Loss of SPINT2 expression frequently occurs in glioma, leading to increased growth and invasion via MMP2

• Type: Article in International Scientific Journal
• Date: 2020

Authors

Pereira, MS (Author) Other; Celeiro, SP (Author) Other; Costa, AM (Author) Other; Pinto, F (Author) Other; Popov, S (Author) Other; de Almeida, GC (Author) Other; Amorim, J (Author) Other; Pires, MM (Author) Other; Pinheiro, C (Author) Other; Lopes, JM (Author) FMUP; Honavar, M (Author) Other; Costa, P (Author) Other; Pimentel, J (Author) Other; Jones, C (Author) Other; Reis, RM (Author) Other; Viana Pereira, M (Author) Other

Journal

Title: Cellular Oncology

Vol. 43

Pages: 107-121

ISSN: 2211-3428

Publisher: Springer Nature

Indexing

ISI Web of Knowledge - 5 Citations

Scopus - 5 Citations

Other information

Authenticus ID: P-00R-8K3

DOI: 10.1007/s13402-019-00475-7

Abstract (EN): Purpose High-grade gliomas (HGG) remain one of the most aggressive tumors, which is primarily due to its diffuse infiltrative nature. Serine proteases and metalloproteases are known to play key roles in cellular migration and invasion mechanisms. SPINT2, also known as HAI-2, is an important serine protease inhibitor that can affect MET signaling. SPINT2 has been found to be frequently downregulated in various tumors, whereby hypermethylation of its promoter appears to serve as a common mechanism. Here, we assessed the clinical relevance of SPINT2 expression and promoter hypermethylation in pediatric and adult HGG and explored its functional role. Methods A series of 371 adult and 77 pediatric primary HGG samples was assessed for SPINT2 protein expression (immunohistochemistry) and promoter methylation (methylation-specific PCR) patterns. After SPINT2 knockdown and knock-in in adult and pediatric HGG cell lines, a variety of in vitro assays was carried out to determine the role of SPINT2 in glioma cell viability and invasion, as well as their mechanistic associations with metalloprotease activities. Results We found that SPINT2 protein expression was frequently absent in adult (85.3%) and pediatric (100%) HGG samples. The SPINT2 gene promoter was found to be hypermethylated in approximately half of both adult and pediatric gliomas. Through functional assays we revealed a suppressor activity of SPINT2 in glioma cell proliferation and viability, as well as in their migration and invasion. These functions appear to be mediated in part by MMP2 expression and activity. Conclusions We conclude that dysregulation of SPINT2 is a common event in both pediatric and adult HGG, in which SPINT2 may act as a tumor suppressor.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 15