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Investigational New Drugs

, Volume 37, Issue 4, pp 646–657 | Cite as

Relationship between expression of XRCC1 and tumor proliferation, migration, invasion, and angiogenesis in glioma

  • Peng-jin Mei
  • Jin Bai
  • Fa-an Miao
  • Zhong-lin Li
  • Chen Chen
  • Jun-nian ZhengEmail author
  • Yue-chao FanEmail author
PRECLINICAL STUDIES
  • 121 Downloads

Summary

Recently, XRCC1 polymorphisms were reported to be associated with glioma in Chinese population. However, only a few studies reported on the XRCC1 expression, and cancer progression. In this study, we investigated whether XRCC1 plays a role in glioma pathogenesis. Using the tissue microarray technology, we found that XRCC1 expression is significantly decreased in glioma compared with tumor adjacent normal brain tissue (P < 0.01, χ2 test) and reduced XRCC1 staining was associated with WHO stages (P < 0.05, χ2 test). The mRNA and protein levels of XRCC1 were significantly downregulated in human primary glioma tissues (P < 0.001, χ2 test). We also found that XRCC1 was significantly decreased in glioma cell lines compared to normal human astrocytes (P < 0.01, χ2 test). Overexpression of XRCC1 dramatically reduced the proliferation and caused cessation of cell cycle. The reduced cell proliferation is due to G1 phase arrest as cyclin D1 is diminished whereas p16 is upregulated. We further demonstrated that XRCC1 overexpression suppressed the glioma cell migration and invasion abilities by targeting MMP-2. In addition, we also found that overexpression of XRCC1 sharply inhibited angiogenesis, which correlated with down-regulation of VEGF. The data indicate that XRCC1 may be a tumor suppressor involved in the progression of glioma.

Keywords

XRCC1 Proliferation Migration Invasion Angiogenesis Glioma 

Notes

Funding

This project is supported by grants from the National Natural Science Foundation of China (No.81502160), and Jiangsu Provincial Medical Youth Talent(No.QNRC2016785), and The Project of Invigorating Health Care through Science, Technology and Education (No.CXTDA2017034).

Compliance with ethical standards

Conflict of interest

The authors have declared that no competing interests exist.

Ethical approval

This study was performed under a protocol approved by the Institutional Review Boards of The Affiliated Hospital of Xuzhou Medical University.

Informed consent

Informed consent was obtained from all individual participants included in the study.

References

  1. 1.
    Van Meir EG et al (2010) Exciting new advances in neuro-oncology: the avenue to a cure for malignant glioma. CA Cancer J Clin 60(3):166–193CrossRefGoogle Scholar
  2. 2.
    Li Y et al (2017) Human fibulin-3 protein variant expresses anti-cancer effects in the malignant glioma extracellular compartment in intracranial xenograft models. Oncotarget 8(63):106311–106323Google Scholar
  3. 3.
    Hundsberger T, Reardon DA, Wen PY (2017) Angiogenesis inhibitors in tackling recurrent glioblastoma. Expert Rev Anticancer Ther 17(6):507–515CrossRefGoogle Scholar
  4. 4.
    Pronin S, Koh CH, Hughes M (2017) Effects of ultraviolet radiation on Glioma: systematic review. J Cell Biochem 118(11):4063–4071CrossRefGoogle Scholar
  5. 5.
    Wood RD, Mitchell M, Sgouros J, Lindahl T (2001) Human DNA repair genes. Science 291(5507):1284–1289CrossRefGoogle Scholar
  6. 6.
    Thompson LH, West MG (2000) XRCC1 keeps DNA from getting stranded. Mutat Res 459(1):1–18CrossRefGoogle Scholar
  7. 7.
    Luo H, Li Z, Qing Y, Zhang SH, Peng Y, Li Q, Wang D (2014) Single nucleotide polymorphisms of DNA base-excision repair genes (APE1, OGG1 and XRCC1) associated with breast cancer risk in a Chinese population. Asian Pac J Cancer Prev 15(3):1133–1140CrossRefGoogle Scholar
  8. 8.
    Yin G, Morita M, Ohnaka K, Toyomura K, Hamajima N, Mizoue T, Ueki T, Tanaka M, Kakeji Y, Maehara Y, Okamura T, Ikejiri K, Futami K, Yasunami Y, Maekawa T, Takenaka K, Ichimiya H, Terasaka R (2012) Genetic polymorphisms of XRCC1, alcohol consumption, and the risk of colorectal cancer in Japan. J Epidemiol 22(1):64–71CrossRefGoogle Scholar
  9. 9.
    Mei J, Duan HX, Wang LL, Yang S, Lu JQ, Shi TY, Zhao Y (2014) XRCC1 polymorphisms and cervical cancer risk: an updated meta-analysis. Tumour Biol 35(2):1221–1231CrossRefGoogle Scholar
  10. 10.
    Bao Y, Jiang L, Zhou JY, Zou JJ, Zheng JY, Chen XF, Liu ZM, Shi YQ (2013) XRCC1 gene polymorphisms and the risk of differentiated thyroid carcinoma (DTC): a meta-analysis of case-control studies. PLoS One 8(5):e64851CrossRefGoogle Scholar
  11. 11.
    Letkova L, Matakova T, Musak L, Sarlinova M, Krutakova M, Slovakova P, Kavcova E, Jakusova V, Janickova M, Drgova A, Berzinec P, Halasova E (2013) DNA repair genes polymorphism and lung cancer risk with the emphasis to sex differences. Mol Biol Rep 40(9):5261–5273CrossRefGoogle Scholar
  12. 12.
    Santonocito C, Scapaticci M, Penitente R, Paradisi A, Capizzi R, Lanza-Silveri S, Ficarra S, Landi F, Zuppi C, Capoluongo E (2012) Polymorphisms in base excision DNA repair genes and association with melanoma risk in a pilot study on central-south Italian population. Clin Chim Acta 413(19–20):1519–1524CrossRefGoogle Scholar
  13. 13.
    Wang C, Ai Z (2014) Association of XRCC1 polymorphisms with thyroid cancer risk. Tumour Biol 35(5):4791–4797CrossRefGoogle Scholar
  14. 14.
    Feng X, Miao G, Han Y, Xu Y, Wu H (2014) Glioma risks associate with genetic polymorphisms of XRCC1 gene in Chinese population. J Cell Biochem 115(6):1122–1127CrossRefGoogle Scholar
  15. 15.
    He LW, Shi R, Jiang L, Zeng Y, Ma WL, Zhou JY (2014) XRCC1 gene polymorphisms and glioma risk in Chinese population: a meta-analysis. PLoS One 9(11):e111981CrossRefGoogle Scholar
  16. 16.
    Li J, Qu Q, Qu J, Luo WM, Wang SY, He YZ, Luo QS, Xu YX, Wang YF (2014) Association between XRCC1 polymorphisms and glioma risk among Chinese population. Med Oncol 31(10):186CrossRefGoogle Scholar
  17. 17.
    Mei PJ, Bai J, Liu H, Li C, Wu YP, Yu ZQ, Zheng JN (2011) RUNX3 expression is lost in glioma and its restoration causes drastic suppression of tumor invasion and migration. J Cancer Res Clin Oncol 137(12):1823–1830CrossRefGoogle Scholar
  18. 18.
    Fu XJ, Shi XJ, Lin K, Lin H, Huang WH, Zhang GJ, Au WW (2015) Environmental and DNA repair risk factors for breast cancer in South China. Int J Hyg Environ Health 218(3):313–318CrossRefGoogle Scholar
  19. 19.
    Lamerdin JE, Montgomery MA, Stilwagen SA, Scheidecker LK, Tebbs RS, Brookman KW, Thompson LH, Carrano AV (1995) Genomic sequence comparison of the human and mouse XRCC1 DNA repair gene regions. Genomics 25(2):547–554CrossRefGoogle Scholar
  20. 20.
    Sterpone, S. and Cozzi, R. (2010) Influence of XRCC1 Genetic Polymorphisms on Ionizing Radiation-Induced DNA Damage and Repair. J Nucleic Acids 2010Google Scholar
  21. 21.
    Horton JK, Stefanick DF, Gassman NR, Williams JG, Gabel SA, Cuneo MJ, Prasad R, Kedar PS, DeRose EF, Hou EW, London RE, Wilson SH (2013) Preventing oxidation of cellular XRCC1 affects PARP-mediated DNA damage responses. DNA Repair (Amst) 12(9):774–785CrossRefGoogle Scholar
  22. 22.
    Barrows LR, Holden JA, Anderson M, D'Arpa P (1998) The CHO XRCC1 mutant, EM9, deficient in DNA ligase III activity, exhibits hypersensitivity to camptothecin independent of DNA replication. Mutat Res 408(2):103–110CrossRefGoogle Scholar
  23. 23.
    Wong HK, Wilson DM 3rd (2005) XRCC1 and DNA polymerase beta interaction contributes to cellular alkylating-agent resistance and single-strand break repair. J Cell Biochem 95(4):794–804CrossRefGoogle Scholar
  24. 24.
    Liu D, Wu J, Shi GY, Zhou HF, Yu Y (2014) Role of XRCC1 and ERCC5 polymorphisms on clinical outcomes in advanced non-small cell lung cancer. Genet Mol Res 13(2):3100–3107CrossRefGoogle Scholar
  25. 25.
    Dai Q, Luo H, Li XP, Huang J, Zhou TJ, Yang ZH (2015) XRCC1 and ERCC1 polymorphisms are related to susceptibility and survival of colorectal cancer in the Chinese population. Mutagenesis 30(3):441–449CrossRefGoogle Scholar
  26. 26.
    Xu J, Ma J, Zong HT, Wang SY, Zhou JW (2014) Pharmacogenetic role of XRCC1 polymorphisms on the clinical outcome of gastric cancer patients with platinum-based chemotherapy: a systematic review and meta-analysis. Genet Mol Res 13(1):1438–1446CrossRefGoogle Scholar
  27. 27.
    Zhu H et al (2015) Impact of polymorphisms of the DNA repair gene XRCC1 and their role in the risk of prostate cancer. Pak J Med Sci 31(2):290–294CrossRefGoogle Scholar
  28. 28.
    Wang D, Hu Y, Gong H, Li J, Ren Y, Li G, Liu A (2012) Genetic polymorphisms in the DNA repair gene XRCC1 and susceptibility to glioma in a Han population in northeastern China: a case-control study. Gene 509(2):223–227CrossRefGoogle Scholar
  29. 29.
    Hu XB et al (2011) Polymorphisms in DNA repair gene XRCC1 and increased genetic susceptibility to glioma. Asian Pac J Cancer Prev 12(11):2981–2984Google Scholar
  30. 30.
    Bhandaru M, Martinka M, Li G, Rotte A (2014) Loss of XRCC1 confers a metastatic phenotype to melanoma cells and is associated with poor survival in patients with melanoma. Pigment Cell Melanoma Res 27(3):366–375CrossRefGoogle Scholar
  31. 31.
    Crnogorac-Jurcevic T, Efthimiou E, Nielsen T, Loader J, Terris B, Stamp G, Baron A, Scarpa A, Lemoine NR (2002) Expression profiling of microdissected pancreatic adenocarcinomas. Oncogene 21(29):4587–4594CrossRefGoogle Scholar
  32. 32.
    Liu QH et al (2017) XRCC1 serves as a potential prognostic indicator for clear cell renal cell carcinoma and inhibits its invasion and metastasis through suppressing MMP-2 and MMP-9. Oncotarget 8(65):109382–109392Google Scholar
  33. 33.
    Sak SC et al (2005) APE1 and XRCC1 protein expression levels predict cancer-specific survival following radical radiotherapy in bladder cancer. Clin Cancer Res 11(17):6205–6211CrossRefGoogle Scholar
  34. 34.
    Wang S, Wu X, Chen Y, Zhang J, Ding J, Zhou Y, He S, Tan Y, Qiang F, Bai J, Zeng J, Gong Z, Li A, Li G, Roe OD, Zhou J (2012) Prognostic and predictive role of JWA and XRCC1 expressions in gastric cancer. Clin Cancer Res 18(10):2987–2996CrossRefGoogle Scholar
  35. 35.
    Abdel-Fatah T, Sultana R, Abbotts R, Hawkes C, Seedhouse C, Chan S, Madhusudan S (2013) Clinicopathological and functional significance of XRCC1 expression in ovarian cancer. Int J Cancer 132(12):2778–2786CrossRefGoogle Scholar
  36. 36.
    Ang MK, Patel MR, Yin XY, Sundaram S, Fritchie K, Zhao N, Liu Y, Freemerman AJ, Wilkerson MD, Walter V, Weissler MC, Shockley WW, Couch ME, Zanation AM, Hackman T, Chera BS, Harris SL, Miller CR, Thorne LB, Hayward MC, Funkhouser WK, Olshan AF, Shores CG, Makowski L, Hayes DN (2011) High XRCC1 protein expression is associated with poorer survival in patients with head and neck squamous cell carcinoma. Clin Cancer Res 17(20):6542–6552CrossRefGoogle Scholar
  37. 37.
    Collins K, Jacks T, Pavletich NP (1997) The cell cycle and cancer. Proc Natl Acad Sci U S A 94(7):2776–2778CrossRefGoogle Scholar
  38. 38.
    Lee MH, Yang HY (2003) Regulators of G1 cyclin-dependent kinases and cancers. Cancer Metastasis Rev 22(4):435–449CrossRefGoogle Scholar
  39. 39.
    Costello JF et al (1996) Silencing of p16/CDKN2 expression in human gliomas by methylation and chromatin condensation. Cancer Res 56(10):2405–2410Google Scholar
  40. 40.
    Koh I, Cha J, Park J, Choi J, Kang SG, Kim P (2018) The mode and dynamics of glioblastoma cell invasion into a decellularized tissue-derived extracellular matrix-based three-dimensional tumor model. Sci Rep 8(1):4608CrossRefGoogle Scholar
  41. 41.
    Fillmore HL, VanMeter TE, Broaddus WC (2001) Membrane-type matrix metalloproteinases (MT-MMPs): expression and function during glioma invasion. J Neuro-Oncol 53(2):187–202CrossRefGoogle Scholar
  42. 42.
    Anderson JC et al (2008) New molecular targets in angiogenic vessels of glioblastoma tumours. Expert Rev Mol Med e23:10Google Scholar
  43. 43.
    Wurdinger T, Tannous BA (2009) Glioma angiogenesis: towards novel RNA therapeutics. Cell Adhes Migr 3(2):230–235CrossRefGoogle Scholar
  44. 44.
    Guillamo JS, de Bouard S, Valable S, Marteau L, Leuraud P, Marie Y, Poupon MF, Parienti JJ, Raymond E, Peschanski M (2009) Molecular mechanisms underlying effects of epidermal growth factor receptor inhibition on invasion, proliferation, and angiogenesis in experimental glioma. Clin Cancer Res 15(11):3697–3704CrossRefGoogle Scholar
  45. 45.
    Cao Y, E G, Wang E, Pal K, Dutta SK, Bar-Sagi D, Mukhopadhyay D (2012) VEGF exerts an angiogenesis-independent function in cancer cells to promote their malignant progression. Cancer Res 72(16):3912–3918CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of NeurosurgeryThe Affiliated Hospital of Xuzhou Medical UniversityXuzhouChina
  2. 2.Jiangsu Key Laboratory of Biological Cancer TherapyXuzhou Medical UniversityXuzhouChina

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