Oncotarget

Research Papers:

Significance of cyclin D1 overexpression in progression and radio-resistance of pediatric ependymomas

Muh-Lii Liang, Tsung-Han Hsieh, Yun-Ru Liu, Yi-Wei Chen, Yi-Yen Lee, Feng-Chi Chang, Shih-Chieh Lin, Ming-Chao Huang, Donald Ming-Tak Ho, Tai-Tong Wong, Yun Yen and Muh-Hwa Yang _

PDF  |  HTML  |  Supplementary Files  |  How to cite  |  Order a Reprint

Oncotarget. 2018; 9:2527-2542. https://doi.org/10.18632/oncotarget.23509

Metrics: PDF 413 views  |   HTML 1183 views  |   ?  


Abstract

Muh-Lii Liang1,2, Tsung-Han Hsieh3,4, Yun-Ru Liu3,4, Yi-Wei Chen5, Yi-Yen Lee1, Feng-Chi Chang6, Shih-Chieh Lin7, Ming-Chao Huang1, Donald Ming-Tak Ho7, Tai-Tong Wong3,8,9,10, Yun Yen3,11,12 and Muh-Hwa Yang2,13,14,15,16

1Division of Pediatric Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan

2Institutes of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan

3Comprehensive Cancer Center of Taipei Medical University, Taipei Medical University, Taipei, Taiwan

4Joint Biobank, Office of Human Research, Taipei Medical University, Taipei, Taiwan

5Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan

6Department of Radiology, Taipei Veterans General Hospital, Taipei, Taiwan

7Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan

8Department of Neurosurgery, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan

9Neuroscience Research Center, Taipei Medical University Hospital, Taipei, Taiwan

10Institutes of Clinical Medicine, Taipei Medical University, Taipei, Taiwan

11PhD Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan

12Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan

13Cancer Research Center & Genome Research Center, National Yang-Ming University, Taipei, Taiwan

14Immunity and Inflammation Research Center, National Yang-Ming University, Taipei, Taiwan

15Division of Hematology-Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan

16Genomic Research Center, Academia Sinica, Taipei, Taiwan

Correspondence to:

Muh-Hwa Yang, email: mhyang2@ym.edu.tw

Yun Yen, email: yyen@tmu.edu.tw

Keyword: ependymoma; pediatric; radio-resistance; CCND1

Received: June 23, 2017     Accepted: December 13, 2017     Published: December 20, 2017

ABSTRACT

Due to the limited efficacy of chemotherapy, the applications of adjuvant irradiation play an important role for ependymoma treatment. However, in the young ages, the resistance of residual and recurrent tumor, and long-term intellectual sequelae remain the major obstacles of radiotherapy. Understanding the mechanism of therapeutic failure caused by radio-resistance is, therefore, crucial in ependymoma treatment. Here we retrospectively analyze clinic-pathological factors in 82 cases of ependymoma less than 20 years old and identify radio-resistant genes through gene expression microarray followed by qRT-PCR validation and immunohistochemistry staining. Thirty-one out of 82 (37.8%) patients are under 3-year-old. The 10 years PFS and OS are 38% and 60%. Gross-total resection is the single significant prognostic factor for longer 10 years PFS and OS in the multivariant analysis (p<0.05). According to the microarray analysis, CCND1 is up-regulated in supratentorial and infratentorial ependymomas and is associated with DNA repair. We demonstrated that 24 primary and 16 recurrent ependymomas were up-regulated, and 5 out of 7 paired samples exhibited higher CCND1 expression in recurrent tumors. We also found RAD51, another DNA repair gene, was up-regulated in supratentorial and infratentorial ependymomas. Knocking down CCND1 reduced cell proliferation and repressed several genes associated with S-phase and DNA repair. Homologous recombination activities of DNA repair were significantly decreased in CCND1-deficient cells while the level of γH2AX was increased after irradiation. In summary, these observations suggest a robust role of CCND1 in regulating cell proliferation and radio-resistance in ependymomas, providing a potential therapeutic target for pediatric ependymomas.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 23509