Journal of the National Cancer Institute Advance Access originally published online on June 12, 2007
JNCI Journal of the National Cancer Institute 2007 99(12):936-948; doi:10.1093/jnci/djm011
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© The Author 2007. Published by Oxford University Press.
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Cell Cycle–Related Kinase: A Novel Candidate Oncogene in Human Glioblastoma
Affiliations of authors: Department of Chemistry, Open Laboratory of Chemical Biology, The University of Hong Kong, Pokfulam, Hong Kong, China (SSMN, YTC, XMA, ML, GHYL, WC, JS, MCL); The State Key Laboratory of Oncology in Southern China, Cancer Center, Sun Yat-Sen University, Guangzhou, China (YCC, DX, HFK); Stanley Ho Centre for Emerging Infectious Diseases, The Chinese University of Hong Kong, Shatin, Hong Kong, China (YCC, MLH, HFK); Institute of Molecular and Chemical Biology, East China Normal University, Shanghai, China (LL); Department of Neurology, The Second Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China (YP); Departments of Medicine (HHXX, BCYW) and Pathology (SYL), Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China
Correspondence to: Marie C. Lin, PhD, Department of Chemistry, Open Laboratory of Chemical Biology, The University of Hong Kong, Pokfulam, Hong Kong, China (e-mail: mcllin{at}hkusua.hku.hk) or Hsiang-Fu Kung, PhD, Centre for Emerging Infectious Diseases, The Chinese University of Hong Kong, Shatin, Hong Kong, China (e-mail: hkung{at}cuhk.edu.hk).
Background: Median survival for patients with glioblastoma multiforme, the most aggressive glioma, is only 12–15 months, despite multimodal treatment that includes surgery, chemotherapy, and radiotherapy. Thus, identification of genes that control the progression of glioblastoma multiforme is crucial for devising new therapies. We investigated the involvement of cell cycle–related kinase (CCRK), a novel protein kinase that is homologous to cyclin-dependent kinase 7, in glioblastoma multiforme carcinogenesis.
Methods: We analyzed the expression levels of CCRK in 26 glioma patient samples (19 high-grade and seven low-grade) and normal brain by semiquantitative reverse transcription–polymerase chain reaction assays. CCRK expression was knocked down in human glioma U-373 MG and U-87 MG cells with small-interfering RNAs and short hairpin RNAs (siCCRK and shCCRK, respectively), and cell proliferation, cell cycle distribution, and cyclin-dependent kinase 2 (CDK2) phosphorylation were examined. A subcutaneous nude mouse xenograft model (n = 4 mice per group) was used to study the effect of CCRK knockdown and overexpression on tumorigenicity and growth of glioblastoma multiforme cells in vivo. All statistical tests were two-sided.
Results: CCRK mRNA was elevated at least 1.5-fold and as much as 3.7-fold in 14 (74%) of 19 high-grade glioblastoma multiforme patient samples and in four (80%) of five glioma cell lines examined compared with normal brain tissue. Suppression of CCRK by siCCRK inhibited the proliferation of U-373 MG and U-87 MG glioblastoma cells in a time- and dose-dependent manner. The growth-inhibiting effect of siCCRK was mediated via G1- to S-phase cell cycle arrest and reduced CDK2 phosphorylation. CCRK knockdown statistically significantly suppressed glioma cell growth in vivo as indicated by the mean tumor volumes at week 6 after tumor cell injection (U-373-control = 1352 mm3, U-373-shCCRK = 294 mm3, difference = 1058 mm3, 95% confidence interval [CI] = 677 to 1439 mm3, P<.001; U-87-control = 1910 mm3, U-87-shCCRK = 552 mm3, difference = 1358 mm3, 95% CI = 977 to 1739 mm3, P<.001).
Conclusions: CCRK is a candidate oncogene in glioblastoma multiforme tumorigenesis.
| CONTEXT AND CAVEATS Prior knowledge Identification of genes that control the progression of glioblastoma multiforme, the most aggressive glioma, is needed to devise new therapies for patients with this cancer. Cell cycle–related kinase (CCRK), a novel protein kinase that is homologous to cyclin-dependent kinase 7, has been implicated in cancer cell proliferation, but its role in glioblastoma multiforme carcinogenesis is unknown. Study design Molecular study in human glioma cell lines, samples from glioma patients, normal brain tissue, and mouse xenograft models. Contribution Increased glioma cell proliferation and tumorigenicity were associated with the overexpression of CCRK, whereas suppression of CCRK expression was associated with the inhibition of glioma xenograft tumor growth. Implications CCRK is a candidate oncogene in glioblastoma multiforme tumorigenesis. Limitations The small number of patient samples precluded analysis of the association between CCRK expression and patient survival. The mechanistic evidence for how CCRK regulates cell cycle progression was indirect.
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Manuscript received November 8, 2006; revised April 20, 2007; accepted May 8, 2007.
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