The role of NF2 gene mutations and pathogenesis-related proteins in sporadic vestibular schwannomas in young individuals

Chen, Hongsai; Zhang, Xiaoman; Zhang, Zhihua; Yang, Tao; Wang, Zhaoyan; Wu, Hao

doi:10.1007/s11010-014-2011-9

Cited by 15 publications

(8 citation statements)

References 27 publications

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“…2D ) . As previously reported 7–9, 15, 19, 21 , most mutations identified were truncating mutations (nonsense, frameshift, and splicing-site mutations) throughout the first 15 exons of the gene. As shown in Table 2, most mutations occurred at the FERM domain of the NF2 protein (exon 1 to 8), but no particular mutational hot spots were found.…”

Section: Resultssupporting

confidence: 68%

“…The “two-hits” inactivation of the NF2 gene that results in total merlin loss has also been demonstrated in sporadic VSs with detection rates ranging from 27% to 61% 7–11 , which is much less than expected. Additionally, conflicting results from merlin expression analyses have been reported in studies on sporadic VSs 11–15 . They are classified by varying protein levels into none (or faint), medium or strong.…”

Section: Introductionmentioning

confidence: 99%

“…However, the biological background of these phenotypical heterogeneities is largely unknown. Some studies have reported that fast-growing tumours tend to occur in younger individuals 15, 18 , suggesting there may be a correlation between age at diagnosis and tumour growth rate in sporadic VSs. To understand the genetic events responsible for the clinical behaviours of sporadic VSs, we divide the tumours into three age groups at equally spaced intervals, including 38 young cases (<30 years old), 191 middle-age cases (31–60 years old) and 53 elderly cases (>60 years old), and perform comparisons of the clinical and genetic characteristics between age groups.…”

Section: Introductionmentioning

confidence: 99%

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Differential NF2 Gene Status in Sporadic Vestibular Schwannomas and its Prognostic Impact on Tumour Growth Patterns

Chen

Xue

Wang

et al. 2017

Sci Rep

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The great majority of sporadic vestibular schwannomas (VSs) are due to the inactivation of the NF2 gene. In this study, we found age-dependent differences in the clinical parameters of sporadic VSs. Young patients were characterized by progressive tumour behaviours, including earlier onset of initial symptoms, shorter symptom duration and larger tumour size. An increased rate of “two-hits” of both NF2 alleles, usually by mutation and allelic loss, was observed in young cases compared to older, and this correlated with the loss of protein and mRNA expression. In contrast, the tumours with a single mutation (referred to as ‘one-hit’) exhibited obvious expression levels. Moreover, a mixture of merlin-expressing tumour cells and non-expressing tumour cells was observed in ‘one-hit’ schwannomas, suggesting that a subset of ‘one-hit’ tumour cells was present in these tumours. To mimic the growth promoting effects by the second hit, we performed lentivirus-mediated NF2 knockdown in the ‘one-hit’ schwannoma cultures. Following the loss of NF2 expression, schwannoma cultures demonstrated increased proliferation rates. Above all, we have identified a correlation between the NF2 status and the growth patterns of sporadic VSs. The treatment decision-making, microsurgery or “wait and scan” strategy, should be carried out according to the tumour’s genetic background.

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Section: Resultssupporting

confidence: 68%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Differential NF2 Gene Status in Sporadic Vestibular Schwannomas and its Prognostic Impact on Tumour Growth Patterns

Chen

Xue

Wang

et al. 2017

Sci Rep

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“…Current treatment modalities include microsurgical removal and stereotactic radiosurgery, but complications from such interventions are not uncommon (Arthurs et al, 2011). Recently, several genes and pathways associated with VS, including NF2 (Chen et al, 2014), vascular endothelial growth factor A (VEGFA; Koutsimpelas et al, 2012;Dilwali et al, 2015), and PI3K/AKT (Jacob et al, 2008), have been identified. However, the molecular events involved in the development of this condition are not well understood.…”

Section: Introductionmentioning

confidence: 99%

miR-1 association with cell proliferation inhibition and apoptosis in vestibular schwannoma by targeting VEGFA

et al. 2016

Genet. Mol. Res.

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A growing body of research has demonstrated the tumor suppressive function of microRNA (miR)-1 in many cancers. Our study aimed to investigate its role in vestibular schwannoma (VS). We examined miR-1 expression in 95 VS specimens and 79 normal vestibular nerves using quantitative real-time polymerase chain reaction. Moreover, miR-1 mimics, miR-1 inhibitors, and negative control oligonucleotides were transfected into HEI-193 human VS cells to investigate the functional significance of miR-1 expression in this condition at a cellular level. Finally, the role of vascular endothelial growth factor A (VEGFA) in miR-1-mediated HEI-193 cell growth was confirmed. miR-1 levels were significantly reduced in VS specimens compared with normal vestibular nerve tissues (P < 0.001). In addition, low levels of miR-1 were associated with larger tumor volumes. In functional assays, miR-1 suppressed HEI-193 cell proliferation and colony formation, and enhanced apoptosis. VEGFA was verified as a target gene of miR-1, and VEGFA overexpression partially negated the effects of miR-1 on HEI-193 cells. These findings suggest that miR-1 suppresses VS growth by targeting VEGFA, and should be considered as a potential therapeutic target for treatment of this condition.

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“…Mutations in NF2 have been identified not only in neurofibromatosis type 2-associated schwannoma, but also in sporadic unilateral VS (6,7). NF2 is located on chromosome 22q12, and although various mutation types, including nonsense, frameshift, missense, insertion, deletion and splice site mutations, have been detected, no mutational hot spots have been previously identified (3).…”

Section: Introductionmentioning

confidence: 99%

A novel alternative splicing isoform of NF2 identified in human Schwann cells

Zhou

et al. 2016

Oncology Letters

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Abstract. Vestibular schwannoma (VS) is a benign, slow-growing cranial tumor that originates from the hypertrophy of Schwann cells. The majority of sporadic VS are unilateral, and the mechanisms underlying VS tumorigenesis are not fully understood. The human neurofibromin 2 (NF2) gene encodes the tumor suppressor protein merlin and the NF2 transcript can be alternatively spliced to form numerous isoforms. The present study investigated human Schwann cells (HSCs) at the mRNA and protein level to understand the function of the alternative splicing (AS) isoform of NF2. The total RNA of HSCs was isolated and the full-length coding sequence of NF2 was amplified. The amplified products were excised from agarose gels, purified and sequenced. NF2 at a protein level was assayed by immunoprecipitation and western blot analysis. The full-length and spliced NF2 forms were amplified by polymerase chain reaction (PCR) from the HSC complementary DNA and ligated into eukaryotic expression vector pcDNA3.1(+). The plasmids were transfected into the HSC HEI-193 cell line and cell proliferation assays were performed using Cell Counting Kit-8. PCR analysis using HSC total RNA as a template revealed the presence of a shortened NF2 transcript, which was due to splicing at the 3'-end of the NF2 mRNA. Sequence analysis confirmed that this AS isoform omitted exons 11, 12, 13, 14, 15 and 16. Immunoprecipitation and western blot analysis demonstrated that the AS isoform was highly expressed in the HSCs at 38 kDa, while the wild-type (WT) isoform, which was expected at 66 kDa, was undetectable. Transfection and cell proliferation assays revealed that the WT isoform exhibited significant growth inhibition, while the AS isoform did not suppress cell growth. In conclusion, the present study detected AS NF2 isoforms in HSC for the first time, and investigated the function of the principle AS isoform. The present study suggests that although HSCs have an undetectable level of WT isoform of the NF2 protein merlin, they are not merlin-null, since they express the AS isoform. Although the AS merlin isoform has no suppressive effect on cell growth, certain mechanisms may exist that underlie this phenomenon, and this may be associated with the genesis and development of VS.

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The role of NF2 gene mutations and pathogenesis-related proteins in sporadic vestibular schwannomas in young individuals

Cited by 15 publications

References 27 publications

Differential NF2 Gene Status in Sporadic Vestibular Schwannomas and its Prognostic Impact on Tumour Growth Patterns

Differential NF2 Gene Status in Sporadic Vestibular Schwannomas and its Prognostic Impact on Tumour Growth Patterns

miR-1 association with cell proliferation inhibition and apoptosis in vestibular schwannoma by targeting VEGFA

A novel alternative splicing isoform of NF2 identified in human Schwann cells

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