title: Radiosensitization by inhibiting STAT1 in renal cell carcinoma.
abstract: 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.
authors.affiliation: Department of Radiology, Division of Radiation Oncology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Zhouguang
authors.initials: Z
authors.lastname: Hui
authors.forename: Maria
authors.initials: M
authors.lastname: Tretiakova
authors.forename: Zhongfa
authors.initials: Z
authors.lastname: Zhang
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Xiaozhen
authors.initials: X
authors.lastname: Wang
authors.forename: Julie Xiaohong
authors.initials: JX
authors.lastname: Zhu
authors.forename: Yuanhong
authors.initials: Y
authors.lastname: Gao
authors.forename: Weiyuan
authors.initials: W
authors.lastname: Mai
authors.forename: Kyle
authors.initials: K
authors.lastname: Furge
authors.forename: Chao-Nan
authors.initials: CN
authors.lastname: Qian
authors.forename: Robert
authors.initials: R
authors.lastname: Amato
authors.forename: E Brian
authors.initials: EB
authors.lastname: Butler
authors.forename: Bin Tean
authors.initials: BT
authors.lastname: Teh
authors.forename: Bin S
authors.initials: BS
authors.lastname: Teh
mesh_terms: 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*
chemical_list: D000970:Antineoplastic Agents; D011838:Radiation-Sensitizing Agents; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D014740:Vidarabine; C024352:fludarabine