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TAGLN expression is upregulated in NF1-associated malignant peripheral nerve sheath tumors by hypomethylation in its promoter and subpromoter regions.

Authors
Park, GH | Lee, SJ | Yim, H  | Han, JH  | Kim, HJ | Sohn, YB  | Ko, JM | Jeong, SY
Citation
Oncology reports, 32(4). : 1347-1354, 2014
Journal Title
Oncology reports
ISSN
1021-335X1791-2431
Abstract
Neurofibromatosis type 1 (NF1) caused by NF1 gene mutation is a commonly

inherited autosomal dominant disorder. Malignant peripheral nerve sheath tumors

(MPNSTs), a type of aggressive sarcoma, are a major cause of mortality in NF1

patients. The malignant transformation of benign plexiform neurofibromas (PNs) to

MPNSTs is a marked peculiarity in NF1 patients, yet the pathogenesis remains

poorly understood. We found that an actin-associated protein transgelin (SM22)

was highly expressed in NF1-deficient MPNST tissues compared to NF1-deficient PN

tissues using immunohistological staining and primary cultured MPNST cells in

western blot analysis. We further found that this transgelin upregulation was

caused by increased transcriptional expression of the TAGLN gene encoding

transgelin. Comparison of DNA methylation values in the promoter and subpromoter

regions of the TAGLN gene in three types of NF1-deficient primary-cultured cells,

derived from an NF1 patient's normal phenotype, a benign PN and MPNST tissues,

revealed that the TAGLN gene was hypomethylated in the MPNST cells. Next, to

determine the functional role of transgelin in MPNST pathogenesis, we manipulated

the TAGLN gene expression and investigated the alteration of the

RAS-mitogen-activated protein kinase (MAPK) signaling pathway in the

normal-phenotypic and malignant tumor cells. The downregulation of TAGLN

expression in NF1-deficient MPNST tumor cells through the treatment of the small

interfering RNA resulted in a decrease in the RAS activation (GTP-RAS) and the

downstream ERK1/2 activation (phosphorylated ERK1/2), while the overexpression of

TAGLN in normal-phenotypic NF1-deficient cells caused an increase in RAS and

ERK1/2 activation. These results indicate that upregulation of transgelin caused

by hypomethylation of the TAGLN gene is closely involved in tumor progression in

NF1.
MeSH

DOI
10.3892/or.2014.3379
PMID
25109740
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Pathology
Journal Papers > School of Medicine / Graduate School of Medicine > Medical Genetics
Ajou Authors
손, 영배  |  임, 현이  |  정, 선용  |  한, 재호
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