CPI-17 Overexpression and Its Correlation With the NF2 Mutation Spectrum in Sporadic Vestibular Schwannomas.

Abstract

HYPOTHESIS:

We hypothesized that CPI-17 expression and NF2 mutations are correlated with merlin phosphorylation in the etiology of sporadic vestibular schwannoma (VS).

BACKGROUND:

NF2 gene mutations have been identified in the majority of sporadic and NF2-associated schwannomas and NF2 gene mutations have been shown to result in merlin protein phosphorylation. CPI-17 can drive Ras activity and promote tumorigenic transformation by inhibiting the tumor suppressor merlin. The aim of this study was to determine the correlation between CPI-17 overexpression and the NF2 mutation spectrum in sporadic VS.

METHODS:

In this study, we measured CPI-17 expression and identified NF2 gene alterations in a series of sporadic VS samples. Freshly frozen tumor and matched peripheral blood leukocytes from 44 individuals with sporadic VS were analyzed using next-generation sequencing and Sanger sequencing. Western blotting was used to determine the level of merlin phosphorylation, and immunohistochemistry and Western blotting were used to measure CPI-17 expression in the sporadic VS samples. CCK-8 and wound-healing assays were used to determine the influence of CPI-17 overexpression on cell proliferation.

RESULTS:

NF2 mutations were identified in 79.5% of sporadic vestibular schwannomas, with all mutations being exclusively somatic. IHC and WB showed the expression of CPI-17 is upregulated in the sporadic VS. NF2 mutation and CPI-17 are positively correlated with merlin phosphorylation. CPI-17 overexpression induces the proliferation of HEI193 cells.

CONCLUSION:

NF2 mutations and CPI-17 expression together induce merlin phosphorylation, which is correlated with the tumorigenesis of sporadic VSs.

• Authors: Jianhui Xu, Yang Zhang, Yuxuan Shi, Dongming Yin, Peidong Dai, Weidong Zhao, Tianyu Zhang
• Journal: Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology (Otol Neurotol) Vol. 41 Issue 1 Pg. e94-e102 (01 2020) ISSN: 1537-4505 [Electronic] United States
• PMID: 31789805 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Intracellular Signaling Peptides and Proteins
• Muscle Proteins
• NF2 protein, human
• Neurofibromin 2
• PPP1R14A protein, human

Topics

• Carcinogenesis (genetics, metabolism, pathology)
• Gene Expression Regulation, Neoplastic (physiology)
• Genes, Neurofibromatosis 2
• Humans
• Intracellular Signaling Peptides and Proteins (metabolism)
• Male
• Muscle Proteins (metabolism)
• Mutation
• Neurofibromin 2 (genetics)
• Neuroma, Acoustic (genetics, metabolism, pathology)
• Phosphorylation