Musculoskeletal Tumor Center, Peking University People's Hospital, No.11 Xizhimen South Street, Beijing, 100044, People's Republic of China.
Beijing Key Laboratory of Musculoskeletal Tumor, Beijing, People's Republic of China.
J Exp Clin Cancer Res. 2019 May 3;38(1):185. doi: 10.1186/s13046-019-1183-2.
Malignant peripheral nerve sheath tumours (MPNSTs) are sarcomas of Schwann cell lineage origin that occur sporadically or in association with the inherited syndrome, neurofibromatosis type 1 (NF1). This study aimed to examine the function of High mobility group protein A2 (HMGA2) in NF1 MPNST progression and the underlying molecular mechanism.
Immunohistochemistry (IHC) was used to detect HMGA2 expression in MPNST and neurofibroma patient samples. Cell Cycle Kit-8 (CCK-8) and 5-ethynyl-20-deoxyuridine (EdU) assays, terminal deoxynucleotidyl transferase-mediated nick end labelling, and transmission electron microscopy were performed to reveal HMGA2 functions in NF1 MPNST cells in vitro and in vivo. Chromatin immunoprecipitation sequencing (ChIP-Seq) and RNA sequencing (RNA-Seq) were used to detect HMGA2-modulated genes regulating autophagy and growth in NF1 MPNSTs in vitro and in vivo.
NF1 MPNST samples exhibit higher HMGA2 positivity rates (13/16) than sporadic MPNST (16/41) and neurofibroma (0/7) patient samples. High HMGA2 expression is correlated with poor prognosis. Neurofibromin 1 (NF1)-deficient MPNST cells display elevated HMGA2 expression. Functional experiments revealed that HMGA2 knockdown inhibits NF1 MPNST cell growth in vitro and in vivo. In addition to promoting cell cycle arrest and apoptosis, HMGA2 knockdown inhibits autophagy, favouring cell death. RNA-Seq and ChIP-Seq revealed that HMGA2 directly activates the Musashi-2 (MSI2) promoter region, and MSI2 overexpression reverses autophagy and growth in shHMGA2-transfected cells. MSI2 interacts with Beclin1, and Beclin1 blockade inhibits autophagy, thereby inhibiting cell proliferation.
HMGA2 knockdown regulates autophagy via MSI2-Beclin1 interactions to inhibit NF1 MPNST growth, revealing potential therapeutic targets for these untreatable tumours.
恶性外周神经鞘瘤（MPNST）是起源于雪旺细胞谱系的肉瘤，其散发性发生或与遗传性综合征神经纤维瘤病 1 型（NF1）相关。本研究旨在探讨高迁移率族蛋白 A2（HMGA2）在 NF1 MPNST 进展中的作用及其潜在的分子机制。
免疫组化（IHC）检测 MPNST 和神经纤维瘤患者样本中 HMGA2 的表达。细胞周期试剂盒-8（CCK-8）和 5-乙炔基-20-脱氧尿苷（EdU）检测、末端脱氧核苷酸转移酶介导的 nick 末端标记、透射电子显微镜用于揭示 HMGA2 在 NF1 MPNST 细胞中的功能在体外和体内。染色质免疫沉淀测序（ChIP-Seq）和 RNA 测序（RNA-Seq）用于检测 HMGA2 调节自噬和生长的基因在 NF1 MPNST 中的表达在体外和体内。
NF1 MPNST 样本的 HMGA2 阳性率（13/16）高于散发性 MPNST（16/41）和神经纤维瘤（0/7）患者样本。高 HMGA2 表达与预后不良相关。神经纤维瘤蛋白 1（NF1）缺陷型 MPNST 细胞显示 HMGA2 表达升高。功能实验表明，HMGA2 敲低抑制 NF1 MPNST 细胞的体外和体内生长。除了促进细胞周期停滞和细胞凋亡外，HMGA2 敲低还抑制自噬，促进细胞死亡。RNA-Seq 和 ChIP-Seq 显示 HMGA2 直接激活 Musashi-2（MSI2）启动子区域，MSI2 过表达逆转 shHMGA2 转染细胞中的自噬和生长。MSI2 与 Beclin1 相互作用，Beclin1 阻断抑制自噬，从而抑制细胞增殖。
HMGA2 敲低通过 MSI2-Beclin1 相互作用调节自噬，从而抑制 NF1 MPNST 生长，为这些无法治疗的肿瘤提供了潜在的治疗靶点。
