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RRM2 as a novel prognostic and therapeutic target of NF1-associated MPNST

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Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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.

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Data availability

The raw sequencing data generated in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found below: https://www.ncbi.nlm.nih.gov/geo/GSE213988.

Abbreviations

NF1:

Neurofibromatosis Type 1

MPNST:

Malignant Peripheral Nerve Sheath Tumor

RRM2:

Ribonucleotide reductase subunit M2

STS:

Soft-tissue sarcoma; plexiform neurofibromas (PNF)

RNR:

Ribonucleotide reductase

dNTP:

Deoxyribonucleotides

HNSCC:

Head and neck squamous cell carcinoma

DEG:

Differentially expressed gene

qPCR:

Quantitative Polymerase Chain Reaction

RNA-seq:

RNA sequencing

SD:

Standard deviation

CHK1:

Checkpoint Kinase 1

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Acknowledgements

We thank Prof. Vincent Keng and Prof. Jilong Yang for providing all the MPNST cell lines.

Funding

This work was supported by grants from National Natural Science Foundation of China (82202470; 82102344; 82172228); Shanghai Rising Star Program supported by Science and Technology Commission of Shanghai Municipality (20QA1405600); Natural Science Foundation of Shanghai (22ZR1422300); Innovative research team of high-level local universities in Shanghai (SHSMU-ZDCX20210400); Clinical Research Plan of SHDC (SHDC2020CR1019B); Shanghai Clinical Research Center of Plastic and Reconstructive Surgery supported by Science and Technology Commission of Shanghai Municipality (Grant No. 22MC1940300).

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Author notes

  1. Man-Hon Chung, Rehanguli Aimaier, Qingxiong Yu, and Haibo Li contributed equally to this work.

Authors and Affiliations

  1. Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China

    Man-Hon Chung, Rehanguli Aimaier, Qingxiong Yu, Yuehua Li, Chengjiang Wei, Yihui Gu, Wei Wang, Zizhen Guo, Qingfeng Li & Zhichao Wang

  2. Department of Plastic Surgery, The Third Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China

    Haibo Li

  3. Department of Pathology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China

    Manmei Long

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Contributions

Conception and design: M.-H.C, Z.W., and Q.Y.; Acquisition of data: M.-H.C, R.A., Y.L., H.L. Y.G., W.W., C.W., Z.G., and M.L.;Analysis and interpretation: M.-H.C, R.A., and Y.L;Writing, re-view of the manuscript: M.-H.C, Z.W., and Q.L.; All authors reviewed and approved the final manuscript.

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Correspondence to Qingfeng Li or Zhichao Wang.

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The study involving human participants was reviewed and approved by the Ethics Committee of Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine. Informed consent was obtained from patients under institutional review board protocols. The animal study was reviewed and approved by the Ethics Committee of Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine.

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Chung, MH., Aimaier, R., Yu, Q. et al. RRM2 as a novel prognostic and therapeutic target of NF1-associated MPNST. Cell Oncol. 46, 1399–1413 (2023). https://doi.org/10.1007/s13402-023-00819-4

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