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DNA Repair Protein Rad51 Induces Tumor Growth and Metastasis in Esophageal Squamous Cell Carcinoma via a p38/Akt-Dependent Pathway

  • Wen-Chin Chiu
  • Pen-Tzu Fang
  • Yi-Chen Lee
  • Yen-Yun Wang
  • Yu-Han Su
  • Stephen Chu-Sung Hu
  • Yuk-Kwan Chen
  • Yu-Tong Tsui
  • Ying-Hsien Kao
  • Ming-Yii HuangEmail author
  • Shyng-Shiou F. YuanEmail author
Translational Research and Biomarkers
  • 68 Downloads

Abstract

Background

Rad51 is a protein which plays a vital role in DNA double-strand break repair and maintenance of telomeres. However, the underlying mechanism for its action in esophageal squamous cell carcinoma (ESCC) remains unclear.

Patients and Methods

Eighty-seven patients with ESCC were enrolled in this study. Expression of Rad51 in ESCC was determined by immunohistochemistry and correlated with clinicopathological variables by Chi square test. The role of Rad51 in patient survival was determined by Kaplan–Meier estimates. The effects of Rad51 knockdown and overexpression on esophageal cancer growth, migration, and invasion were examined using TE8, CE81T, and KYSE70 cells. The mechanisms involved were also analyzed. Nude mice models were used for assessment of tumor growth.

Results

Rad51 staining was predominantly observed in ESCC patients. ESCC patients with high Rad51 expression had significantly decreased survival (P < 0.001) combined with increased tumor size (P = 0.034) and lymph node metastasis (P = 0.039). Rad51 overexpression promoted, while its knockdown attenuated, esophageal cancer cell viability through cell cycle entry and migration/invasion via epithelial–mesenchymal transition. Moreover, Rad51 overexpression increased colony formation in vitro and tumor growth in vivo. In addition, high Rad51 expression increased cancer progression through the p38/Akt/Snail signaling pathway.

Conclusions

This study indicates a new biological role for Rad51 in ESCC progression. Rad51 may serve as a potential prognostic biomarker and therapeutic target for ESCC patients.

Notes

Acknowledgment

This work was financially supported by grants from Kaohsiung Medical University Research Center Grant (Center for Cancer Research KMU-TC108A04), Kaohsiung Medical University Hospital (KMUH103-3M41, KMUH104-4M46), and the Center for Intelligent Drug Systems and Smart Bio-devices (IDS2B) from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan.

Disclosure

The authors declare no conflicts of interest.

Supplementary material

10434_2019_8043_MOESM1_ESM.doc (48 kb)
Supplementary material 1 (DOC 47 kb)
10434_2019_8043_MOESM2_ESM.doc (48 kb)
Supplementary material 2 (DOC 48 kb)

References

  1. 1.
    Rustgi AK, El-Serag HB. Esophageal carcinoma. N Engl J Med. 2014;371:2499–509.CrossRefGoogle Scholar
  2. 2.
    Pennathur A, Gibson MK, Jobe BA, Luketich JD. Oesophageal carcinoma. Lancet. 2013;381:400–12.CrossRefGoogle Scholar
  3. 3.
    Liang H, Fan JH, Qiao YL. Epidemiology, etiology, and prevention of esophageal squamous cell carcinoma in China. Cancer Biol Med. 2017;14:33–41.CrossRefGoogle Scholar
  4. 4.
    Sakaeda T, Yamamori M, Kuwahara A, Nishiguchi K. Pharmacokinetics and pharmacogenomics in esophageal cancer chemoradiotherapy. Adv Drug Deliv Rev. 2009;61:388–401.CrossRefGoogle Scholar
  5. 5.
    Hartlerode AJ, Scully R. Mechanisms of double-strand break repair in somatic mammalian cells. Biochem J. 2009;423:157–68.CrossRefGoogle Scholar
  6. 6.
    Nagaria P, Robert C, Rassool FV. DNA double-strand break response in stem cells: mechanisms to maintain genomic integrity. Biochim Biophys Acta. 2013;1830:2345–53.CrossRefGoogle Scholar
  7. 7.
    Powell SN, Bindra RS. Targeting the DNA damage response for cancer therapy. DNA Repair (Amst). 2009;8:1153–65.CrossRefGoogle Scholar
  8. 8.
    Chapman JR, Taylor MR, Boulton SJ. Playing the end game: DNA double-strand break repair pathway choice. Mol Cell. 2012;47:497–510.CrossRefGoogle Scholar
  9. 9.
    Krejci L, Altmannova V, Spirek M, Zhao X. Homologous recombination and its regulation. Nucleic Acids Res. 2012;40:5795–818.CrossRefGoogle Scholar
  10. 10.
    Sugiyama T, Kantake N. Dynamic regulatory interactions of rad51, rad52, and replication protein-a in recombination intermediates. J Mol Biol. 2009;390:45–55.CrossRefGoogle Scholar
  11. 11.
    Tsuzuki T, Fujii Y, Sakumi K, et al. Targeted disruption of the Rad51 gene leads to lethality in embryonic mice. Proc Natl Acad Sci USA. 1996;93:6236–40.CrossRefGoogle Scholar
  12. 12.
    Henning W, Sturzbecher HW. Homologous recombination and cell cycle checkpoints: Rad51 in tumour progression and therapy resistance. Toxicology. 2003;193:91–109.CrossRefGoogle Scholar
  13. 13.
    Klein HL. The consequences of Rad51 overexpression for normal and tumor cells. DNA Repair (Amst). 2008;7:686–93.CrossRefGoogle Scholar
  14. 14.
    Nagathihalli NS, Nagaraju G. RAD51 as a potential biomarker and therapeutic target for pancreatic cancer. Biochim Biophys Acta. 2011;1816:209–18.PubMedGoogle Scholar
  15. 15.
    Chiu WC, Lee YC, Su YH, et al. The synthetic beta-nitrostyrene derivative CYT-Rx20 inhibits esophageal tumor growth and metastasis via PI3K/AKT and STAT3 pathways. PLoS ONE. 2016;11:e0166453.CrossRefGoogle Scholar
  16. 16.
    Tsai JH, Yang J. Epithelial-mesenchymal plasticity in carcinoma metastasis. Genes Dev. 2013;27:2192–206.CrossRefGoogle Scholar
  17. 17.
    Xu W, Yang Z, Lu N. A new role for the PI3K/Akt signaling pathway in the epithelial-mesenchymal transition. Cell Adhes Migr. 2015;9:317–24.CrossRefGoogle Scholar
  18. 18.
    Lee JL, Park SI, Kim SB, et al. A single institutional phase III trial of preoperative chemotherapy with hyperfractionation radiotherapy plus surgery versus surgery alone for resectable esophageal squamous cell carcinoma. Ann Oncol. 2004;15:947–54.CrossRefGoogle Scholar
  19. 19.
    Burmeister BH, Smithers BM, Gebski V, et al. Surgery alone versus chemoradiotherapy followed by surgery for resectable cancer of the oesophagus: a randomised controlled phase III trial. Lancet Oncol. 2005;6:659–68.CrossRefGoogle Scholar
  20. 20.
    Li Y, Yu H, Luo RZ, et al. Elevated expression of Rad51 is correlated with decreased survival in resectable esophageal squamous cell carcinoma. J Surg Oncol. 2011;104:617–22.CrossRefGoogle Scholar
  21. 21.
    Nakanoko T, Saeki H, Morita M, et al. Rad51 expression is a useful predictive factor for the efficacy of neoadjuvant chemoradiotherapy in squamous cell carcinoma of the esophagus. Ann Surg Oncol. 2014;21:597–604.CrossRefGoogle Scholar
  22. 22.
    Sawyers CL. Shifting paradigms: the seeds of oncogene addiction. Nat Med. 2009;15:1158–61.CrossRefGoogle Scholar
  23. 23.
    Holien T, Vatsveen TK, Hella H, Waage A, Sundan A. Addiction to c-MYC in multiple myeloma. Blood. 2012;120:2450–3.CrossRefGoogle Scholar
  24. 24.
    Hall A, Meyle KD, Lange MK, et al. Dysfunctional oxidative phosphorylation makes malignant melanoma cells addicted to glycolysis driven by the (V600E)BRAF oncogene. Oncotarget. 2013;4:584–99.CrossRefGoogle Scholar
  25. 25.
    Demidenko ZN, An WG, Lee JT, Romanova LY, McCubrey JA, Blagosklonny MV. Kinase-addiction and bi-phasic sensitivity-resistance of Bcr-Abl- and Raf-1-expressing cells to imatinib and geldanamycin. Cancer Biol Ther. 2005;4:484–90.CrossRefGoogle Scholar
  26. 26.
    Cuenda A, Rousseau S. p38 MAP-kinases pathway regulation, function and role in human diseases. Biochim Biophys Acta. 2007;1773:1358–75.CrossRefGoogle Scholar
  27. 27.
    Igea A, Nebreda AR. The stress kinase p38alpha as a target for cancer therapy. Cancer Res. 2015;75:3997–4002.CrossRefGoogle Scholar
  28. 28.
    Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest. 2009;119:1420–8.CrossRefGoogle Scholar
  29. 29.
    Minn AJ, Gupta GP, Siegel PM, et al. Genes that mediate breast cancer metastasis to lung. Nature. 2005;436:518–24.CrossRefGoogle Scholar
  30. 30.
    Ferrara N, Kerbel RS. Angiogenesis as a therapeutic target. Nature. 2005;438:967–74.CrossRefGoogle Scholar
  31. 31.
    Aiello NM, Maddipati R, Norgard RJ, et al. EMT subtype influences epithelial plasticity and mode of cell migration. Dev Cell. 2018;45:681–95.CrossRefGoogle Scholar
  32. 32.
    Wheelock MJ, Shintani Y, Maeda M, Fukumoto Y, Johnson KR. Cadherin switching. J Cell Sci. 2008;121:727–35.CrossRefGoogle Scholar
  33. 33.
    Yang SX, Polley E, Lipkowitz S. New insights on PI3K/AKT pathway alterations and clinical outcomes in breast cancer. Cancer Treat Rev. 2016;45:87–96.CrossRefGoogle Scholar
  34. 34.
    Beck JT, Ismail A, Tolomeo C. Targeting the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway: an emerging treatment strategy for squamous cell lung carcinoma. Cancer Treat Rev. 2014;40:980–9.CrossRefGoogle Scholar
  35. 35.
    Toulany M, Rodemann HP. Potential of Akt mediated DNA repair in radioresistance of solid tumors overexpressing erbB-PI3K-Akt pathway. Transl Cancer Res. 2013;2:190–202.Google Scholar
  36. 36.
    Yu H, Bian X, Gu D, He X. Metformin synergistically enhances cisplatin-induced cytotoxicity in esophageal squamous cancer cells under glucose-deprivation conditions. Biomed Res Int. 2016;2016:8678634.PubMedPubMedCentralGoogle Scholar
  37. 37.
    Lennon FE, Mirzapoiazova T, Mambetsariev B, et al. The Mu opioid receptor promotes opioid and growth factor-induced proliferation, migration and Epithelial Mesenchymal Transition (EMT) in human lung cancer. PLoS ONE. 2014;9:e91577.CrossRefGoogle Scholar
  38. 38.
    Le Scodan R, Cizeron-Clairac G, Fourme E, et al. DNA repair gene expression and risk of locoregional relapse in breast cancer patients. Int J Radiat Oncol Biol Phys. 2010;78:328–36.CrossRefGoogle Scholar
  39. 39.
    Zhang N, Wu X, Yang L, et al. FoxM1 inhibition sensitizes resistant glioblastoma cells to temozolomide by downregulating the expression of DNA-repair gene Rad51. Clin Cancer Res. 2012;18:5961–71.CrossRefGoogle Scholar
  40. 40.
    Kasagi Y, Morita M, Otsu H, et al. Clinicopathological characteristics of esophageal squamous cell carcinoma in patients younger than 50 years. Ann Surg Oncol. 2015;22:311–5.CrossRefGoogle Scholar

Copyright information

© Society of Surgical Oncology 2019

Authors and Affiliations

  1. 1.Translational Research Center, Kaohsiung Medical University HospitalKaohsiung Medical UniversityKaohsiungTaiwan
  2. 2.Department of Radiation Oncology, Kaohsiung Medical University HospitalKaohsiung Medical UniversityKaohsiungTaiwan
  3. 3.Department of Anatomy, School of Medicine, College of MedicineKaohsiung Medical UniversityKaohsiungTaiwan
  4. 4.School of Dentistry, College of Dental MedicineKaohsiung Medical UniversityKaohsiungTaiwan
  5. 5.Department of Dermatology, Kaohsiung Medical University HospitalKaohsiung Medical UniversityKaohsiungTaiwan
  6. 6.Division of Oral Pathology and Maxillofacial RadiologyKaohsiung Medical University HospitalKaohsiungTaiwan
  7. 7.Oral and Maxillofacial Imaging Center, College of Dental MedicineKaohsiung Medical UniversityKaohsiungTaiwan
  8. 8.Department of Medical ResearchE-Da HospitalKaohsiungTaiwan
  9. 9.Department of Medical Research, Kaohsiung Medical University HospitalKaohsiung Medical UniversityKaohsiungTaiwan
  10. 10.Graduate Institute of Medicine, College of MedicineKaohsiung Medical UniversityKaohsiungTaiwan
  11. 11.Department of Biological Science and Technology, College of Biological Science and TechnologyNational Chiao Tung UniversityHsinchuTaiwan
  12. 12.Center for Intelligent Drug Systems and Smart Bio-devices (IDS2B)National Chiao Tung UniversityHsinchuTaiwan
  13. 13.Center for Cancer ResearchKaohsiung Medical UniversityKaohsiungTaiwan

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