title: TAGLN expression is upregulated in NF1-associated malignant peripheral nerve sheath tumors by hypomethylation in its promoter and subpromoter regions.
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.
authors.affiliation: Department of Medical Genetics, Ajou University School of Medicine, Suwon, Republic of Korea.
authors.forename: Gun-Hoo
authors.initials: GH
authors.lastname: Park
authors.affiliation: Department of Medical Genetics, Ajou University School of Medicine, Suwon, Republic of Korea.
authors.forename: Su-Jin
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Department of Pathology, Ajou University School of Medicine, Suwon, Republic of Korea.
authors.forename: Hyunee
authors.initials: H
authors.lastname: Yim
authors.affiliation: Department of Pathology, Ajou University School of Medicine, Suwon, Republic of Korea.
authors.forename: Jae-Ho
authors.initials: JH
authors.lastname: Han
authors.affiliation: Department of Medical Genetics, Ajou University School of Medicine, Suwon, Republic of Korea.
authors.forename: Hyon J
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Medical Genetics, Ajou University School of Medicine, Suwon, Republic of Korea.
authors.forename: Young-Bae
authors.initials: YB
authors.lastname: Sohn
authors.affiliation: Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Republic of Korea.
authors.forename: Jung Min
authors.initials: JM
authors.lastname: Ko
authors.affiliation: Department of Medical Genetics, Ajou University School of Medicine, Suwon, Republic of Korea.
authors.forename: Seon-Yong
authors.initials: SY
authors.lastname: Jeong
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D019175:DNA Methylation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D016514:Genes, Neurofibromatosis 1; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism; D009442:Neurilemmoma / Q000235:genetics* / Q000378:metabolism; D018318:Neurofibroma, Plexiform / Q000235:genetics* / Q000378:metabolism; D009456:Neurofibromatosis 1 / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics*; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D015854:Up-Regulation; D055815:Young Adult; D018631:ras Proteins / Q000378:metabolism
chemical_list: D008840:Microfilament Proteins; D009124:Muscle Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C051615:transgelin; D018631:ras Proteins
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