Higher expression of XPF is a critical factor in intrinsic chemotherapy resistance of human renal cell carcinoma. Issue 12 (16th September 2016)

• Record Type: Journal Article
• Authors: Zhang, Qiao; Shi, Jiazhong; Yuan, Fang; Wang, Huanhuan; Fu, Weihua; Pan, Jinhong; Huang, Yaqin; Yu, Jin; Yang, Jin; Chen, Zhiwen
• Is Part Of: International journal of cancer. Volume 139:Issue 12(2016:Dec. 15)
• Page Start: 2827
• Page End: 2837
• Publication Date: 2016-09-16
• Subjects: renal cancer -- chemoresistance -- XPF; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.30396
• Languages: English
• ISSNs: 0020-7136

Abstract

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. Abstract : What's new? Human renal cell carcinoma (RCC) is extremely resistant to chemotherapy, due to mechanisms that are poorly understood. In this study, the authors found that expression of the XPF excision‐repair gene was significantly higher in RCC than in bladder or testicular cancer. Knockdown of XPF expression increased the sensitivity of RCC cells to cisplatin by affecting the DNA‐damage response, and also increased survival in vivo. These results suggest that XPF may be a potential therapeutic target for overcoming chemoresistance in RCC.