恶性周围神经鞘肿瘤 (MPNSTs) 是一种侵袭性的肉瘤，通常在神经纤维瘤类型 1 (NF1) 的情况下产生并造成重大的发病率。传统治疗对 MPNSTs 往往无效。核糖核酸还原酶亚基 M2 (RRM2) 参与 DNA 合成和修复，并在多种癌症中过度表达。然而，其在 NF1 相关的 MPNSTs 中的作用还不清楚。我们的目标是确定 RRM2 在 NF1 相关的 MPNSTs 中的治疗和预后潜力。通过使用 NF1 相关的 MPNST 微阵列数据集进行核心基因的鉴定。我们通过免疫化学染色检测 MPNST 组织微阵列中的 RRM2 表达，并评估在 MPNST 基因组中 RRM2 的临床和预后意义。RRM2 沉默和 RRM2 抑制剂 Triapine 被用于评估 NF1 相关的 MPNST 细胞在体外和体内的增殖和凋亡。通过转录组分析揭示了 RRM2 在 NF1 相关 MPNST 中的潜在机制。RRM2 是一个关键的核心基因，其在 NF1 相关的 MPNST 中的表达显著升高。我们发现高表达的 RRM2 占了较大的比例，并确认了高表达 RRM2 与较差的总体生存率之间的相关性。RRM2 沉默抑制了 NF1 相关的 MPNST 细胞增殖并促进了凋亡和 S 期阻滞。RRM2 抑制剂 Triapine 在体外具有剂量依赖性的抑制作用，并在 NF1 相关的 MPNST 组织中显著减少了肿瘤增长。RRM2 沉默诱导的转录组变化显示了 AKT-mTOR 信号通路的抑制作用。RRM2 的过表达通过激活 AKT 通路促进 NF1 相关的 MPNST 细胞增殖。RRM2 在 NF1 相关的 MPNST 中的表达显著升高，高表达 RRM2 与更差的预后结果相关。RRM2 通过 AKT-mTOR 信号通路在 NF1 相关的 MPNST 细胞增殖中起着重要作用。抑制 RRM2 可能是 NF1 相关的 MPNST 的一种有前途的治疗策略。©2023. Springer Nature Switzerland AG.

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas that typically develop in the setting of neurofibromatosis type 1 (NF1) and cause significant morbidity. Conventional therapies are often ineffective for MPNSTs. Ribonucleotide reductase subunit M2 (RRM2) is involved in DNA synthesis and repair, and is overexpressed in multiple cancers. However, its role in NF1-associated MPNSTs remains unknown. Our objective was to determine the therapeutic and prognostic potential of RRM2 in NF1-associated MPNSTs.Identification of hub genes was performed by using NF1-associated MPNST microarray datasets. We detected RRM2 expression by immunochemical staining in an MPNST tissue microarray, and assessed the clinical and prognostic significance of RRM2 in an MPNST cohort. RRM2 knockdown and the RRM2 inhibitor Triapine were used to assess cell proliferation and apoptosis in NF1-associated MPNST cells in vitro and in vivo. The underlying mechanism of RRM2 in NF1-associated MPNST was revealed by transcriptome analysis.RRM2 is a key hub gene and its expression is significantly elevated in NF1-associated MPNST. We revealed that high RRM2 expression accounted for a larger proportion of NF1-associated MPNSTs and confirmed the correlation of high RRM2 expression with poor overall survival. Knockdown of RRM2 inhibited NF1-associated MPNST cell proliferation and promoted apoptosis and S-phase arrest. The RRM2 inhibitor Triapine displayed dose-dependent inhibitory effects in vitro and induced significant tumor growth reduction in vivo in NF1-associated MPNST. Analysis of transcriptomic changes induced by RRM2 knockdown revealed suppression of the AKT-mTOR signaling pathway. Overexpression of RRM2 activates the AKT pathway to promote NF1-associated MPNST cell proliferation.RRM2 expression is significantly elevated in NF1-associated MPNST and that high RRM2 expression correlates with poorer outcomes. RRM2 acts as an integral part in the promotion of NF1-associated MPNST cell proliferation via the AKT-mTOR signaling pathway. Inhibition of RRM2 may be a promising therapeutic strategy for NF1-associated MPNST.© 2023. Springer Nature Switzerland AG.