Polo-Like Kinase 1 as Predictive Marker and Therapeutic Target for Radiotherapy in Rectal Cancer
| Autor: | Robina Bashary, Franz Rödel, Claus Rödel, Manfred Kaufmann, Birgit Spänkuch, Gianni Capalbo, Klaus Strebhardt, Sarah Keppner |
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| Rok vydání: | 2010 |
| Předmět: |
Pathology
medicine.medical_specialty Microarray Colorectal cancer medicine.medical_treatment Cell Cycle Proteins Caspase 3 Protein Serine-Threonine Kinases Biology Radiation Tolerance Pathology and Forensic Medicine Targeted therapy Radiation sensitivity Cell Line Tumor Proto-Oncogene Proteins Biomarkers Tumor medicine Humans RNA Small Interfering Predictive marker Rectal Neoplasms Cancer Microarray Analysis medicine.disease Radiation therapy Cancer research Regular Articles |
| Zdroj: | The American Journal of Pathology. 177:918-929 |
| ISSN: | 0002-9440 |
| DOI: | 10.2353/ajpath.2010.100040 |
| Popis: | The ability to predict tumor sensitivity toward radiotherapy may significantly impact the selection of patients for preoperative combined-modality therapy. The aim of the present study was to test the predictive value of Polo-like kinase 1 (PLK1) in rectal cancer patients and to investigate whether PLK1 plays a direct role in mediating radiation sensitivity. PLK1 expression was evaluated by immunohistochemistry (n = 76) or Affymetrix HG133 microarray (n = 20) on pretreatment biopsies of patients with advanced rectal cancer. Expression was correlated with both tumor regression in the resected specimen and long-term clinical outcome. Furthermore, we used small interfering RNAs (siRNAs) to down-regulate PLK1 expression in colorectal cancer cells and analyzed the effects of PLK1-specific siRNAs by Western blot and quantitative real-time PCR analysis, FACScan analysis, caspase 3/7 assays, and colony-forming assays. We observed that increased PLK1 protein expression was significantly related to a poorer tumor regression and a higher risk of local recurrence in uni- and multivariate analysis. A significant decrease of PLK1 expression by siRNAs in combination with ionizing radiation induced an increased percentage of apoptotic cells and increased caspase 3/7 activity. Furthermore, enhanced G(2)-M levels, decreased cellular viability, and reduced clonogenic survival were demonstrated, indicating a radiosensitizing effect of PLK1 depletion. Therefore, PLK1 may be a novel predictive marker for radiation response as well as a promising therapeutic target in rectal cancer patients. |
| Databáze: | OpenAIRE |
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