Knockdown of NCOR2 Inhibits Cell Proliferation via BDNF/TrkB/ERK in NF1-Derived MPNSTs

Abstract

(1) Background: malignant peripheral nerve sheath tumours (MPNSTs) are aggressive Schwann cell-derived sarcomas with dismal prognoses. Previous studies have shown that nuclear receptor corepressor 2 (NCOR2) plays a vital role in neurodevelopment and in various tumours. However, the impact of NCOR2 on the progression of MPNST remains unclear. (2) Methods: by GEO database, MPNST tissue microarray, and NF1-related tumour tissues and cell lines were used to explore NCOR2 expression level in the MPNSTs. The role and mechanism of NCOR2 in NF1-derived MPNSTs were explored by experiments in vivo and in vitro and by transcriptome high-throughput sequencing. (3) Results: NCOR2 expression is significantly elevated in NF1-derived MPNSTs and is associated with patient 10-year survival time. Knockdown of NCOR2 suppressed NF1-derived MPNST cell proliferation by blocking the cell cycle in the G0/G1 phase. Moreover, decreased NCOR2 expression could down-regulate MAPK signal activity through the BDNF/TrkB pathway. (4) Conclusions: our findings demonstrated that NCOR2 expression is significantly elevated in NF1-derived MPNSTs. NCOR2 knockdown can inhibit NF1-derived MPNST cell proliferation by weakened BDNF/TrkB/ERK signalling. Targeting NF1-derived MPNSTs with TrkB inhibitors, or in combination with ERK inhibitors, may be a novel therapeutic strategy for clinical trials.

Giant Cell Tumors With HMGA2::NCOR2 Fusion

“…NCOR2 encodes for a poorly characterized corepressor, which induces gene downregulation through epigenetic modification of DNA 20 . Further, NCOR2 has been shown to contribute to tumor cell proliferation and resistance to hormone therapy 20–22 . To date, 3 different HMGA2::NCOR2 fusion types have been described, including, in decreasing order of frequency: (1) 5’ HMGA2 exons 1 to 3 fused to 3’ NCOR2 exons 16 to 49; (2) 5’ HMGA2 exons 1 to 3 fused to 3’ NCOR2 exons 20 to 49; (3) 5’ HMGA2 exons 1 and 2 fused to 3’ NCOR2 exons 16 to 49.…”

“…20 Further, NCOR2 has been shown to contribute to tumor cell proliferation and resistance to hormone therapy. [20][21][22] To date, 3 different HMGA2:: NCOR2 fusion types have been described, including, in decreasing order of frequency: (1) 5' HMGA2 exons 1 to 3 fused to 3' NCOR2 exons 16 to 49; (2) 5' HMGA2 exons 1 to 3 fused to 3' NCOR2 exons 20 to 49; (3) 5' HMGA2 exons 1 and 2 fused to 3' NCOR2 exons 16 to 49. These fusions are predicted to produce a functional chimeric protein retaining the DNA-binding domains of HMGA2 and most functional and interaction domains of NCOR2.…”

Distinctive mesenchymal-like neurofibroma stem cells shape NF1 clinical phenotypes controlled by BDNF microenvironment

“…Nuclear receptor core suppressor 2 (NCOR2) knockdown can inhibit NF1-derived MPNST cell proliferation through diminished BDNF/TrkB/ERK signaling, which indicate the crucial role of BDNF in the progress of NF1 [29] . Therefore, we performed BDNF immunohistochemical staining of neurofibroma tissues and found that trunk neurofibroma tissues expressed significantly less BDNF than head NF, as demonstrated by BDNF immunostaining index ( Fig.…”