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.

The Drug-Resistance Mechanisms of Five Platinum-Based Antitumor Agents

“…However, Spada et al reported that ERCC1 had no significant correlation with the clinical outcome with oxaliplatin-based chemotherapy in advanced neuroendocrine tumors (Spada et al, 2016). ERCC4 (XPF), a necessary component in NER, interstrand cross-links repair, homologous recombination repair (HRR) but not in nonhomologous end-joining (Lehmann et al, 2017), contributes to the intrinsic resistance of cisplatin, and its expression level is tissue-specific (Zhang et al, 2016a). ERCC1 and XPF can form the human ERCC1-XPF complex which works as a nuclease in NER and the late stage of HRR (Gillet and Scharer, 2006;Al-Minawi et al, 2009).…”

Notch signaling plays a crucial role in cancer stem-like cells maintaining stemness and mediating chemotaxis in renal cell carcinoma

“…Moreover, RCC recurs within the first 5 years in 40% of patients with an initially localized disease even after a nephrectomy [1]. Besides, renal cancer is extremely resistant to chemotherapy and radiation therapy [7]. It is gradually accepted that the initiation, chemoresistance, metastasis and recurrence of tumors are driven by a small subpopulation of cells endowed with stem-like properties called cancer stem cells (CSCs).…”

Betulinic acid induces apoptosis and inhibits metastasis of human renal carcinoma cells in vitro and in vivo

“…Despite great advances in the diagnosis and treatment of RCC, the overall survival remains poor. Tremendous metastatic potential and considerable chemotherapy resistance are responsible for the poor prognosis of RCC patients to a great extent . Thus, it is an urgent demand to develop novel therapeutic strategies for the therapy of RCC.…”

“…It was estimated that 62 700 new cases of RCC were diagnosed and 14 240 patients died from RCC in the United States in 2016 . Considerable metastatic potential and chemotherapy resistance may account for the high mortality of RCC in a large part . It is well known that surgical resection, followed by chemotherapy and radiotherapy, remains the primary therapeutic approach for RCC .…”