Epithelial Membrane Protein 2 (EMP2) Is Upregulated in Vestibular Schwannomas as a Novel Surface Protein Biomarker and Is Associated with Increased Western Blot Protein Expression

Background: Vestibular schwannomas (VS) are benign neoplasms that derive from the myelin-forming Schwann cells of the vestibulocochlear nerve. Although histologically benign, their proximity to brainstem structures implies that both the tumor and treatment may be associated with significant morbidity. In both sporadic and neurofibromatosis type 2 (NF-2)-associated VS, the molecular hallmark is biallelic inactivation of the NF2 gene located on chromosome 22, which encodes for the tumor suppressor protein Merlin. Despite this understanding, the molecular pathogenesis and tumor microenvironment of the neoplasm remains largely unclear. One possible gene that may be implicated in this process is epithelial membrane protein-2 (EMP2). While EMP2 is not expressed in healthy brain tissue, it is upregulated in various intracranial neoplasms such as meningiomas and glioblastomas. However, its role in VS has not been investigated. Here, we evaluate the involvement of EMP2 in tumor features, clinical presentation, and its correlation with molecular markers of VS.

Methods: A retrospective review of adult sporadic VS patients who underwent resection at our institution between 2011 and 2019 was performed. VS tumor specimens were stained for EMP2 using immunohistochemistry (IHC) and were scored by a neuropathologist. Logistic and linear regressions were performed to determine the degree of association between the EMP2 IHC scoring and symptomatology, radiographic features, and prognosis. Furthermore, three datasets (GSE54934, GSE141801, GSE108524) from the NCBI Gene Expression Omnibus (GEO) repository were queried for publicly available mRNA expression data from VS and nonpathologic control nerve tissue. Linear regression was performed between EMP2 expression and markers of the VS microenvironment.

Results: A total of 15 patients met the inclusion criteria (9 males, 6 females). The average age of diagnosis was 53 years (range: 34–76 years). The mean tumor volume was 20.26 cm³. Two samples (13%) had weak staining, while 13 (87%) patients had strong staining. Protein expression was further validated via Western blots. Upon analysis of the GEO repository, EMP2 mRNA expression was higher in VS specimens compared with control nerve tissues, and this reached statistical significance in two-thirds datasets GSE108524 (n = 43, p < 0.01) and GSE141801 (n = 31, p < 0.01). Interferon gamma expression was significantly correlated with EMP2 expression in two datasets (GSE54934, p = 0.04; GSE141801 p < 0.01). Furthermore, EMP2 had a significant positive correlation with VEGF-A expression in two datasets (GSE141801, p = 0.01; GSE108524, p < 0.01). One dataset, GSE108524, showed a significant positive correlation between EMP2 expression and transcription of TGF-b (p < 0.001), CD68 (p < 0.01), and CD163 (p < 0.001).

Conclusion: We have identified EMP2 as a potential novel surface protein biomarker given its strong expression and upregulation in VS compared with nonpathologic nerve tissues, and its correlation with markers of the tumor microenvironment. Future studies are needed to evaluate EMP2 as a potential therapeutic target in both in vitro and in vivo models.

Publication History

Article published online:
01 February 2023