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Amplification/overexpression of a mitotic kinase gene in human bladder cancer
Subrata Sen1, Hongyi Zhou, Ruo-Dan Zhang
1Division of Pathology and Laboratory Medicine, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
Background:
The mitotic kinase-encoding gene STK15/BTAK/ AuroraA is associated with aneuploidy and transformation when overexpressed in mammalian cells. STK15 overexpression activates an unknown oncogenic pathway that involves centrosome amplification and results in missegregation of chromosomes. Because clinical prognosis and tumor aneuploidy are tightly linked in human bladder cancer, we examined whether increased STK15 copy number and protein levels are linked to aneuploidy in bladder cancers.
Methods:
STK15 protein was visualized by immunohistochemistry in 205 formalin-fixed, paraffin-embedded human bladder tumors. STK15 gene copy number was evaluated in 61 tumors by Southern blot hybridization and in 21 of these 61 tumors by fluorescence in situ hybridization (FISH). Copy numbers of chromosomes 3, 17, 20, and 21 were evaluated by FISH with chromosome-specific probes. STK15 expression levels were related to histologic grade, stage, and DNA ploidy of the tumors and to the patients' follow-up data. The chi-square test for association was used to analyze the relationship between STK15 expression and pathologic features. All statistical tests were two-sided.
Results:
Tumors with low levels of STK15 amplification (3-4 copies) showed minimal deviation in their chromosome copy number and diploid or near-diploid total nuclear DNA content. Tumors with higher levels of STK15 amplification (>4 copies) had a major increase of chromosome copy number and of their total nuclear DNA content, i.e., exhibited pronounced aneuploidy. Elevated expression of STK15 was strongly associated with parameters of clinical aggressiveness including high histologic grade (P<.001), invasion (P<.001), increased rate of metastasis (P<.001), and decreased metastasis-free (P<.001) and overall (P<.001) survival of patients with bladder cancer.
Conclusion:
STK15 gene amplification and associated increased expression of the mitotic kinase it encodes are associated with aneuploidy and aggressive clinical behavior in human bladder cancer.
Insights
STK15 gene amplification correlates with increased aneuploidy and aggressive features in bladder cancer. This mitotic kinase overexpression is linked to poorer patient survival and increased metastasis, indicating its oncogenic role.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- STK15 (STK15/BTAK/AuroraA) is a mitotic kinase gene linked to aneuploidy and cell transformation when overexpressed.
- Overexpression of STK15 activates oncogenic pathways, causing centrosome amplification and chromosome missegregation.
- Aneuploidy and clinical prognosis are strongly correlated in human bladder cancer.
Purpose of the Study:
- To investigate the association between STK15 gene copy number and protein levels with aneuploidy in human bladder cancers.
- To determine if STK15 alterations correlate with clinical aggressiveness and patient outcomes in bladder cancer.
Main Methods:
- Immunohistochemistry used to assess STK15 protein levels in 205 bladder tumors.
- STK15 gene copy number analyzed by Southern blot and FISH in tumor samples.
- FISH used to evaluate copy numbers of chromosomes 3, 17, 20, and 21.
- STK15 expression correlated with tumor grade, stage, DNA ploidy, and patient follow-up data.
Main Results:
- Tumors with STK15 amplification (>4 copies) exhibited significant increases in chromosome copy number and DNA content, indicating pronounced aneuploidy.
- Elevated STK15 expression strongly correlated with high histologic grade, invasion, and increased metastasis.
- Increased STK15 expression was associated with decreased metastasis-free and overall survival in bladder cancer patients.
Conclusions:
- STK15 gene amplification and elevated expression are linked to aneuploidy in human bladder cancer.
- Increased STK15 expression is a marker of aggressive clinical behavior and poor prognosis in bladder cancer.
- STK15 plays a significant role in the development and progression of bladder cancer.