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- Title
Cell Cycle-Related Kinase: A Novel Candidate Oncogene in Human Glioblastoma.
- Authors
Ng, Samuel S. M.; Yuen-Ting Cheung; Xiao-Meng An; Yang Chao Chen; Ming Li; Hoi-Yee Li, Gloria; Cheung, William; Sze, Johnny; Lihui Lai; Ying Peng; Xia, Harry H. X.; Wong, Benjamin C. Y.; Suet-Yi Leung; Dan Xie; Ming-Liang He; Hsiang-Fu Kung; Lin, Marie C.
- Abstract
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% Cl = 977 to 1739 mm³, P<.001). Conclusions CCRK is a candidate oncogene in glioblastoma multiforme tumorigenesis.
- Subjects
CELL cycle; GLIOBLASTOMA multiforme; ONCOGENES; POLYMERASE chain reaction; DRUG therapy; RADIOTHERAPY
- Publication
JNCI: Journal of the National Cancer Institute, 2007, Vol 99, Issue 12, p936
- ISSN
0027-8874
- Publication type
Article
- DOI
10.1093/jnci/djm011