title: Higher expression of XPF is a critical factor in intrinsic chemotherapy resistance of human renal cell carcinoma.
abstract: Human renal cancer is extremely resistant to chemotherapy and radiation therapy. This clinical characteristic reduces the efficacy of chemotherapeutic agents in the treatment of recurrence or metastasis following surgical resection. Understanding the mechanism of chemotherapy resistance in renal cell carcinoma remains a significant challenge. In this study, we have shown that varied level of XPF expression was organ-tissue specific by comparing human renal cancer, bladder cancer, testicular cancer and their normal tissue counterparts, respectively. The expression of XPF was significantly higher in renal cancer than in bladder cancer and testicular cancer and correlated with the clinical characteristic of their chemotherapeutics sensitivity. These novel findings proposed that the intrinsic chemoresistance of human renal cell carcinomas might be derived from the high level of XPF expression. In a panel of five cancer cell lines, decreasing cisplatin sensitivity correlated with increasing levels of XPF expression. Knockdown of XPF expression not only increased sensitivity of renal carcinoma cells to cisplatin treatment by affecting the DNA damage response, including DNA repair, cell cycle regulation and apoptosis, but also increased senescence of renal cancer cell. Furthermore, experiment in vivo confirmed that silenced XPF significantly increased the sensitivity and survival following treatment with cisplatin in xenograft mice bearing renal cell tumor. These findings firstly uncover a partial mechanism of intrinsic chemoresistance in renal cancer and may provide a new approach to break through the obstacle of intrinsic chemoresistance by targeting the XPF protein with a potential new inhibitor.
authors.affiliation: Department of Cell Biology, The Third Military Medical University, Chongqing, China.
authors.forename: Qiao
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Cell Biology, The Third Military Medical University, Chongqing, China.
authors.forename: Jiazhong
authors.initials: J
authors.lastname: Shi
authors.affiliation: Department of Urology, Chongqing Oncology Hospital, Chongqing, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Yuan
authors.affiliation: Department of Cell Biology, The Third Military Medical University, Chongqing, China.
authors.forename: Huanhuan
authors.initials: H
authors.lastname: Wang
authors.affiliation: Urology Institute of PLA, Southwest Hospital, The Third Military Medical University, Chongqing, China.
authors.forename: Weihua
authors.initials: W
authors.lastname: Fu
authors.affiliation: Urology Institute of PLA, Southwest Hospital, The Third Military Medical University, Chongqing, China.
authors.forename: Jinhong
authors.initials: J
authors.lastname: Pan
authors.affiliation: Department of Cell Biology, The Third Military Medical University, Chongqing, China.
authors.forename: Yaqin
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Cell Biology, The Third Military Medical University, Chongqing, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Cell Biology, The Third Military Medical University, Chongqing, China. jinyang@tmmu.edu.cn.
authors.forename: Jin
authors.initials: J
authors.lastname: Yang
authors.affiliation: Urology Institute of PLA, Southwest Hospital, The Third Military Medical University, Chongqing, China. zhiwen@tmmu.edu.cn.|Southwest Cancer Center, Southwest Hospital, The Third Military Medical University, Chongqing, China. zhiwen@tmmu.edu.cn.
authors.forename: Zhiwen
authors.initials: Z
authors.lastname: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics; D002945:Cisplatin / Q000494:pharmacology; D004260:DNA Repair / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D051379:Mice; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; C095888:xeroderma pigmentosum group F protein; D002945:Cisplatin
keywords: XPF; chemoresistance; renal cancer