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

Autor: Pereira MS; Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057, Braga, Portugal.; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal., Celeiro SP; Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057, Braga, Portugal.; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal., Costa ÂM; I3S - Instituto de Investigação e Inovação em Saúde, Porto, Portugal.; INEB - Institute of Biomedical Engineering, Porto, Portugal., Pinto F; Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057, Braga, Portugal.; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.; I3S - Instituto de Investigação e Inovação em Saúde, Porto, Portugal.; IPATIMUP - Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal., Popov S; Department of Cellular Pathology, University Hospital of Wales, Cardiff, United Kingdom., de Almeida GC; Department of Pathology, Barretos Cancer Hospital, S. Paulo, Brazil., Amorim J; Department of Oncology, Hospital de Braga, Braga, Portugal., Pires MM; Unity of Neuropathology, Centro Hospitalar Universitário Porto, Porto, Portugal., Pinheiro C; Department of Neurosurgery, Centro Hospitalar Universitário Porto, Porto, Portugal., Lopes JM; IPATIMUP - Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal.; Department of Pathology, Hospital São João, Porto, Portugal., Honavar M; Department of Pathology, Hospital Pedro Hispano, Matosinhos, Portugal., Costa P; Department of Radiotherapy, Hospital de Braga, Braga, Portugal., Pimentel J; Laboratory of Neuropathology, Hospital de Santa Maria, Lisbon, Portugal., Jones C; Divisions of Molecular Pathology and Cancer Therapeutics, Institute of Cancer Research, London, United Kingdom., Reis RM; Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057, Braga, Portugal. rreis@med.uminho.pt.; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal. rreis@med.uminho.pt.; Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, São Paulo, Brazil. rreis@med.uminho.pt., Viana-Pereira M; Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057, Braga, Portugal. martavianap@gmail.com.; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal. martavianap@gmail.com.
Jazyk: angličtina
Zdroj: Cellular oncology (Dordrecht) [Cell Oncol (Dordr)] 2020 Feb; Vol. 43 (1), pp. 107-121. Date of Electronic Publication: 2019 Nov 07.
DOI: 10.1007/s13402-019-00475-7
Abstrakt: 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.
Databáze: MEDLINE
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