Neurofibromin Deficiency Causes Epidermal Growth Factor Receptor Upregulation through the Activation of Ras/ERK/SP1 Signaling Pathway in Neurofibromatosis Type 1-Associated Malignant Peripheral Nerve Sheet Tumor.

Gun-Hoo Park,Jeonghyun Kim,Seon-Yong Jeong,Su-Jin Lee,Chang-Gun Lee,Eunkuk Park

doi:10.3390/ijms222413308

Abstract

Neurofibromatosis type 1 (NF1) is an autosomal dominant human genetic disorder. The progression of benign plexiform neurofibromas to malignant peripheral nerve sheet tumors (MPNSTs) is a major cause of mortality in patients with NF1. Although elevated epidermal growth factor receptor (EGFR) expression plays a crucial role in the pathogenesis of MPNST, the cause of EGFR overexpression remains unclear. Here, we assessed EGFR expression levels in MPNST tissues of NF1 patients and NF1 patient-derived MPNST cells. We found that the expression of EGFR was upregulated in MPNST tissues and MPNST cells, while the expression of neurofibromin was significantly decreased. Manipulation of NF1 expression by NF1 siRNA treatment or NF1-GAP-related domain overexpression demonstrated that EGFR expression levels were closely and inversely correlated with neurofibromin levels. Notably, knockdown of the NF1 gene by siRNA treatment augmented the nuclear localization of phosphorylated SP1 (pSP1) and enhanced pSP1 binding to the EGFR gene promoter region. Our results suggest that neurofibromin deficiency in NF1-associated MPNSTs enhances the Ras/ERK/SP1 signaling pathway, which in turn may lead to the upregulation of EGFR expression. This study provides insight into the progression of benign tumors and novel therapeutic approaches for treatment of NF1-associated MPNSTs.

Highlights

Neurofibromatosis type 1 (NF1), a genetic disease, is caused by a novel germline mutation on the NF1 gene or hereditary transmission of NF1 mutations [1]
We examined the hypothesis that neurofibromin depletion may promote activation of the RAS/extracellular regulatory kinase (ERK) signaling pathway, leading to epidermal growth factor receptor (EGFR) overexpression in NF1-malignant peripheral nerve sheet tumors (MPNSTs) cells
We found that EGFR expression was significantly increased but that of neurofibromin was significantly decreased in MPNSTs

Summary

Introduction

Neurofibromatosis type 1 (NF1), a genetic disease, is caused by a novel germline mutation on the NF1 gene or hereditary transmission of NF1 mutations [1]. The NF1 tumor suppressor gene encodes a neurofibromin that negatively regulates of Ras by switching. Loss of neurofibromin promotes activation of the Ras effector pathways and phosphoinositide 3-kinase (PI3K) pathways, which are engaged in the control of cell proliferation, survival, and metabolism [3]. Patients with NF1 have a variety of symptoms that affect the skin, bone, peripheral nervous system, and soft tissues [5]. The clinical hallmark of NF1 is the neurofibroma, a slow-growing benign tumor [7]. This tumor progression is related with loss of heterozygosity of NF1 gene function in the Schwann lineage cells [8]. Half of all patients with NF1 are affected with benign plexiform neurofibromas (PNs) [9].

Methods

Discussion

Conclusion