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DJ-1, a novel biomarker and a selected target gene for overcoming chemoresistance in pancreatic cancer

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Abstract

Purpose

Aberrant expression of DJ-1 has been proven to be associated with tumorigenesis in many carcinomas. However, its role in pancreatic cancer is unknown. The aims of this study were to investigate whether the serum DJ-1 might be a potential biomarker for pancreatic cancer and to determine the biologic function of DJ-1 expression in gemcitabine-induced chemoresistance of pancreatic cancer.

Methods

The serum level of DJ-1 was higher in 128 pancreatic cancer patients compared with 62 healthy controls by ELISA. To determine the effect of DJ-1 on pancreatic tumor chemoresistance, a siRNA-targeting DJ-1 was synthesized and a stably transfected cell line with DJ-1 over-expression was constructed. The mechanism of tumor chemoresistance was assessed by multiple methods, such as MTT assay, real-time PCR, Western blot and flow cytometry.

Results

The serum level of DJ-1 was higher in pancreatic cancer patients than healthy controls, and it has the relationship with tumor differentiation in pancreatic cancer. Down-regulation of DJ-1 enhanced gemcitabine-induced apoptosis in three pancreatic cancer cell lines. On the contrary, over-expression of DJ-1 desensitized the MIA PaCa-2 to the induction of apoptosis by gemcitabine.

Conclusions

Our results suggest that the serum level of DJ-1 may be a potential biomarker for pancreatic cancer, and that DJ-1 plays critical roles in the pancreatic tumor chemoresistance, supporting the development of chemotherapeutic approaches targeting this oncogene.

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Reference

  • Aleyasin H, Rousseaux MW, Marcogliese PC, Hewitt SJ, Irrcher I, Joselin AP, Parsanejad M, Kim RH, Rizzu P, Callaghan SM, Slack RS, Mak TW, Park DS (2010) DJ-1 protects the nigrostriatal axis from the neurotoxin MPTP by modulation of the AKT pathway. Proc Natl Acad Sci USA 107(7):3186–3191. doi:10.1073/pnas.0914876107

    Article  PubMed  CAS  Google Scholar 

  • Banerjee S, Zhang Y, Ali S, Bhuiyan M, Wang Z, Chiao PJ, Philip PA, Abbruzzese J, Sarkar FH (2005) Molecular evidence for increased antitumor activity of gemcitabine by genistein in vitro and in vivo using an orthotopic model of pancreatic cancer. Cancer Res 65(19):9064–9072. doi:10.1158/0008-5472.CAN-05-1330

    Article  PubMed  CAS  Google Scholar 

  • Bergman PJ, Harris D (1997) Radioresistance, chemoresistance, and apoptosis resistance. The past, present, and future. Vet Clin North Am Small Anim Pract 27(1):47–57

    PubMed  CAS  Google Scholar 

  • Brand RE, Nolen BM, Zeh HJ, Allen PJ, Eloubeidi MA, Goldberg M, Elton E, Arnoletti JP, Christein JD, Vickers SM, Langmead CJ, Landsittel DP, Whitcomb DC, Grizzle WE, Lokshin AE (2011) Serum biomarker panels for the detection of pancreatic cancer. Clin Cancer Res 17(4):805–816. doi:10.1158/1078-0432.CCR-10-0248

    Article  PubMed  CAS  Google Scholar 

  • Brognard J, Clark AS, Ni Y, Dennis PA (2001) Akt/protein kinase B is constitutively active in non-small cell lung cancer cells and promotes cellular survival and resistance to chemotherapy and radiation. Cancer Res 61(10):3986–3997

    PubMed  CAS  Google Scholar 

  • Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD (1997) Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 15(6):2403–2413

    PubMed  CAS  Google Scholar 

  • Chen J, Li L, Chin LS (2010) Parkinson disease protein DJ-1 converts from a zymogen to a protease by carboxyl-terminal cleavage. Hum Mol Genet 19(12):2395–2408. doi:10.1093/hmg/ddq113

    Article  PubMed  CAS  Google Scholar 

  • Clements CM, McNally RS, Conti BJ, Mak TW, Ting JP (2006) DJ-1, a cancer- and Parkinson’s disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2. Proc Natl Acad Sci USA 103(41):15091–15096. doi:10.1073/pnas.0607260103

    Article  PubMed  CAS  Google Scholar 

  • Covey TM, Edes K, Coombs GS, Virshup DM, Fitzpatrick FA (2010) Alkylation of the tumor suppressor PTEN activates Akt and beta-catenin signaling: a mechanism linking inflammation and oxidative stress with cancer. PLoS ONE 5(10):e13545. doi:10.1371/journal.pone.0013545

    Article  PubMed  Google Scholar 

  • Fan J, Ren H, Jia N, Fei E, Zhou T, Jiang P, Wu M, Wang G (2008) DJ-1 decreases Bax expression through repressing p53 transcriptional activity. J Biol Chem 283(7):4022–4030. doi:10.1074/jbc.M707176200

    Article  PubMed  CAS  Google Scholar 

  • Fraser M, Leung BM, Yan X, Dan HC, Cheng JQ, Tsang BK (2003) p53 is a determinant of X-linked inhibitor of apoptosis protein/Akt-mediated chemoresistance in human ovarian cancer cells. Cancer Res 63(21):7081–7088

    PubMed  CAS  Google Scholar 

  • Gaviraghi M, Tunici P, Valensin S, Rossi M, Giordano C, Magnoni L, Dandrea M, Montagna L, Ritelli R, Scarpa A, Bakker A (2011) Pancreatic cancer spheres are more than just aggregates of stem marker-positive cells. Biosci Rep 31(1):45–55. doi:10.1042/BSR20100018

    Article  PubMed  CAS  Google Scholar 

  • Gronborg M, Kristiansen TZ, Iwahori A, Chang R, Reddy R, Sato N, Molina H, Jensen ON, Hruban RH, Goggins MG, Maitra A, Pandey A (2006) Biomarker discovery from pancreatic cancer secretome using a differential proteomic approach. Mol Cell Proteomics 5(1):157–171. doi:10.1074/mcp.M500178-MCP200

    PubMed  CAS  Google Scholar 

  • Harsha HC, Kandasamy K, Ranganathan P, Rani S, Ramabadran S, Gollapudi S, Balakrishnan L, Dwivedi SB, Telikicherla D, Selvan LD, Goel R, Mathivanan S, Marimuthu A, Kashyap M, Vizza RF, Mayer RJ, Decaprio JA, Srivastava S, Hanash SM, Hruban RH, Pandey A (2009) A compendium of potential biomarkers of pancreatic cancer. PLoS Med 6(4):e1000046. doi:10.1371/journal.pmed.1000046

    Article  PubMed  CAS  Google Scholar 

  • He XY, Liu BY, Yao WY, Zhao XJ, Zheng Z, Li JF, Yu BQ, Yuan YZ (2011) Serum DJ-1 as a diagnostic marker and prognostic factor for pancreatic cancer. J Dig Dis 12(2):131–137. doi:10.1111/j.1751-2980.2011.00488.x

    Article  PubMed  CAS  Google Scholar 

  • Heinemann V (2002) Gemcitabine-based combination treatment of pancreatic cancer. Semin Oncol 29(1 Suppl 3):25–35

    Article  PubMed  CAS  Google Scholar 

  • Hermann PC, Bhaskar S, Cioffi M, Heeschen C (2010) Cancer stem cells in solid tumors. Semin Cancer Biol 20(2):77–84. doi:10.1016/j.semcancer.2010.03.004

    Article  PubMed  CAS  Google Scholar 

  • Hibi T, Mori T, Fukuma M, Yamazaki K, Hashiguchi A, Yamada T, Tanabe M, Aiura K, Kawakami T, Ogiwara A, Kosuge T, Kitajima M, Kitagawa Y, Sakamoto M (2009) Synuclein-gamma is closely involved in perineural invasion and distant metastasis in mouse models and is a novel prognostic factor in pancreatic cancer. Clin Cancer Res 15(8):2864–2871. doi:10.1158/1078-0432.CCR-08-2946

    Article  PubMed  CAS  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 

  • Junn E, Taniguchi H, Jeong BS, Zhao X, Ichijo H, Mouradian MM (2005) Interaction of DJ-1 with Daxx inhibits apoptosis signal-regulating kinase 1 activity and cell death. Proc Natl Acad Sci USA 102(27):9691–9696. doi:10.1073/pnas.0409635102

    Article  PubMed  CAS  Google Scholar 

  • Kim RH, Peters M, Jang Y, Shi W, Pintilie M, Fletcher GC, DeLuca C, Liepa J, Zhou L, Snow B, Binari RC, Manoukian AS, Bray MR, Liu FF, Tsao MS, Mak TW (2005) DJ-1, a novel regulator of the tumor suppressor PTEN. Cancer Cell 7(3):263–273. doi:10.1016/j.ccr.2005.02.010

    Article  PubMed  CAS  Google Scholar 

  • Kunnumakkara AB, Guha S, Krishnan S, Diagaradjane P, Gelovani J, Aggarwal BB (2007) Curcumin potentiates antitumor activity of gemcitabine in an orthotopic model of pancreatic cancer through suppression of proliferation, angiogenesis, and inhibition of nuclear factor-kappaB-regulated gene products. Cancer Res 67(8):3853–3861. doi:10.1158/0008-5472.CAN-06-4257

    Article  PubMed  CAS  Google Scholar 

  • Le Naour F, Misek DE, Krause MC, Deneux L, Giordano TJ, Scholl S, Hanash SM (2001) Proteomics-based identification of RS/DJ-1 as a novel circulating tumor antigen in breast cancer. Clin Cancer Res 7(11):3328–3335

    PubMed  Google Scholar 

  • Li Z, Sclabas GM, Peng B, Hess KR, Abbruzzese JL, Evans DB, Chiao PJ (2004) Overexpression of synuclein-gamma in pancreatic adenocarcinoma. Cancer 101(1):58–65. doi:10.1002/cncr.20321

    Article  PubMed  CAS  Google Scholar 

  • Lo M, Ling V, Wang YZ, Gout PW (2008) The xc- cystine/glutamate antiporter: a mediator of pancreatic cancer growth with a role in drug resistance. Br J Cancer 99(3):464–472. doi:10.1038/sj.bjc.6604485

    Article  PubMed  CAS  Google Scholar 

  • Longley DB, Johnston PG (2005) Molecular mechanisms of drug resistance. J Pathol 205(2):275–292. doi:10.1002/path.1706

    Article  PubMed  CAS  Google Scholar 

  • MacKeigan JP, Clements CM, Lich JD, Pope RM, Hod Y, Ting JP (2003) Proteomic profiling drug-induced apoptosis in non-small cell lung carcinoma: identification of RS/DJ-1 and RhoGDIalpha. Cancer Res 63(20):6928–6934

    PubMed  CAS  Google Scholar 

  • Makin G, Dive C (2001) Apoptosis and cancer chemotherapy. Trends Cell Biol 11(11):S22–26

    Article  PubMed  CAS  Google Scholar 

  • McCoy MK, Cookson MR (2011) DJ-1 regulation of mitochondrial function and autophagy through oxidative stress. Autophagy 7(5):531–532

    Article  PubMed  CAS  Google Scholar 

  • Melle C, Ernst G, Escher N, Hartmann D, Schimmel B, Bleul A, Thieme H, Kaufmann R, Felix K, Friess HM, Settmacher U, Hommann M, Richter KK, Daffner W, Taubig H, Manger T, Claussen U, von Eggeling F (2007) Protein profiling of microdissected pancreas carcinoma and identification of HSP27 as a potential serum marker. Clin Chem 53(4):629–635. doi:10.1373/clinchem.2006.079194

    Article  PubMed  CAS  Google Scholar 

  • Michaud DS (2004) Epidemiology of pancreatic cancer. Minerva Chir 59(2):99–111

    PubMed  CAS  Google Scholar 

  • Moore DJ, Zhang L, Troncoso J, Lee MK, Hattori N, Mizuno Y, Dawson TM, Dawson VL (2005) Association of DJ-1 and parkin mediated by pathogenic DJ-1 mutations and oxidative stress. Hum Mol Genet 14(1):71–84. doi:10.1093/hmg/ddi007

    Article  PubMed  CAS  Google Scholar 

  • Nagakubo D, Taira T, Kitaura H, Ikeda M, Tamai K, Iguchi-Ariga SM, Ariga H (1997) DJ-1, a novel oncogene which transforms mouse NIH3T3 cells in cooperation with ras. Biochem Biophys Res Commun 231(2):509–513. doi:10.1006/bbrc.1997.6132

    Article  PubMed  CAS  Google Scholar 

  • Oki E, Baba H, Tokunaga E, Nakamura T, Ueda N, Futatsugi M, Mashino K, Yamamoto M, Ikebe M, Kakeji Y, Maehara Y (2005) Akt phosphorylation associates with LOH of PTEN and leads to chemoresistance for gastric cancer. Int J Cancer 117(3):376–380. doi:10.1002/ijc.21170

    Article  PubMed  CAS  Google Scholar 

  • Pannala R, Basu A, Petersen GM, Chari ST (2009) New-onset diabetes: a potential clue to the early diagnosis of pancreatic cancer. Lancet Oncol 10(1):88–95. doi:10.1016/S1470-2045(08)70337-1

    Article  PubMed  Google Scholar 

  • Simeone DM, Ji B, Banerjee M, Arumugam T, Li D, Anderson MA, Bamberger AM, Greenson J, Brand RE, Ramachandran V, Logsdon CD (2007) CEACAM1, a novel serum biomarker for pancreatic cancer. Pancreas 34(4):436–443. doi:10.1097/MPA.0b013e3180333ae3

    Article  PubMed  CAS  Google Scholar 

  • Singleton AB, Farrer M, Johnson J, Singleton A, Hague S, Kachergus J, Hulihan M, Peuralinna T, Dutra A, Nussbaum R, Lincoln S, Crawley A, Hanson M, Maraganore D, Adler C, Cookson MR, Muenter M, Baptista M, Miller D, Blancato J, Hardy J, Gwinn-Hardy K (2003) alpha-Synuclein locus triplication causes Parkinson’s disease. Science 302(5646):841. doi:10.1126/science.1090278

    Article  PubMed  CAS  Google Scholar 

  • Soengas MS, Lowe SW (2003) Apoptosis and melanoma chemoresistance. Oncogene 22(20):3138–3151. doi:10.1038/sj.onc.1206454

    Article  PubMed  CAS  Google Scholar 

  • Taira T, Takahashi K, Kitagawa R, Iguchi-Ariga SM, Ariga H (2001) Molecular cloning of human and mouse DJ-1 genes and identification of Sp1-dependent activation of the human DJ-1 promoter. Gene 263(1–2):285–292

    Article  PubMed  CAS  Google Scholar 

  • Takahashi K, Taira T, Niki T, Seino C, Iguchi-Ariga SM, Ariga H (2001) DJ-1 positively regulates the androgen receptor by impairing the binding of PIASx alpha to the receptor. J Biol Chem 276(40):37556–37563. doi:10.1074/jbc.M101730200

    Article  PubMed  CAS  Google Scholar 

  • Tian M, Cui YZ, Song GH, Zong MJ, Zhou XY, Chen Y, Han JX (2008) Proteomic analysis identifies MMP-9, DJ-1 and A1BG as overexpressed proteins in pancreatic juice from pancreatic ductal adenocarcinoma patients. BMC Cancer 8:241. doi:10.1186/1471-2407-8-241

    Article  PubMed  Google Scholar 

  • Vareed SK, Bhat VB, Thompson C, Vasu VT, Fermin D, Choi H, Creighton CJ, Gayatri S, Lan L, Putluri N, Thangjam GS, Kaur P, Shabahang M, Giri JG, Nesvizhskii AI, Asea AA, Cashikar AG, Rao A, McLoughlin J, Sreekumar A (2011) Metabolites of purine nucleoside phosphorylase (NP) in serum have the potential to delineate pancreatic adenocarcinoma. PLoS ONE 6(3):e17177. doi:10.1371/journal.pone.0017177

    Article  PubMed  CAS  Google Scholar 

  • Yang Y, Gehrke S, Haque ME, Imai Y, Kosek J, Yang L, Beal MF, Nishimura I, Wakamatsu K, Ito S, Takahashi R, Lu B (2005) Inactivation of Drosophila DJ-1 leads to impairments of oxidative stress response and phosphatidylinositol 3-kinase/Akt signaling. Proc Natl Acad Sci USA 102(38):13670–13675. doi:10.1073/pnas.0504610102

    Article  PubMed  CAS  Google Scholar 

  • Yuen HF, Chan YP, Law S, Srivastava G, El-Tanani M, Mak TW, Chan KW (2008) DJ-1 could predict worse prognosis in esophageal squamous cell carcinoma. Cancer Epidemiol Biomarkers Prev 17(12):3593–3602. doi:10.1158/1055-9965.EPI-08-0214

    Article  PubMed  CAS  Google Scholar 

  • Zeng HZ, Qu YQ, Zhang WJ, Xiu B, Deng AM, Liang AB (2011) Proteomic analysis identified DJ-1 as a cisplatin resistant marker in non-small cell lung cancer. Int J Mol Sci 12(6):3489–3499. doi:10.3390/ijms12063489

    Article  PubMed  CAS  Google Scholar 

  • Zhou W, Freed CR (2005) DJ-1 up-regulates glutathione synthesis during oxidative stress and inhibits A53T alpha-synuclein toxicity. J Biol Chem 280(52):43150–43158. doi:10.1074/jbc.M507124200

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (nos. 81172158, 81001094, 81071960, 30901445 and 81100549).

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We confirm that there is no competing financial or other interest in this paper, as described in the instruction for authors.

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Authors and Affiliations

  1. Department of Surgery, Second Affiliated Hospital, College of Medicine, Cancer Institute of Zhejiang University, Zhejiang University, #88 Jiefang Road, Hangzhou, 310009, Zhejiang Province, People’s Republic of China

    Ying Chen, Muxing Kang, Wenjie Lu, Qingqu Guo, Bo Zhang, Qiuping Xie & Yulian Wu

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  1. Ying Chen
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  2. Muxing Kang
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Correspondence to Yulian Wu.

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Chen, Y., Kang, M., Lu, W. et al. DJ-1, a novel biomarker and a selected target gene for overcoming chemoresistance in pancreatic cancer. J Cancer Res Clin Oncol 138, 1463–1474 (2012). https://doi.org/10.1007/s00432-012-1205-3

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  • DOI: https://doi.org/10.1007/s00432-012-1205-3

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