Radiosensitization by inhibiting STAT1 in renal cell carcinoma.
OBJECTIVE
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
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(-8) for clear cell; and p = 3.6 x 10(-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.


CONCLUSIONS
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.
Hui
Zhouguang
Z
Department of Radiology, Division of Radiation Oncology, Baylor College of Medicine, Houston, TX, USA.
Tretiakova
Maria
M
Zhang
Zhongfa
Z
Li
Yan
Y
Wang
Xiaozhen
X
Zhu
Julie Xiaohong
JX
Gao
Yuanhong
Y
Mai
Weiyuan
W
Furge
Kyle
K
Qian
Chao-Nan
CN
Amato
Robert
R
Butler
E Brian
EB
Teh
Bin Tean
BT
Teh
Bin S
BS
D000970:Antineoplastic Agents / Q000008:administration & dosage; D002292:Carcinoma, Renal Cell / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects* / Q000528:radiation effects*; D006801:Humans; D007680:Kidney Neoplasms / Q000378:metabolism* / Q000473:pathology*; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage*; D050794:STAT1 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives*
D000970:Antineoplastic Agents; D011838:Radiation-Sensitizing Agents; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D014740:Vidarabine; C024352:fludarabine