Radiosensitization by Inhibiting STAT1 in Renal Cell Carcinoma
Journal Article
·
· International Journal of Radiation Oncology, Biology and Physics
OSTI ID:21172566
- Department of Radiology, Division of Radiation Oncology, Baylor College of Medicine, Houston, TX (United States)
- Department of Pathology, University of Chicago Pritzker School of Medicine, Chicago, IL (United States)
- Laboratory of Cancer Genetics, Van Andel Research Institute, Grand Rapids, MI (United States)
- Laboratory of Computational Biology, Van Andel Research Institute, Grand Rapids, MI (United States)
- Department of Genitourinary Oncology, Methodist Hospital, Houston, TX (United States)
- Department of Radiation Oncology, Methodist Hospital and Methodist Hospital Research Institute, Houston, TX (United States)
Purpose: Renal cell carcinoma (RCC) has been historically regarded as a radioresistant malignancy, but the molecular mechanism underlying its radioresistance is not understood. This study investigated the role of signal transducer and activator of transcription 1 (STAT1), a transcription factor downstream of the interferon-signaling pathway, in radioresistant RCC. Methods and Materials: The expressions of STAT1 and STAT3 in 164 human clear cell RCC samples, 47 papillary RCC samples, and 15 normal kidney tissue samples were examined by microarray expression profiling and immunohistochemistry. Western blotting was performed to evaluate the total and phosphorylated STAT1 expression in CRL-1932 (786-O) (human clear cell RCC), SKRC-39 (human papillary RCC), CCL-116 (human fibroblast), and CRL-1441 (G-401) (human Wilms tumor). STAT1 was reduced or inhibited by fludarabine and siRNA, respectively, and the effects on radiation-induced cell death were investigated using clonogenic assays. Results: STAT1 expression, but not STAT3 expression, was significantly greater in human RCC samples (p = 1.5 x 10{sup -8} for clear cell; and p = 3.6 x 10{sup -4} for papillary). Similarly, the expression of STAT1 was relatively greater in the two RCC cell lines. STAT1 expression was reduced by both fludarabine and siRNA, significantly increasing the radiosensitivity in both RCC cell lines. Conclusion: This is the first study reporting the overexpression of STAT1 in human clear cell and papillary RCC tissues. Radiosensitization in RCC cell lines was observed by a reduction or inhibition of STAT1 signaling, using fludarabine or siRNA. Our data suggest that STAT1 may play a key role in RCC radioresistance and manipulation of this pathway may enhance the efficacy of radiotherapy.
- OSTI ID:
- 21172566
- Journal Information:
- International Journal of Radiation Oncology, Biology and Physics, Journal Name: International Journal of Radiation Oncology, Biology and Physics Journal Issue: 1 Vol. 73; ISSN IOBPD3; ISSN 0360-3016
- Country of Publication:
- United States
- Language:
- English
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