Radiosensitization by Inhibiting STAT1 in Renal Cell Carcinoma

Zhouguang Hui, Maria Tretiakova, Zhongfa Zhang, Yan Li, Xiaozhen Wang, Julie Xiaohong Zhu, Yuanhong Gao, Weiyuan Mai, Kyle Furge, Chao Nan Qian, Robert Amato, E. Brian Butler, Bin Tean Teh, Bin S. Teh

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

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 × 10-8 for clear cell; and p = 3.6 × 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. 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.

Original languageEnglish (US)
Pages (from-to)288-295
Number of pages8
JournalInternational Journal of Radiation Oncology Biology Physics
Volume73
Issue number1
DOIs
StatePublished - Jan 1 2009

Keywords

  • Gene expression
  • Radiosensitization
  • Renal cell carcinoma
  • Signal transducer and activator of transcription 1
  • siRNA
  • STAT1

ASJC Scopus subject areas

  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Radiation
  • Cancer Research

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