Chung Man-Hon, Aimaier Rehanguli, Yu Qingxiong, Li Haibo, Li Yuehua, Wei Chengjiang, Gu Yihui, Wang Wei, Guo Zizhen, Long Manmei, Li Qingfeng, Wang Zhichao
Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
Department of Plastic Surgery, The Third Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China.
Cell Oncol (Dordr). 2023 Oct;46(5):1399-1413. doi: 10.1007/s13402-023-00819-4. Epub 2023 Apr 22.
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.
恶性外周神经鞘瘤（MPNSTs）是侵袭性肉瘤，通常在1型神经纤维瘤病（NF1）背景下发生，并导致严重的发病情况。传统疗法对MPNSTs往往无效。核糖核苷酸还原酶亚基M2（RRM2）参与DNA合成和修复，且在多种癌症中过表达。然而，其在NF1相关MPNSTs中的作用仍不清楚。我们的目的是确定RRM2在NF1相关MPNSTs中的治疗和预后潜力。
利用NF1相关MPNST微阵列数据集进行枢纽基因的鉴定。我们通过免疫化学染色在MPNST组织微阵列中检测RRM2表达，并在MPNST队列中评估RRM2的临床和预后意义。使用RRM2基因敲低和RRM2抑制剂曲磷胺来评估体外和体内NF1相关MPNST细胞的增殖和凋亡。通过转录组分析揭示RRM2在NF1相关MPNST中的潜在机制。
RRM2是一个关键枢纽基因，其表达在NF1相关MPNST中显著升高。我们发现高RRM2表达在NF1相关MPNST中占较大比例，并证实高RRM2表达与总体生存率差相关。敲低RRM2可抑制NF1相关MPNST细胞增殖，促进凋亡和S期阻滞。RRM2抑制剂曲磷胺在体外显示出剂量依赖性抑制作用，并在体内诱导NF1相关MPNST肿瘤显著生长减缓。对RRM2基因敲低诱导的转录组变化分析显示AKT-mTOR信号通路受到抑制。RRM2的过表达激活AKT通路以促进NF1相关MPNST细胞增殖。
RRM2表达在NF1相关MPNST中显著升高，且高RRM2表达与较差的预后相关。RRM2通过AKT-mTOR信号通路在促进NF1相关MPNST细胞增殖中起重要作用。抑制RRM2可能是NF1相关MPNST的一种有前景的治疗策略。
