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Elevated DNA damage response in pancreatic cancer

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Abstract

Pancreatic cancer is one of the most aggressive and intractable human malignant tumors and a leading cause of cancer-related death across the world, with incidence equaling mortality. Because of the extremely high malignance, this disease is usually diagnosed at its advanced stage and recurs even after surgical excision. Pancreatic adenocarcinoma is generally thought to arise from pathological changes of pancreatic duct, and the pancreatic ductal adenocarcinoma accounts for more than 90 % of malignant neoplasms of the pancreas. To date, scientists have revealed several risk factors for pancreatic cancer, including smoking, family history, and aging. However, the underlying molecular mechanism remains unclear. Meanwhile, more mutations of DNA damage response factors have been identified in familial pancreatic cancers, implying a potential link between DNA damage and pancreatic cancer. DNA damage is a recurring phenomenon in our bodies which could be induced by exogenous agents and endogenous metabolism. Accumulated DNA lesions cause genomic instability which eventually results in tumorigenesis. In this study, we showed obvious DNA damages existed in human pancreatic cancer, which activated DNA damage response and the DNA repair pathway including ataxia-telangiectasia mutated, DNA-PK, CHK1, and CHK2. The persistent DNA damage in pancreatic tissue may be the source for its tumorigenesis.

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References

  • Abraham RT (2001) Cell cycle checkpoint signaling through the ATM and ATR kinases. Genes Dev 15(17):2177–2196

    Article  CAS  PubMed  Google Scholar 

  • Bardeesy N, DePinho RA (2002) Pancreatic cancer biology and genetics. Nat Rev Cancer 2(12):897–909

    Article  CAS  PubMed  Google Scholar 

  • Bristow RG, Hill RP (2008) Hypoxia and metabolism. Hypoxia, DNA repair and genetic instability. Nat Rev Cancer 8(3):180–192

    Article  CAS  PubMed  Google Scholar 

  • Campbell PJ, Yachida S, Mudie LJ, Stephens PJ, Pleasance ED, Stebbings LA, Morsberger LA, Latimer C, McLaren S, Lin ML, McBride DJ, Varela I, Nik-Zainal SA, Leroy C, Jia M, Menzies A, Butler AP, Teague JW, Griffin CA, Burton J, Swerdlow H, Quail MA, Stratton MR, Iacobuzio-Donahue C, Futreal PA (2010) The patterns and dynamics of genomic instability in metastatic pancreatic cancer. Nature 467(7319):1109–1113

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Chen L, Trujillo K, Sung P, Tomkinson AE (2000) Interactions of the DNA ligase IV-XRCC4 complex with DNA ends and the DNA-dependent protein kinase. J Biol Chem 275(34):26196–26205

    Article  CAS  PubMed  Google Scholar 

  • Chiu CC, Li CH, Ung MW, Fuh TS, Chen WL, Fang K (2005) Etoposide (VP-16) elicits apoptosis following prolonged G2-M cell arrest in p53-mutated human non-small cell lung cancer cells. Cancer Lett 223(2):249–258

    Article  CAS  PubMed  Google Scholar 

  • Ciccia A, Elledge SJ (2010) The DNA damage response: making it safe to play with knives. Mol Cell 40(2):179–204

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Collins MA, Bednar F, Zhang Y, Brisset JC, Galban S, Galban CJ, Rakshit S, Flannagan KS, Adsay NV, Pasca di Magliano M (2012) Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice. J Clin Invest 122(2):639–653

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Cortez D, Wang Y, Qin J, Elledge SJ (1999) Requirement of ATM-dependent phosphorylation of brca1 in the DNA damage response to double-strand breaks. Science 286(5442):1162–1166

    Article  CAS  PubMed  Google Scholar 

  • Eckel F, Schneider G, Schmid RM (2006) Pancreatic cancer: a review of recent advances. Expert Opin Investig Drugs 15(11):1395–1410

    Article  CAS  PubMed  Google Scholar 

  • Falck J, Coates J, Jackson SP (2005) Conserved modes of recruitment of ATM, ATR and DNA-PKcs to sites of DNA damage. Nature 434(7033):605–611

    Article  CAS  PubMed  Google Scholar 

  • Garcea G, Neal CP, Pattenden CJ, Steward WP, Berry DP (2005) Molecular prognostic markers in pancreatic cancer: a systematic review. Eur J Cancer 41(15):2213–2236

    Article  CAS  PubMed  Google Scholar 

  • Ghosal G, Chen J (2013) DNA damage tolerance: a double-edged sword guarding the genome. Transl Cancer Res 2(3):107–129

    PubMed Central  PubMed  Google Scholar 

  • Hirose Y, Berger MS, Pieper RO (2001) p53 effects both the duration of G2/M arrest and the fate of temozolomide-treated human glioblastoma cells. Cancer Res 61(5):1957–1963

    CAS  PubMed  Google Scholar 

  • Jackson SP, Bartek J (2009) The DNA-damage response in human biology and disease. Nature 461(7267):1071–1078

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Jemal A, Siegel R, Ward E, Murray T, Xu J, Smigal C, Thun MJ (2006) Cancer statistics. CA Cancer J Clin 56(2):106–130

    Article  PubMed  Google Scholar 

  • Jones S, Hruban RH, Kamiyama M, Borges M, Zhang X, Parsons DW, Lin JC, Palmisano E, Brune K, Jaffee EM, Iacobuzio-Donahue CA, Maitra A, Parmigiani G, Kern SE, Velculescu VE, Kinzler KW, Vogelstein B, Eshleman JR, Goggins M, Klein AP (2009) Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. Science 324(5924):217

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kadlubar FF, Anderson KE, Haussermann S, Lang NP, Barone GW, Thompson PA, MacLeod SL, Chou MW, Mikhailova M, Plastaras J, Marnett LJ, Nair J, Velic I, Bartsch H (1998) Comparison of DNA adduct levels associated with oxidative stress in human pancreas. Mutat Res 405(2):125–133

    Article  CAS  PubMed  Google Scholar 

  • Kastan MB, Bartek J (2004) Cell-cycle checkpoints and cancer. Nature 432(7015):316–323

    Article  CAS  PubMed  Google Scholar 

  • Komuro Y, Watanabe T, Hosoi Y, Matsumoto Y, Nakagawa K, Suzuki N, Nagawa H (2005) Prognostic significance of Ku70 protein expression in patients with advanced colorectal cancer. Hepatogastroenterology 52(64):995–998

    PubMed  Google Scholar 

  • Li M, Yu X (2013) Function of BRCA1 in the DNA damage response is mediated by ADP-ribosylation. Cancer Cell 23(5):693–704

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Li D, Firozi PF, Zhang W, Shen J, DiGiovanni J, Lau S, Evans D, Friess H, Hassan M, Abbruzzese JL (2002) DNA adducts, genetic polymorphisms, and K-ras mutation in human pancreatic cancer. Mutat Res 513(1–2):37–48

    Article  CAS  PubMed  Google Scholar 

  • Li D, Xie K, Wolff R, Abbruzzese JL (2004) Pancreatic cancer. Lancet 363(9414):1049–1057

    Article  CAS  PubMed  Google Scholar 

  • Li M, Lu LY, Yang CY, Wang S, Yu X (2013) The FHA and BRCT domains recognize ADP-ribosylation during DNA damage response. Genes Dev 27(16):1752–1768

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Lord CJ, Ashworth A (2012) The DNA damage response and cancer therapy. Nature 481(7381):287–294

    Article  CAS  PubMed  Google Scholar 

  • Ma J, Jemal A (2013) The rise and fall of cancer mortality in the USA: why does pancreatic cancer not follow the trend? Future Oncol 9(7):917–919

    Article  CAS  PubMed  Google Scholar 

  • Matsuoka S, Ballif BA, Smogorzewska A, McDonald ER 3rd, Hurov KE, Luo J, Bakalarski CE, Zhao Z, Solimini N, Lerenthal Y, Shiloh Y, Gygi SP, Elledge SJ (2007) ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science 316(5828):1160–1166

    Article  CAS  PubMed  Google Scholar 

  • Mohammed A, Janakiram NB, Lightfoot S, Gali H, Vibhudutta A, Rao CV (2012) Early detection and prevention of pancreatic cancer: use of genetically engineered mouse models and advanced imaging technologies. Curr Med Chem 19(22):3701–3713

    Article  CAS  PubMed  Google Scholar 

  • Morrison C, Sonoda E, Takao N, Shinohara A, Yamamoto K, Takeda S (2000) The controlling role of ATM in homologous recombinational repair of DNA damage. EMBO J 19(3):463–471

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Nagathihalli NS, Nagaraju G (2011) RAD51 as a potential biomarker and therapeutic target for pancreatic cancer. Biochim Biophys Acta 1816(2):209–218

    CAS  PubMed  Google Scholar 

  • Ozcelik H, Schmocker B, Di Nicola N, Shi XH, Langer B, Moore M, Taylor BR, Narod SA, Darlington G, Andrulis IL, Gallinger S, Redston M (1997) Germline BRCA2 6174delT mutations in Ashkenazi Jewish pancreatic cancer patients. Nat Genet 16(1):17–18

    Article  CAS  PubMed  Google Scholar 

  • Patel KJ, Yu VP, Lee H, Corcoran A, Thistlethwaite FC, Evans MJ, Colledge WH, Friedman LS, Ponder BA, Venkitaraman AR (1998) Involvement of Brca2 in DNA repair. Mol Cell 1(3):347–357

    Article  CAS  PubMed  Google Scholar 

  • Paull TT, Rogakou EP, Yamazaki V, Kirchgessner CU, Gellert M, Bonner WM (2000) A critical role for histone H2AX in recruitment of repair factors to nuclear foci after DNA damage. Curr Biol 10(15):886–895

    Article  CAS  PubMed  Google Scholar 

  • Polo SE, Jackson SP (2011) Dynamics of DNA damage response proteins at DNA breaks: a focus on protein modifications. Genes Dev 25(5):409–433

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Reinhardt HC, Yaffe MB (2009) Kinases that control the cell cycle in response to DNA damage: chk1, Chk2, and MK2. Curr Opin Cell Biol 21(2):245–255

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Roberts NJ, Jiao Y, Yu J, Kopelovich L, Petersen GM, Bondy ML, Gallinger S, Schwartz AG, Syngal S, Cote ML, Axilbund J, Schulick R, Ali SZ, Eshleman JR, Velculescu VE, Goggins M, Vogelstein B, Papadopoulos N, Hruban RH, Kinzler KW, Klein AP (2012) ATM mutations in patients with hereditary pancreatic cancer. Cancer Discov 2(1):41–46

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Rustgi AK (2014) Familial pancreatic cancer: genetic advances. Genes Dev 28(1):1–7

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Sancar A, Lindsey-Boltz LA, Unsal-Kacmaz K, Linn S (2004) Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Annu Rev Biochem 73:39–85

    Article  CAS  PubMed  Google Scholar 

  • Sandhu JK, Haqqani AS, Birnboim HC (2000) Effect of dietary vitamin E on spontaneous or nitric oxide donor-induced mutations in a mouse tumor model. J Natl Cancer Inst 92(17):1429–1433

    Article  CAS  PubMed  Google Scholar 

  • Sengupta S, Harris CC (2005) p53: traffic cop at the crossroads of DNA repair and recombination. Nat Rev Mol Cell Biol 6(1):44–55

    Article  CAS  PubMed  Google Scholar 

  • Srivastava N, Gochhait S, de Boer P, Bamezai RN (2009) Role of H2AX in DNA damage response and human cancers. Mutat Res 681(2–3):180–188

    Article  CAS  PubMed  Google Scholar 

  • Thompson PA, Seyedi F, Lang NP, MacLeod SL, Wogan GN, Anderson KE, Tang YM, Coles B, Kadlubar FF (1999) Comparison of DNA adduct levels associated with exogenous and endogenous exposures in human pancreas in relation to metabolic genotype. Mutat Res 424(1–2):263–274

    Article  CAS  PubMed  Google Scholar 

  • Traven A, Heierhorst J (2005) SQ/TQ cluster domains: concentrated ATM/ATR kinase phosphorylation site regions in DNA-damage-response proteins. BioEssays 27(4):397–407

    Article  CAS  PubMed  Google Scholar 

  • van der Heijden MS, Yeo CJ, Hruban RH, Kern SE (2003) Fanconi anemia gene mutations in young-onset pancreatic cancer. Cancer Res 63(10):2585–2588

    PubMed  Google Scholar 

  • Wang M, Abbruzzese JL, Friess H, Hittelman WN, Evans DB, Abbruzzese MC, Chiao P, Li D (1998) DNA adducts in human pancreatic tissues and their potential role in carcinogenesis. Cancer Res 58(1):38–41

    CAS  PubMed  Google Scholar 

  • Warshaw AL, Fernandez-del Castillo C (1992) Pancreatic carcinoma. N Engl J Med 326(7):455–465

    Article  CAS  PubMed  Google Scholar 

  • Yang L, Besschetnova TY, Brooks CR, Shah JV, Bonventre JV (2010) Epithelial cell cycle arrest in G2/M mediates kidney fibrosis after injury. Nat Med 16(5):535–543 (531 p following 143)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Zhang F, Ma J, Wu J, Ye L, Cai H, Xia B, Yu X (2009) PALB2 links BRCA1 and BRCA2 in the DNA-damage response. Curr Biol 19(6):524–529

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

This study was supported by National Institute of Health (CA132755 and CA130899 to X.Y.), Ovarian Cancer Research Fund (292728 to M. L.), and National Natural Science Foundation of China (81272756 to Fei Li).

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Correspondence to Mo Li, Xiaochun Yu or Fei Li.

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Michael Osterman, Deion Kathawa and Diangang Liu have contributed equally to this work.

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Osterman, M., Kathawa, D., Liu, D. et al. Elevated DNA damage response in pancreatic cancer. Histochem Cell Biol 142, 713–720 (2014). https://doi.org/10.1007/s00418-014-1245-7

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