal control nerve tissues than that in vestibular schwannoma tissues. There was no correlation between the phosphorylation level on Merlin and clinical stages, tumor size, clinical course and cystic degeneration. The S518 phosphorylated Merlin bound CD44 was higher than wild-type Merlin bound CD44 in vestibular schwannoma tissues.</p><p><b>CONCLUSIONS</b>The affinity of Merlin to CD44 was increased after phosphorylation at S518. Different cellular biological results might be triggered through binding to wild type Merlin and S518 phosphorylated Merlin.</p>

Expression and localization of merlin in vestibular schwannoma / 中华耳鼻咽喉头颈外科杂志

<p><b>OBJECTIVE</b>To clarify the expression and subcellular localization of merlin in vestibular schwannoma.</p><p><b>METHODS</b>Fifty four paraffin embedded vestibular schwannoma samples confirmed by pathology after resection were included in the study. The expression of merlin in vestibular schwannoma was analyzed by immunohistochemistry. Nerve tissues that were resected during surgical treatment for trigeminal neuralgia and Meniere's disease were used as control. Western blotting was used to analyze the electrophoresis migration of merlin in the acoustic neuroma. Image analysis was used to calculate the positive expression percentage of merlin in each individual. The expression percentage of merlin in the tumor tissue was compared with age and gender of the patients, clinical course of the tumor, tumor growth index, tumor diameter and clinical stage.</p><p><b>RESULTS</b>Merlin was expressed in 0 to 87.5% of the cells in vestibular schwannoma tissue with a mean of (46.66 +/- 5.75)%. There was a negative correlation between merlin expression percentage and tumor growth index. There were no correlations between merlin expression percentage and the age, gender, tumor diameter and clinical stage. There exists a difference for the location of merlin, mainly in the nucleus and perinucleus. There was also a cytoplasmic location. Merlin in the tumor tissue was shown by western blot to be in 65000 and 125000 positions.</p><p><b>CONCLUSIONS</b>Merlin was expressed in vestibular schwannoma tissue, with a different intra-cellular location. Merlin might also exist as a complex with other proteins in the tumor tissue.</p>

Merlin Represses Ras-Induced Cyclin D1 Transcription through the Cyclic AMP-Responsive Element

Mutations in the NF2 tumor suppressor gene cause neurofibromatosis type 2, an autosomal dominant inherited syndrome predisposed to the multiple tumors of the nervous system. Merlin, the NF2 gene product was reported to block Ras-mediated cell transformation and represses Ras-induced expression of cyclin D1. However, the potential mechanism underlying the anti-Ras function of merlin on the cyclin D1 is still unclear. In this study, we investigated whether merlin decreases Ha-ras-induced accumulation of cyclin D1 at the transcriptional level, and demonstrated that merlin suppressed Ras-induced cyclin D1 promoter activity mediated by the cyclic AMP-responsive element (CRE) in SK-N-BE (2) C neuroblastoma cells. Furthermore, we found that merlin attenuated active Ras and forskolin-induced CRE-driven promoter activity. These results suggest that the transcriptional repression of the cyclin D1 expression by merlin may contribute to the inhibition of Ras-induced cell proliferation