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.

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.

• Authors: Gun-Hoo Park, Su-Jin Lee, Chang-Gun Lee, Jeonghyun Kim, Eunkuk Park, Seon-Yong Jeong
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 22 Issue 24 (Dec 10 2021) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 34948100 (Publication Type: Journal Article)

Chemical References

• NF1 protein, human
• Neurofibromin 1
• Sp1 Transcription Factor
• Sp1 protein, human
• EGFR protein, human
• ErbB Receptors
• Extracellular Signal-Regulated MAP Kinases
• ras Proteins

Topics

• Cell Line, Tumor
• ErbB Receptors (biosynthesis, genetics)
• Extracellular Signal-Regulated MAP Kinases (genetics, metabolism)
• Gene Expression Regulation, Neoplastic
• Humans
• MAP Kinase Signaling System
• Neurofibromatosis 1 (genetics, metabolism)
• Neurofibromin 1 (genetics, metabolism)
• Sp1 Transcription Factor (genetics, metabolism)
• Up-Regulation
• ras Proteins (genetics, metabolism)