Expression and its clinical significance of cell-cycle dependent kinase 1 in malignant peripheral nerve sheath tumors_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

LIU Yuanxin ¹ , FU Laihua ^1,2 , LIU Haotian ¹ , ZHANG Gengpu ¹ , XIAO Wanyi ¹ , GAO Ziwei ¹ , ZHANG Hongliang ^1,3 ,  YANG Jilong ¹

1. Department of Bone and Soft Tissue Tumors of Tianjin Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Tianjin Clinical Research Center for Malignant Tumors, Tianjin, 300060, P. R. China;
2. National Cancer Center, National Clinical Research Center for Cancer, Department of Orthopaedics of Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen Guangdong, 518116, P. R. China;
3. Department of Bone and Soft Tissue Tumors of Tianjin Hospital, Tianjin, 300211, P. R. China;

Corresponding author：

YANG Jilong, Email: yangjilong@tjmuch.com

Keywords：

Malignant peripheral nerve sheath tumor; cell-cycle dependent kinase 1; transcriptome sequencing; bioinformatics analysis; prognosis

DOI：

10.7507/1002-1892.202406090

Video：

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Objective To explore the role and clinical significance of cell-cycle dependent kinase 1 (CDK1) and its upstream and downstream molecules in the development of malignant peripheral nerve sheath tumor (MPNST) through the analysis of clinical tissue samples. Methods A total of 56 tumor samples from MPNST patients (“Tianjin” dataset) who underwent surgical resection, confirmed by histology and pathology between September 2011 and March 2020, along with 17 normal tissue samples, were selected as the research subjects. MPNST-related hub genes were identified through transcriptome sequencing, bioinformatics analysis, immunohistochemistry staining, and survival analysis, and their expression levels and prognostic associations were analyzed. Results Transcriptome sequencing and bioinformatics analysis revealed that upregulated genes in MPNST were predominantly enriched in cell cycle-related pathways, with CDK1 occupying a central position among all differentially expressed genes. Further differential analysis demonstrated that CDK1 mRNA expression in sarcoma tissues was significantly higher than in normal tissues [based on searching the cancer genome atlas (TCGA) dataset, P<0.05]. In MPNST tissues, CDK1 mRNA expression was not only significantly higher than in normal tissues (based on Tianjin, GSE141438 datasets, P<0.05), but also significantly higher than in neurofibromatosis (NF) and plexiform neurofibromas (PNF) (based on GSE66743 and GSE145064 datasets, P<0.05). Immunohistochemical staining results indicated that the expression rate of CDK1 protein in MPNST tissues was 40.31%. Survival analysis results demonstrated that CDK1 expression was associated with poor prognosis. The survival time of MPNST patients with high CDK1 mRNA expression was significantly lower than that of the low expression group (P<0.05), and the overall survival trend of patients with positive CDK1 protein expression was worse than that of patients with negative CDK1 expression. Additionally, differential analysis of CDK family genes (CDK1-8) revealed that only CDK1 was significantly upregulated in MPNST, NF, and PNF. Conclusion Increased expression of CDK1 is associated with poor prognosis in MPNST patients. Compared to other CDK family members, CDK1 exhibits a unique expression pattern, suggesting its potential as a therapeutic target for MPNST.

Citation： LIU Yuanxin, FU Laihua, LIU Haotian, ZHANG Gengpu, XIAO Wanyi, GAO Ziwei, ZHANG Hongliang, YANG Jilong. Expression and its clinical significance of cell-cycle dependent kinase 1 in malignant peripheral nerve sheath tumors. Chinese Journal of Reparative and Reconstructive Surgery, 2024, 38(10): 1220-1228. doi: 10.7507/1002-1892.202406090 Copy

1.	Kroep JR, Ouali M, Gelderblom H, et al. First-line chemotherapy for malignant peripheral nerve sheath tumor (MPNST) versus other histological soft tissue sarcoma subtypes and as a prognostic factor for MPNST: an EORTC soft tissue and bone sarcoma group study. Ann Oncol, 2011, 22(1): 207-214.
2.	Zhang J, Di Y, Zhang B, et al. CDK1 and CCNA2 play important roles in oral squamous cell carcinoma. Medicine (Baltimore), 2024, 103(16): e37831. doi: 10.1097/MD.0000000000037831.
3.	Goel S, Bergholz JS, Zhao JJ. Targeting CDK4 and CDK6 in cancer. Nat Rev Cancer, 2022, 22(6): 356-372.
4.	Braal CL, Jongbloed EM, Wilting SM, et al. Inhibiting CDK4/6 in breast cancer with palbociclib, ribociclib, and abemaciclib: Similarities and differences. Drugs, 2021, 81(3): 317-331.
5.	Zhang C, Shen H, Yang T, et al. A single-cell analysis reveals tumor heterogeneity and immune environment of acral melanoma. Nat Commun, 2022, 13(1): 7250. doi: 10.1038/s41467-022-34877-3.
6.	Li T, Zhang C, Zhao G, et al. IGFBP2 regulates PD-L1 expression by activating the EGFR-STAT3 signaling pathway in malignant melanoma. Cancer Lett, 2020, 477: 19-30.
7.	Wang C, Xie X, Li W, et al. Expression of KIF2A, NDC80, CDK1, and CCNB1 in breast cancer patients: Their interaction and linkage with tumor features and prognosis. J Clin Lab Anal, 2022, 36(9): e24647. doi: 10.1002/jcla.24647.
8.	Wang Q, Bode AM, Zhang T. Targeting CDK1 in cancer: mechanisms and implications. NPJ Precis Oncol, 2023, 7(1): 58. doi: 10.1038/s41698-023-00407-7.
9.	Wijnen R, Pecoraro C, Carbone D, et al. Cyclin dependent kinase-1 (CDK-1) inhibition as a novel therapeutic strategy against pancreatic ductal adenocarcinoma (PDAC). Cancers (Basel), 2021, 13(17): 4389. doi: 10.3390/cancers13174389.
10.	Xi M, Chen T, Wu C, et al. CDK8 as a therapeutic target for cancers and recent developments in discovery of CDK8 inhibitors. Eur J Med Chem, 2019, 164: 77-91.
11.	Dong S, Huang F, Zhang H, et al. Overexpression of BUB1B, CCNA2, CDC20, and CDK1 in tumor tissues predicts poor survival in pancreatic ductal adenocarcinoma. Biosci Rep, 2019, 39(2): BSR20182306. doi: 10.1042/BSR20182306.
12.	Xu X, Ding Y, Jin J, et al. Post-translational modification of CDK1-STAT3 signaling by fisetin suppresses pancreatic cancer stem cell properties. Cell Biosci, 2023, 13(1): 176. doi: 10.1186/s13578-023-01118-z.
13.	Luo C, He J, Yang Y, et al. SRSF9 promotes cell proliferation and migration of glioblastoma through enhancing CDK1 expression. J Cancer Res Clin Oncol, 2024, 150(6): 292. doi: 10.1007/s00432-024-05797-0.
14.	Ohba S, Tang Y, Johannessen TA, et al. PKM2 interacts with the Cdk1-CyclinB complex to facilitate cell cycle progression in gliomas. Front Oncol, 2022, 12: 844861. doi: 10.3389/fonc.2022.844861.
15.	Lu P, Shangguan W, Zhao Q. HIC2 promotes cell cycle transitions by upregulating CDK1 expression in glioblastoma. Asian J Surg, 2023, 46(10): 4536-4538.
16.	Zeng K, Li W, Wang Y, et al. Inhibition of CDK1 overcomes oxaliplatin resistance by regulating ACSL4-mediated ferroptosis in colorectal cancer. Adv Sci (Weinh), 2023, 10(25): e2301088. doi: 10.1002/advs.202301088.
17.	Han Z, Jia Q, Zhang J, et al. Deubiquitylase YOD1 regulates CDK1 stability and drives triple-negative breast cancer tumorigenesis. J Exp Clin Cancer Res, 2023, 42(1): 228. doi: 10.1186/s13046-023-02781-3.
18.	Matthews HK, Bertoli C, de Bruin RAM. Cell cycle control in cancer. Nat Rev Mol Cell Biol, 2022, 23(1): 74-88.
19.	Schachter MM, Fisher RP. The CDK-activating kinase Cdk7: taking yes for an answer. Cell Cycle, 2013, 12(20): 3239-3240.
20.	Dougherty J, Harvey K, Liou A, et al. Identification of therapeutic sensitivities in a spheroid drug combination screen of Neurofibromatosis type Ⅰ associated high grade gliomas. PLoS One, 2023, 18(2): e0277305. doi: 10.1371/journal.pone.0277305.

1. Kroep JR, Ouali M, Gelderblom H, et al. First-line chemotherapy for malignant peripheral nerve sheath tumor (MPNST) versus other histological soft tissue sarcoma subtypes and as a prognostic factor for MPNST: an EORTC soft tissue and bone sarcoma group study. Ann Oncol, 2011, 22(1): 207-214.
2. Zhang J, Di Y, Zhang B, et al. CDK1 and CCNA2 play important roles in oral squamous cell carcinoma. Medicine (Baltimore), 2024, 103(16): e37831. doi: 10.1097/MD.0000000000037831.
3. Goel S, Bergholz JS, Zhao JJ. Targeting CDK4 and CDK6 in cancer. Nat Rev Cancer, 2022, 22(6): 356-372.
4. Braal CL, Jongbloed EM, Wilting SM, et al. Inhibiting CDK4/6 in breast cancer with palbociclib, ribociclib, and abemaciclib: Similarities and differences. Drugs, 2021, 81(3): 317-331.
5. Zhang C, Shen H, Yang T, et al. A single-cell analysis reveals tumor heterogeneity and immune environment of acral melanoma. Nat Commun, 2022, 13(1): 7250. doi: 10.1038/s41467-022-34877-3.
6. Li T, Zhang C, Zhao G, et al. IGFBP2 regulates PD-L1 expression by activating the EGFR-STAT3 signaling pathway in malignant melanoma. Cancer Lett, 2020, 477: 19-30.
7. Wang C, Xie X, Li W, et al. Expression of KIF2A, NDC80, CDK1, and CCNB1 in breast cancer patients: Their interaction and linkage with tumor features and prognosis. J Clin Lab Anal, 2022, 36(9): e24647. doi: 10.1002/jcla.24647.
8. Wang Q, Bode AM, Zhang T. Targeting CDK1 in cancer: mechanisms and implications. NPJ Precis Oncol, 2023, 7(1): 58. doi: 10.1038/s41698-023-00407-7.
9. Wijnen R, Pecoraro C, Carbone D, et al. Cyclin dependent kinase-1 (CDK-1) inhibition as a novel therapeutic strategy against pancreatic ductal adenocarcinoma (PDAC). Cancers (Basel), 2021, 13(17): 4389. doi: 10.3390/cancers13174389.
10. Xi M, Chen T, Wu C, et al. CDK8 as a therapeutic target for cancers and recent developments in discovery of CDK8 inhibitors. Eur J Med Chem, 2019, 164: 77-91.
11. Dong S, Huang F, Zhang H, et al. Overexpression of BUB1B, CCNA2, CDC20, and CDK1 in tumor tissues predicts poor survival in pancreatic ductal adenocarcinoma. Biosci Rep, 2019, 39(2): BSR20182306. doi: 10.1042/BSR20182306.
12. Xu X, Ding Y, Jin J, et al. Post-translational modification of CDK1-STAT3 signaling by fisetin suppresses pancreatic cancer stem cell properties. Cell Biosci, 2023, 13(1): 176. doi: 10.1186/s13578-023-01118-z.
13. Luo C, He J, Yang Y, et al. SRSF9 promotes cell proliferation and migration of glioblastoma through enhancing CDK1 expression. J Cancer Res Clin Oncol, 2024, 150(6): 292. doi: 10.1007/s00432-024-05797-0.
14. Ohba S, Tang Y, Johannessen TA, et al. PKM2 interacts with the Cdk1-CyclinB complex to facilitate cell cycle progression in gliomas. Front Oncol, 2022, 12: 844861. doi: 10.3389/fonc.2022.844861.
15. Lu P, Shangguan W, Zhao Q. HIC2 promotes cell cycle transitions by upregulating CDK1 expression in glioblastoma. Asian J Surg, 2023, 46(10): 4536-4538.
16. Zeng K, Li W, Wang Y, et al. Inhibition of CDK1 overcomes oxaliplatin resistance by regulating ACSL4-mediated ferroptosis in colorectal cancer. Adv Sci (Weinh), 2023, 10(25): e2301088. doi: 10.1002/advs.202301088.
17. Han Z, Jia Q, Zhang J, et al. Deubiquitylase YOD1 regulates CDK1 stability and drives triple-negative breast cancer tumorigenesis. J Exp Clin Cancer Res, 2023, 42(1): 228. doi: 10.1186/s13046-023-02781-3.
18. Matthews HK, Bertoli C, de Bruin RAM. Cell cycle control in cancer. Nat Rev Mol Cell Biol, 2022, 23(1): 74-88.
19. Schachter MM, Fisher RP. The CDK-activating kinase Cdk7: taking yes for an answer. Cell Cycle, 2013, 12(20): 3239-3240.
20. Dougherty J, Harvey K, Liou A, et al. Identification of therapeutic sensitivities in a spheroid drug combination screen of Neurofibromatosis type Ⅰ associated high grade gliomas. PLoS One, 2023, 18(2): e0277305. doi: 10.1371/journal.pone.0277305.

Chinese Journal of Reparative and Reconstructive Surgery

Expression and its clinical significance of cell-cycle dependent kinase 1 in malignant peripheral nerve sheath tumors

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