Skip to main content
SpringerLink
Log in

The Oncogenic Role of Cyclin-Dependent Kinase Inhibitor 2C in Lower-Grade Glioma

  • Research
  • Published:
Journal of Molecular Neuroscience Aims and scope Submit manuscript

Abstract

Lower-grade gliomas (LGGs) are slow-growing, indolent tumors that usually affect younger patients and present a therapeutic challenge due to the heterogeneity of their clinical presentation. Dysregulation of cell cycle regulatory factors is implicated in the progression of many tumors, and drugs that target cell cycle machinery have shown efficacy as promising therapeutic approaches. To date, however, no comprehensive study has examined how cell cycle-related genes affect LGG outcomes. The cancer genome atlas (TCGA) data were used as the training set for differential analysis of gene expression and patient outcomes; the Chinese glioma genome atlas (CGGA) was used for validation. Levels of one candidate protein, cyclin-dependent kinase inhibitor 2C (CDKN2C), and its relationship to clinical prognosis were determined using a tissue microarray containing 34 LGG tumors. A nomogram was constructed to model the putative role of candidate factors in LGG. Cell type proportion analysis was performed to evaluate immune cell infiltration in LGG. Various genes encoding cell cycle regulatory factors showed increased expression in LGG and were significantly related to isocitrate dehydrogenase and chromosome arms 1p and 19q mutation status. CDKN2C expression independently predicted the outcome of LGG patients. High M2 macrophage values along with elevated CDKN2C expression were associated with poorer prognosis in LGG patients. CDKN2C plays an oncogenic role in LGG, which is associated with M2 macrophages.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

Data Availability

All data generated or analyzed during this study are included in this published article (and its supplementary information files).

References

  • Brat DJ, Verhaak RG, Aldape KD, Yung WK, Salama SR, Cooper LA et al (2015) Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. N Engl J Med 372:2481–2498

    Article  CAS  PubMed  Google Scholar 

  • Brennan CW, Verhaak RG, McKenna A, Campos B, Noushmehr H, Salama SR et al (2013) The somatic genomic landscape of glioblastoma. Cell 155:462–477

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bronner SM, Merrick KA, Murray J, Salphati L, Moffat JG, Pang J et al (2019) Design of a brain-penetrant CDK4/6 inhibitor for glioblastoma. Bioorg Med Chem Lett 29:2294–2301

    Article  CAS  PubMed  Google Scholar 

  • Burkhart DL, Sage J (2008) Cellular mechanisms of tumour suppression by the retinoblastoma gene. Nat Rev Cancer 8:671–682

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cavaliere R, Lopes MB, Schiff D (2005) Low-grade gliomas: an update on pathology and therapy. Lancet Neurol 4:760–770

    Article  PubMed  Google Scholar 

  • Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM et al (2009) Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462:739–744

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Das A, Henderson FC Jr, Alshareef M, Porto GBF, Kanginakudru I, Infinger LK et al (2021) MGMT-inhibitor in combination with TGF-βRI inhibitor or CDK 4/6 inhibitor increases temozolomide sensitivity in temozolomide-resistant glioblastoma cells. Clin Transl Oncol 23:612–619

    Article  CAS  PubMed  Google Scholar 

  • Deng T, Gong YZ, Wang XK, Liao XW, Huang KT, Zhu GZ et al (2019) Use of genome-scale integrated analysis to identify key genes and potential molecular mechanisms in recurrence of lower-grade brain glioma. Med Sci Monit 25:3716–3727

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Deng X, Lin D, Zhang X, Shen X, Yang Z, Yang L et al (2020) Profiles of immune-related genes and immune cell infiltration in the tumor microenvironment of diffuse lower-grade gliomas. J Cell Physiol 235:7321–7331

    Article  CAS  PubMed  Google Scholar 

  • Driver KE, Song H, Lesueur F, Ahmed S, Barbosa-Morais NL, Tyrer JP et al (2008) Association of single-nucleotide polymorphisms in the cell cycle genes with breast cancer in the British population. Carcinogenesis 29:333–341

    Article  CAS  PubMed  Google Scholar 

  • Dunn GP, Rinne ML, Wykosky J, Genovese G, Quayle SN, Dunn IF et al (2012) Emerging insights into the molecular and cellular basis of glioblastoma. Genes Dev 26:756–784

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Escudier B, Sharma P, McDermott DF, George S, Hammers HJ, Srinivas S et al (2017) CheckMate 025 randomized phase 3 study: outcomes by key baseline factors and prior therapy for nivolumab versus everolimus in advanced renal cell carcinoma. Eur Urol 72:962–971

    Article  CAS  PubMed  Google Scholar 

  • Gluick T, Yuan Z, Libutti SK, Marx SJ (2013) Mutations in CDKN2C (p18) and CDKN2D (p19) may cause sporadic parathyroid adenoma. Endocr Relat Cancer 20:L27-29

    Article  CAS  PubMed  Google Scholar 

  • Grubbs EG, Williams MD, Scheet P, Vattathil S, Perrier ND, Lee JE et al (2016) Role of CDKN2C copy number in sporadic medullary thyroid carcinoma. Thyroid 26:1553–1562

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Guan KL, Jenkins CW, Li Y, Nichols MA, Wu X, O’Keefe CL et al (1994) Growth suppression by p18, a p16INK4/MTS1- and p14INK4B/MTS2-related CDK6 inhibitor, correlates with wild-type pRb function. Genes Dev 8:2939–2952

    Article  CAS  PubMed  Google Scholar 

  • Hossain MG, Iwata T, Mizusawa N, Qian ZR, Shima SW, Okutsu T et al (2009) Expression of p18(INK4C) is down-regulated in human pituitary adenomas. Endocr Pathol 20:114–121

    Article  CAS  PubMed  Google Scholar 

  • Kirsch M, Mörz M, Pinzer T, Schackert HK, Schackert G (2009) Frequent loss of the CDKN2C (p18INK4c) gene product in pituitary adenomas. Genes Chromosomes Cancer 48:143–154

    Article  CAS  PubMed  Google Scholar 

  • Lapenna S, Giordano A (2009) Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov 8:547–566

    Article  CAS  PubMed  Google Scholar 

  • Lapointe J, Lachance Y, Labrie Y, Labrie C (1996) A p18 mutant defective in CDK6 binding in human breast cancer cells. Cancer Res 56:4586–4589

    CAS  PubMed  Google Scholar 

  • Leone PE, Walker BA, Jenner MW, Chiecchio L, Dagrada G, Protheroe RK et al (2008) Deletions of CDKN2C in multiple myeloma: biological and clinical implications. Clin Cancer Res 14:6033–6041

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li C, Tang Z, Zhang W, Ye Z, Liu F (2021) GEPIA2021: integrating multiple deconvolution-based analysis into GEPIA. Nucleic Acids Res 49:W242-w246

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li G, Jiang Y, Lyu X, Cai Y, Zhang M, Wang Z et al (2019) Deconvolution and network analysis of IDH-mutant lower grade glioma predict recurrence and indicate therapeutic targets. Epigenomics 11:1323–1333

    Article  CAS  PubMed  Google Scholar 

  • Li J, Byeon IJ, Ericson K, Poi MJ, O’Maille P, Selby T et al (1999) Tumor suppressor INK4: determination of the solution structure of p18INK4C and demonstration of the functional significance of loops in p18INK4C and p16INK4A. Biochemistry 38:2930–2940

    Article  CAS  PubMed  Google Scholar 

  • Li T, Fan J, Wang B, Traugh N, Chen Q, Liu JS et al (2017) TIMER: a web server for comprehensive analysis of tumor-infiltrating immune cells. Cancer Res 77:e108–e110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li T, Fu J, Zeng Z, Cohen D, Li J, Chen Q et al (2020) TIMER2.0 for analysis of tumor-infiltrating immune cells. Nucleic Acids Res 48:W509-w514

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liao X, Hong Y, Mao Y, Chen N, Wang Q, Wang Z et al (2020) SPH3643: a novel cyclin-dependent kinase 4/6 inhibitor with good anticancer efficacy and strong blood-brain barrier permeability. Cancer Sci 111:1761–1773

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu S, Yuan D, Li Y, Qi Q, Guo B, Yang S et al (2019) Involvement of phosphatase and tensin homolog in cyclin-dependent kinase 4/6 inhibitor-induced blockade of glioblastoma. Front Pharmacol 10:1316

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK et al (2016) The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol 131:803–820

    Article  PubMed  Google Scholar 

  • Lv J, Liu H, Su J, Wu X, Liu H, Li B et al (2012) DiseaseMeth: a human disease methylation database. Nucleic Acids Res 40:D1030-1035

    Article  CAS  PubMed  Google Scholar 

  • Mayakonda A, Lin DC, Assenov Y, Plass C, Koeffler HP (2018) Maftools: efficient and comprehensive analysis of somatic variants in cancer. Genome Res 28:1747–1756

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mazor T, Chesnelong C, Pankov A, Jalbert LE, Hong C, Hayes J et al (2017) Clonal expansion and epigenetic reprogramming following deletion or amplification of mutant IDH1. Proc Natl Acad Sci U S A 114:10743–10748

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McCurdy SR, Pacal M, Ahmad M, Bremner R (2017) A CDK2 activity signature predicts outcome in CDK2-low cancers. Oncogene 36:2491–2502

    Article  CAS  PubMed  Google Scholar 

  • McDuff SGR, Dietrich J, Atkins KM, Oh KS, Loeffler JS, Shih HA (2020) Radiation and chemotherapy for high-risk lower grade gliomas: choosing between temozolomide and PCV. Cancer Med 9:3–11

    Article  CAS  PubMed  Google Scholar 

  • Miller TW, Traphagen NA, Li J, Lewis LD, Lopes B, Asthagiri A et al (2019) Tumor pharmacokinetics and pharmacodynamics of the CDK4/6 inhibitor ribociclib in patients with recurrent glioblastoma. J Neurooncol 144:563–572

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Modhukur V, Iljasenko T, Metsalu T, Lokk K, Laisk-Podar T, Vilo J (2018) MethSurv: a web tool to perform multivariable survival analysis using DNA methylation data. Epigenomics 10:277–288

    Article  CAS  PubMed  Google Scholar 

  • Noh SJ, Li Y, Xiong Y, Guan KL (1999) Identification of functional elements of p18INK4C essential for binding and inhibition of cyclin-dependent kinase (CDK) 4 and CDK6. Cancer Res 59:558–564

    CAS  PubMed  Google Scholar 

  • Nomura M, Saito K, Aihara K, Nagae G, Yamamoto S, Tatsuno K et al (2019) DNA demethylation is associated with malignant progression of lower-grade gliomas. Sci Rep 9:1903

    Article  PubMed  PubMed Central  Google Scholar 

  • Ohgaki H, Kleihues P (2005) Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas. J Neuropathol Exp Neurol 64:479–489

    Article  CAS  PubMed  Google Scholar 

  • Ostrom QT, Gittleman H, Truitt G, Boscia A, Kruchko C, Barnholtz-Sloan JS (2018) CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2011–2015. Neuro Oncol iv1–iv86

  • Pang FM, Yan H, Mo JL, Li D, Chen Y, Zhang L et al (2020) Integrative analyses identify a DNA damage repair gene signature for prognosis prediction in lower grade gliomas. Future Oncol 16:367–382

    Article  CAS  PubMed  Google Scholar 

  • Reis GF, Pekmezci M, Hansen HM, Rice T, Marshall RE, Molinaro AM et al (2015) CDKN2A loss is associated with shortened overall survival in lower-grade (World Health Organization Grades II-III) astrocytomas. J Neuropathol Exp Neurol 74:442–452

    Article  CAS  PubMed  Google Scholar 

  • Rosvall M, Axelsson D, Bergstrom CT (2009) The map equation. The European Physical Journal Special Topics 178:13–23

    Article  Google Scholar 

  • Schettini F, De Santo I, Rea CG, De Placido P, Formisano L, Giuliano M et al (2018) CDK 4/6 inhibitors as single agent in advanced solid tumors. Front Oncol 8:608

    Article  PubMed  PubMed Central  Google Scholar 

  • Taylor JW, Parikh M, Phillips JJ, James CD, Molinaro AM, Butowski NA et al (2018) Phase-2 trial of palbociclib in adult patients with recurrent RB1-positive glioblastoma. J Neurooncol 140:477–483

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tien AC, Li J, Bao X, Derogatis A, Kim S, Mehta S et al (2019) A phase 0 trial of ribociclib in recurrent glioblastoma patients incorporating a tumor pharmacodynamic- and pharmacokinetic-guided expansion cohort. Clin Cancer Res 25:5777–5786

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Turcan S, Rohle D, Goenka A, Walsh LA, Fang F, Yilmaz E et al (2012) IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature 483:479–483

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • van Veelen W, Klompmaker R, Gloerich M, van Gasteren CJ, Kalkhoven E, Berger R et al (2009) P18 is a tumor suppressor gene involved in human medullary thyroid carcinoma and pheochromocytoma development. Int J Cancer 124:339–345

    Article  PubMed  Google Scholar 

  • Wang H, Zhang X, Teng L, Legerski RJ (2015) DNA damage checkpoint recovery and cancer development. Exp Cell Res 334:350–358

    Article  CAS  PubMed  Google Scholar 

  • Wang J, Li B, Wang C, Luo Y, Zhao M, Chen P (2019) Long noncoding RNA FOXD2-AS1 promotes glioma cell cycle progression and proliferation through the FOXD2-AS1/miR-31/CDK1 pathway. J Cell Biochem 120:19784–19795

    Article  CAS  PubMed  Google Scholar 

  • Wang X, Tan Y, Li Y, Li J, Jin W, Wang K (2016) Repression of CDKN2C caused by PML/RARα binding promotes the proliferation and differentiation block in acute promyelocytic leukemia. Front Med 10:420–429

    Article  PubMed  Google Scholar 

  • Wharton SB, Chan KK, Anderson JR, Stoeber K, Williams GH (2001) Replicative Mcm2 protein as a novel proliferation marker in oligodendrogliomas and its relationship to Ki67 labelling index, histological grade and prognosis. Neuropathol Appl Neurobiol 27:305–313

    Article  CAS  PubMed  Google Scholar 

  • Wiedemeyer R, Brennan C, Heffernan TP, Xiao Y, Mahoney J, Protopopov A et al (2008) Feedback circuit among INK4 tumor suppressors constrains human glioblastoma development. Cancer Cell 13:355–364

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wilkerson MD, Hayes DN (2010) ConsensusClusterPlus: a class discovery tool with confidence assessments and item tracking. Bioinformatics 26:1572–1573

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu T, Dai Y (2017) Tumor microenvironment and therapeutic response. Cancer Lett 387:61–68

    Article  CAS  PubMed  Google Scholar 

  • Xiao K, Liu Q, Peng G, Su J, Qin CY, Wang XY (2020) Identification and validation of a three-gene signature as a candidate prognostic biomarker for lower grade glioma. PeerJ 8:e8312

    Article  PubMed  PubMed Central  Google Scholar 

  • Xiong Y, Wei Y, Gu Y, Zhang S, Lyu J, Zhang B et al (2017) DiseaseMeth version 2.0: a major expansion and update of the human disease methylation database. Nucleic Acids Res 45:D888-d895

    Article  CAS  PubMed  Google Scholar 

  • Xu G, Li JY (2018) CDK4, CDK6, cyclin D1, p16(INK4a) and EGFR expression in glioblastoma with a primitive neuronal component. J Neurooncol 136:445–452

    Article  CAS  PubMed  Google Scholar 

  • Zhang M, Wang X, Chen X, Zhang Q, Hong J (2020) Novel immune-related gene signature for risk stratification and prognosis of survival in lower-grade glioma. Front Genet 11:363

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang Q, Wang G, Xu L, Yao Z, Song L (2019) Long non-coding RNA LINC00473 promotes glioma cells proliferation and invasion by impairing miR-637/CDK6 axis. Artif Cells Nanomed Biotechnol 47:3896–3903

    Article  CAS  PubMed  Google Scholar 

  • Zhao L, Zhang J, Liu Z, Zhao P (2020) Identification of biomarkers for the transition from low-grade glioma to secondary glioblastoma by an integrated bioinformatic analysis. Am J Transl Res 12:1222–1238

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was Sponsored by Shanghai Sailing Program (20YF1427000) and Ruijin Youth NSCF Cultivation Fund (KY20194238).

Author information

Authors and Affiliations

  1. Department of Pharmacy, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China

    Qiongni Zhu

  2. Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, People’s Republic of China

    Ying Guo

  3. Department of Pharmacy, Peking University People’s Hospital, Beijing, 100044, China

    Lei Hu

  4. Department of Pharmaceutics, Shanghai Eighth People’s Hospital, Shanghai, 200235, China

    Zhimin Zhu

  5. Department of Anatomy and Cell Biology, The University of Western Ontario, London, ON, Canada

    Stephen James Renaud

Authors
  1. Qiongni Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhimin Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stephen James Renaud
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lei Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ying Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Qiongni Zhu, Zhimin Zhu, Lei Hu, and Ying Guo. The first draft of the manuscript was written by Qiongni Zhu and Lei Hu. Writing review and editing of the manuscript were done by Stephen James Renaud and Ying Guo. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Lei Hu or Ying Guo.

Ethics declarations

Ethics Approval

Not applicable.

Consent to Participate

Not applicable.

Competing Interests

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 6502 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhu, Q., Zhu, Z., Renaud, S.J. et al. The Oncogenic Role of Cyclin-Dependent Kinase Inhibitor 2C in Lower-Grade Glioma. J Mol Neurosci 73, 327–344 (2023). https://doi.org/10.1007/s12031-023-02120-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12031-023-02120-3

Keywords

Search

Navigation