title: Inhibition of STAT1 sensitizes renal cell carcinoma cells to radiotherapy and chemotherapy.
abstract: Renal cell carcinoma is resistant to chemotherapy and radiotherapy. STAT1 is overexpressed in human RCC tissue. Downregulation of STAT1 expression could significantly increase the radiosensitivity in RCC cell lines. To further investigate the function of STAT1 in RCC resistance to chemoradiotherapy, a stable STAT1 knockdown cell line was established. Knockdown of STAT1 led to significant growth suppression in vitro and in vivo. Inhibition of STAT1 sensitized 786-O cells to radiotherapy and Taxol treatment. Cells with low STAT1 expression accumulated more strongly in the G 2/M phase after treatment with chemotherapy and radiotherapy. The Human Cell Cycle and DNA Damage Signaling Pathway Real-time PCR arrays were performed and 3 genes upregulated and 16 genes downregulated after STAT1 knockdown were selected. Functional gene grouping showed that genes involved in the M phase, S phase and DNA replication did not differ between the two cell lines. G 1 phase related genes ANAPC2, CCNE1, CUL1 were downregulated, and G 2/M checkpoint genes p21, GADD45A and Rb were strongly reduced by STAT1 knockdown. DNA damage-related genes GADD45A, MAP2K6, were significantly downregulated. The results prove that overexpression of STAT1 in human RCC is associated with the chemoradioresistance. Targeting of STAT1 might be a potential strategy to sensitize RCC to chemotherapy and radiotherapy.
authors.affiliation: Laboratory of Cell and Molecular Biology, State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences; Beijing, China.
authors.forename: Hongxia
authors.initials: H
authors.lastname: Zhu
authors.forename: Zaozao
authors.initials: Z
authors.lastname: Wang
authors.forename: Qing
authors.initials: Q
authors.lastname: Xu
authors.forename: Ye
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yirui
authors.initials: Y
authors.lastname: Zhai
authors.forename: Jinfeng
authors.initials: J
authors.lastname: Bai
authors.forename: Mei
authors.initials: M
authors.lastname: Liu
authors.forename: Zhouguang
authors.initials: Z
authors.lastname: Hui
authors.forename: Ningzhi
authors.initials: N
authors.lastname: Xu
mesh_terms: D000818:Animals; D001483:Base Sequence; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy*; D018797:Cell Cycle Proteins / Q000235:genetics; D002455:Cell Division / Q000235:genetics; D044842:Cullin Proteins / Q000235:genetics; D019927:Cyclin E / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy*; D048669:MAP Kinase Kinase 6 / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics; D015513:Oncogene Proteins / Q000235:genetics; D017239:Paclitaxel / Q000494:pharmacology; D011836:Radiation Tolerance / Q000235:genetics; D016196:S Phase / Q000235:genetics; D050794:STAT1 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D000097642:GADD45 Proteins
chemical_list: D018797:Cell Cycle Proteins; D044842:Cullin Proteins; D019927:Cyclin E; D050759:Cyclin-Dependent Kinase Inhibitor p21; D048669:MAP Kinase Kinase 6; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D017239:Paclitaxel; D050794:STAT1 Transcription Factor; C475820:CCNE1 protein, human; C493956:CDKN1A protein, human; C100318:Cullin 1; C439070:GADD45A protein, human; D000097642:GADD45 Proteins; C494079:STAT1 protein, human; C482566:MAP2K6 protein, human