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.

TRAF6-Mediated SM22α K21 Ubiquitination Promotes G6PD Activation and NADPH Production, Contributing to GSH Homeostasis and VSMC Survival In Vitro and In Vivo

“…[16][17][18] Here, we further identified that the expression of SM22α at both the mRNA and protein level was decreased in VSMCs after PDGF-BB stimulation for 3 and 12 hours (Online Figure II; Figure 2C). Furthermore, we recently found that SM22α was polyubiquitinated after 6 hours of PDGF-BB stimulation.…”

Identification Hub Genes in Colorectal Cancer by Integrating Weighted Gene Co-Expression Network Analysis and Clinical Validation in vivo and vitro

“…Among them, studies have shown that HCLS1 might be a potential therapeutic target gene of chronic lymphocytic leukemia (29). EVI2B enhanced the migration of NF1-associated malignant peripheral nerve sheath tumors (30). CD48 plays a vital role as an environmental sensor for regulating stem cells and inhibiting tumor development (31).…”

Transgelin gene is frequently downregulated by promoter DNA hypermethylation in breast cancer

“…While some studies negatively correlated TAGLN expression with lymph node status in colon [ 32 ] and prostate cancers [ 61 ], others found positive correlation in colorectal cancer [ 34 ]. Increased expression of TAGLN in metastatic nerve sheath tumors was also shown [ 62 ]. At least part of the discrepancies in the expression levels of TAGLN in different studies has been explained as a result of higher TAGLN expression in the tumor stroma of invasive tumors rather than the tumor tissue itself, which is revealed by subsequent IHC staining analyses [ 33 , 63 – 65 ].…”