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

LI Yiping; ZHANG Yufei; SUN Guangzhi; YE Yunyao; SHEN Xiaozhou; HAN Gaohua

doi:10.11889/j.1000-3436.2022-0122

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

RADIOBIOLOGY AND RADIOMEDICINE | 更新时间：2023-06-21

- PARPi increases radiotherapy sensitivity of esophageal squamous cell carcinoma by inhibiting XRCC1 expression
- Journal of Radiation Research and Radiation Processing Vol. 41, Issue 3, Pages: 30303(2023)
- 作者机构：
  
  1.南京医科大学附属泰州人民医院肿瘤科泰州 225300
  2.南京医科大学附属泰州人民医院放疗中心泰州 225300
- 作者简介：
  
  LI Yiping (female) was born in September 1980 and received her bachelor's degree in medicine from Nanjing Medical University in 2010, majoring in radiation damage protection
  HAN Gaohua, chief physician, E-mail: danny_75@njmu.edu.cn
- 基金信息：
  
  the Health Top Talent Project of“Six One Projects”in Jiangsu Province(LGY2019038);the“311 Project”of Taizhou City(RCPY201813)
- DOI：10.11889/j.1000-3436.2022-0122
  CLC：
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LI Yiping, ZHANG Yufei, SUN Guangzhi, et al. PARPi increases radiotherapy sensitivity of esophageal squamous cell carcinoma by inhibiting XRCC1 expression. [J]. Journal of Radiation Research and Radiation Processing 41(3):030303(2023)
DOI：

LI Yiping, ZHANG Yufei, SUN Guangzhi, et al. PARPi increases radiotherapy sensitivity of esophageal squamous cell carcinoma by inhibiting XRCC1 expression. [J]. Journal of Radiation Research and Radiation Processing 41(3):030303(2023) DOI： 10.11889/j.1000-3436.2022-0122.

摘要

探讨PARP抑制剂（PARPi）对XRCC1的表达以及对食管鳞癌（ESCC）放射治疗敏感性的影响。收集接受直线加速器辐照治疗的ESCC患者组织标本，免疫组化法检测其中XRCC1、PARP-1表达，观察其表达对ESCC患者放疗近期疗效的影响。ECA109细胞经AZD2281（PARP抑制剂）处理后接受加速器辐照，检测PARPi的放疗增敏比（SER）。利用RT-PCR实验检测AZD2281联合辐照后XRCC1mRNA转录情况，探讨PARPi对辐照后ECA109细胞XRCC1mRNA转录的影响。结果发现，XRCC1阳性者放疗的客观有效率（ORR）低于阴性者（38.1% ,vs,. 88.9%，,p,=0.017）；PARP-1阳性者放疗的ORR低于阴性者（36.8% ,vs., 81.8%， ,p,=0.026）。AZD2281的浓度为3 μmol/L时，联合组的SER=1.744。AZD2281可增强ECA109细胞的辐射损伤作用。辐射后48 h XRCC1mRNA相对表达量明显上升；联合PARPi可抑制辐射诱导的XRCC1mRNA表达上调。本组结果显示，XRCC1、PARP-1高表达者放疗近期疗效较差，放疗可诱导XRCC1基因转录，AZD2281能有效抑制辐射诱导的XRCC1 mRNA表达上调，其可能的机制是PARPi抑制DNA-PKcs进而下调XRCC1表达。该结果提示PARPi可能通过抑制XRCC1表达、减少DNA损伤修复，从而增加ESCC放疗敏感性。

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.

关键词

食管鳞癌放射敏感性聚（腺苷二磷酸核糖）聚合酶抑制剂X射线损伤修复基因-1

Keywords

Esophageal squamous cell carcinomaradiotherapy sensitivityPoly(ADP-ribose)polymerase inhibitorX-ray cross complementing gene-1

references

郑荣寿, 孙可欣, 张思维, 等. 2015年中国恶性肿瘤流行情况分析[J]. 中华肿瘤杂志, 2019, 41(1): 19-28. DOI: 10.3760/cma.j.issn.0253-3766.2019.01.008http://dx.doi.org/10.3760/cma.j.issn.0253-3766.2019.01.008.

ZHENG Rongshou, SUN Kexin, ZHANG Siwei, et al. Report of cancer epidemiology in China, 2015[J]. Chinese Journal of Oncology, 2019, 41(1): 19-28. DOI: 10.3760/cma.j.issn.0253-3766.2019.01.008http://dx.doi.org/10.3760/cma.j.issn.0253-3766.2019.01.008.

Tang Q, Çağlayan M. The scaffold protein XRCC1 stabilizes the formation of polβ/gap DNA and ligase Ⅲα/nick DNA complexes in base excision repair[J]. Journal of Biological Chemistry, 2021, 297(3): 101025. DOI: 10. 1016/j.jbc.2021.101025http://dx.doi.org/10.1016/j.jbc.2021.101025.

Gong L, Luo M, Sun R H, et al. Significant association between XRCC1 expression and its rs25487 polymorphism and radiotherapy-related cancer prognosis[J]. Frontiers in Oncology, 2021, 11: 654784. DOI: 10. 3389/fonc.2021.654784http://dx.doi.org/10.3389/fonc.2021.654784.

Thakur N, Yim K, Abdul-Ghafar J, et al. High poly(ADP-ribose) polymerase expression does relate to poor survival in solid cancers: a systematic review and meta-analysis[J]. Cancers, 2021, 13(22): 5594. DOI: 10.3390/cancers13225594http://dx.doi.org/10.3390/cancers13225594.

Zhang Y W, Dong S W, Xu R P, et al. Prognostic and predictive role of COX-2, XRCC1 and RASSF1 expression in patients with esophageal squamous cell carcinoma receiving radiotherapy[J]. Oncology Letters, 2017, 13(4): 2549-2556. DOI: 10.3892/ol.2017.5780http://dx.doi.org/10.3892/ol.2017.5780.

Niu Y J, Zhang X, Zheng Y X, et al. XRCC1 deficiency increased the DNA damage induced by γ-ray in HepG2 cell: involvement of DSB repair and cell cycle arrest[J]. Environmental Toxicology and Pharmacology, 2013, 36(2): 311-319. DOI: 10.1016/j.etap.2013.04.009http://dx.doi.org/10.1016/j.etap.2013.04.009.

Wu Z C, Miao X Y, Zhang Y F, et al. XRCC1 is a promising predictive biomarker and facilitates chemo-resistance in gallbladder cancer[J]. Frontiers in Molecular Biosciences, 2020, 7: 70. DOI: 10.3389/fmolb.2020. 00070http://dx.doi.org/10.3389/fmolb.2020.00070.

Hastak K, Bhutra S, Parry R, et al. Poly (ADP-ribose) polymerase inhibitor, an effective radiosensitizer in lung and pancreatic cancers[J]. Oncotarget, 2017, 8(16): 26344-26355. DOI: 10.18632/oncotarget.15464http://dx.doi.org/10.18632/oncotarget.15464.

Feng F Y, Speers C, Liu M L, et al. Targeted radiosensitization with PARP1 inhibition: optimization of therapy and identification of biomarkers of response in breast cancer[J]. Breast Cancer Research and Treatment, 2014, 147(1): 81-94. DOI: 10.1007/s10549-014-3085-5http://dx.doi.org/10.1007/s10549-014-3085-5.

Mueller S, Bhargava S, Molinaro A M, et al. Poly (ADP-Ribose) polymerase inhibitor MK-4827 together with radiation as a novel therapy for metastatic neuroblastoma[J]. Anticancer Research, 2013, 33(3): 755-762.

Demin A A, Hirota K, Tsuda M, et al. XRCC1 prevents toxic PARP1 trapping during DNA base excision repair[J]. Molecular Cell, 2021, 81(14): 3018-3030.e5. DOI: 10.1016/j.molcel.2021.05.009http://dx.doi.org/10.1016/j.molcel.2021.05.009.

Rashid I, Hammel M, Sverzhinsky A, et al. Direct interaction of DNA repair protein tyrosyl DNA phosphodiesterase 1 and the DNA ligase Ⅲ catalytic domain is regulated by phosphorylation of its flexible N-terminus[J]. Journal of Biological Chemistry, 2021, 297(2): 100921. DOI: 10.1016/j.jbc.2021.100921http://dx.doi.org/10.1016/j.jbc.2021.100921.

Vasil'eva I A, Moor N A, Lavrik O I. Effect of human XRCC1 protein oxidation on the functional activity of its complexes with the key enzymes of DNA base excision repair[J]. Biochemistry (Moscow), 2020, 85(3): 288-299. DOI: 10.1134/S0006297920030049http://dx.doi.org/10.1134/S0006297920030049.

Wang W M, Yang J J, Yu Y, et al. Expression of JWA and XRCC1 as prognostic markers for gastric cancer recurrence[J]. International Journal of Clinical and Experimental Pathology, 2020, 13(12): 3120-3127.

Pascal J M. The comings and goings of PARP-1 in response to DNA damage[J]. DNA Repair, 2018, 71: 177-182. DOI: 10.1016/j.dnarep.2018.08.022http://dx.doi.org/10.1016/j.dnarep.2018.08.022.

Hanzlikova H, Kalasova I, Demin A A, et al. The importance of poly(ADP-ribose) polymerase as a sensor of unligated Okazaki fragments during DNA replication[J]. Molecular Cell, 2018, 71(2): 319-331.e3. DOI: 10. 1016/j.molcel.2018.06.004http://dx.doi.org/10.1016/j.molcel.2018.06.004.

Abbotts R, Wilson D M Ⅲ. Coordination of DNA single strand break repair[J]. Free Radical Biology and Medicine, 2017, 107: 228-244. DOI: 10.1016/j.freeradbiomed.2016.11.039http://dx.doi.org/10.1016/j.freeradbiomed.2016.11.039.

Tallis M, Morra R, Barkauskaite E, et al. Poly(ADP-ribosyl)ation in regulation of chromatin structure and the DNA damage response[J]. Chromosoma, 2014, 123(1): 79-90. DOI: 10.1007/s00412-013-0442-9http://dx.doi.org/10.1007/s00412-013-0442-9.

Breslin C, Hornyak P, Ridley A, et al. The XRCC1 phosphate-binding pocket binds poly (ADP-ribose) and is required for XRCC1 function[J]. Nucleic Acids Research, 2015, 43(14): 6934-6944. DOI: 10.1093/nar/gkv623http://dx.doi.org/10.1093/nar/gkv623.

Kumar A, Reed A J, Zahurancik W J, et al. Interlocking activities of DNA polymerase β in the base excision repair pathway[J]. Proceedings of the National Academy of Sciences of the United States of America, 2022, 119(10): e2118940119. DOI: 10.1073/pnas.2118940119http://dx.doi.org/10.1073/pnas.2118940119.

Polo L M, Xu Y Q, Hornyak P, et al. Efficient single-strand break repair requires binding to both poly(ADP-ribose) and DNA by the central BRCT domain of XRCC1[J]. Cell Reports, 2019, 26(3): 573-581.e5. DOI: 10.1016/j.celrep.2018.12.082http://dx.doi.org/10.1016/j.celrep.2018.12.082.

Lavrik O I. PARPs' impact on base excision DNA repair[J]. DNA Repair, 2020, 93: 102911. DOI: 10.1016/j.dnarep.2020.102911http://dx.doi.org/10.1016/j.dnarep.2020.102911.

Ali R, Alabdullah M, Alblihy A, et al. PARP1 blockade is synthetically lethal in XRCC1 deficient sporadic epithelial ovarian cancers[J]. Cancer Letters, 2020, 469: 124-133. DOI: 10.1016/j.canlet.2019.10.035http://dx.doi.org/10.1016/j.canlet.2019.10.035.

D'Andrea A D. Mechanisms of PARP inhibitor sensitivity and resistance[J]. DNA Repair, 2018, 71: 172-176. DOI: 10.1016/j.dnarep.2018.08.021http://dx.doi.org/10.1016/j.dnarep.2018.08.021.

Ferrara R, Simionato F, Ciccarese C, et al. The development of PARP as a successful target for cancer therapy[J]. Expert Review of Anticancer Therapy, 2018, 18(2): 161-175. DOI: 10.1080/14737140.2018.1419870http://dx.doi.org/10.1080/14737140.2018.1419870.

Fong P C, Boss D S, Yap T A, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers[J]. The New England Journal of Medicine, 2009, 361(2): 123-134. DOI: 10.1056/NEJMoa0900212http://dx.doi.org/10.1056/NEJMoa0900212.

Nickoloff J A, Sharma N, Taylor L. Clustered DNA double-strand breaks: biological effects and relevance to cancer radiotherapy[J]. Genes, 2020, 11(1): 99. DOI: 10.3390/genes11010099http://dx.doi.org/10.3390/genes11010099.

Reber J M, Božić-Petković J, Lippmann M, et al. PARP1 and XRCC1 exhibit a reciprocal relationship in genotoxic stress response[J]. Cell Biology and Toxicology, 2022: 1-20. DOI: 10.1007/s10565-022-09739-9http://dx.doi.org/10.1007/s10565-022-09739-9.

Prasad C B, Prasad S B, Yadav S S, et al. Olaparib modulates DNA repair efficiency, sensitizes cervical cancer cells to cisplatin and exhibits anti-metastatic property[J]. Scientific Reports, 2017, 7: 12876. DOI: 10. 1038/s41598-017-13232-3http://dx.doi.org/10.1038/s41598-017-13232-3.

Cho E A, Juhnn Y S. The cAMP signaling system inhibits the repair of γ-ray-induced DNA damage by promoting Epac1-mediated proteasomal degradation of XRCC1 protein in human lung cancer cells[J]. Biochemical and Biophysical Research Communications, 2012, 422(2): 256-262. DOI: 10.1016/j.bbrc.2012.04.139http://dx.doi.org/10.1016/j.bbrc.2012.04.139.

Mei P J, Bai J, Miao F A, et al. Relationship between expression of XRCC1 and tumor proliferation, migration, invasion, and angiogenesis in glioma[J]. Investigational New Drugs, 2019, 37(4): 646-657. DOI: 10.1007/s10637-018-0667-9http://dx.doi.org/10.1007/s10637-018-0667-9.

Rezapoor S, Shirazi A, Abbasi S, et al. Modulation of radiation-induced base excision repair pathway gene expression by melatonin[J]. Journal of Medical Physics, 2017, 42(4): 245-250. DOI: 10.4103/jmp.JMP_9_17http://dx.doi.org/10.4103/jmp.JMP_9_17.

Toulany M, Dittmann K, Fehrenbacher B, et al. PI3K-Akt signaling regulates basal, but MAP-kinase signaling regulates radiation-induced XRCC1 expression in human tumor cells in vitro[J]. DNA Repair, 2008, 7(10): 1746-1756. DOI: 10.1016/j.dnarep.2008.06.017http://dx.doi.org/10.1016/j.dnarep.2008.06.017.

Huang R X, Zhou P K. DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer[J]. Signal Transduction and Targeted Therapy, 2020, 5: 60. DOI: 10.1038/s41392-020-0150-xhttp://dx.doi.org/10.1038/s41392-020-0150-x.

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