PARPi increases radiotherapy sensitivity of esophageal squamous cell carcinoma by inhibiting XRCC1 expression

Abstract

This study investigated the effect of poly-ADP ribose polymerase inhibitor (PARPi) on X-ray repair cross complementing 1 gene (XRCC1) expression and radiotherapy sensitivity of esophageal squamous cell carcinoma (ESCC). Tissue samples from patients with ESCC treated with irradiation using a linear accelerator were collected to detect the expression of XRCC1 and PARP-1 with immunohistochemical staining, and the effect of their expression on radiotherapy efficacy was evaluated. A linear accelerator was used to irradiate ECA109 cells after treatment with different concentrations of AZD2281 (a PARP inhibitor) to detect the radiotherapy sensitization ratio (SER) of PARPi. An RT-PCR assay was used to assess the relative expression of XRCC1 mRNA in ECA109 cells treated with irradiation and AZD2281 and to explore the effect of PARPi on the transcription of the XRCC1 gene in ECA109 cells after irradiation. Our data indicated that the objective response rate (ORR) of XRCC1-positive patients was lower than that of XRCC1-negative patients (38.1% vs. 88.9%, p=0.017), while the ORR of PARP-1-positive patients was lower than that of PARP-1-negative patients (36.8% vs. 81.8%, p=0.026). The SER of the cells treated with irradiation and AZD2281 at a concentration of 3 μmol/L was 1.744, implying that AZD2281 can enhance the irradiation damage of ECA109 cells. The relative expression level of XRCC1 mRNA increased significantly at 48 h after irradiation; however, when combined with PARPi, the radiation-induced up-regulation of XRCC1 mRNA was inhibited. The results of this study showed that patients with ESCC with a high expression of XRCC1 and PARP-1 display poor short-term radiotherapy efficacy and that irradiation can induce XRCC1 gene transcription. AZD2281 effectively inhibited the radiation-induced up-regulation of XRCC1 expression and increased the radiosensitivity of ECA109 cells. A possible mechanism is that PARPi inhibited DNA-PKcs and then down-regulated XRCC1 expression. These results suggest that PARPi may increase the radiotherapy sensitivity of patients with ESCC by inhibiting XRCC1 expression and reducing DNA damage repair.

Keywords

• esophageal squamous cell carcinoma
• radiotherapy sensitivity
• poly(adp-ribose)polymerase inhibitor
• x-ray cross complementing gene-1