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Medical Oncology

, 31:25 | Cite as

KAP-1 is overexpressed and correlates with increased metastatic ability and tumorigenicity in pancreatic cancer

  • Chao Yu
  • Lei Zhan
  • Jianxin Jiang
  • Yaozhen Pan
  • Hong Zhang
  • Xu Li
  • Feng Pen
  • Min Wang
  • Renyi Qin
  • Chenyi SunEmail author
Original Paper

Abstract

This study aimed to investigate the role in metastasis and prognostic value of KAP-1 in pancreatic cancer (PC). The expression of KAP-1 was analyzed by quantitative real-time polymerase chain reaction, Western blotting, and immunohistochemical staining in 91 human PC tissue samples. Capan-2 cells were transfected with a lentiviral vector expressing KAP-1 (Capan-2/KAP-1) or the empty vector (Capan-2/vector); cell migration and invasion were assayed in vitro using Transwell migration and wound-healing assays, and in vivo using a xenograft model in nude mice. KAP-1 was found to be overexpressed in human PC, and the expression of KAP-1 correlated with clinical stage. Overexpression of KAP-1 increased the invasion and migration of Capan-2 cells in vitro. Furthermore, overexpression of KAP-1 promoted the growth and metastatic ability of PC cells in a xenograft model in nude mice. Moreover, overexpression of KAP-1 induced the epithelial–mesenchymal transition (EMT) in PC cells both in vitro and in vivo, as indicated by increased expression of mesenchymal markers such as vimentin and decreased expression of E-cadherin. This study indicates that KAP-1 may promote metastasis in PC by regulating the EMT and suggests that KAP-1 may have potential as a predictor of metastasis in patients with pancreatic cancer.

Keywords

KAP-1 EMT Metastasis Tumorigenicity Pancreatic cancer 

Notes

Acknowledgments

The authors thank the other members of the Professor Chengyi Sun and Renyi Qin’s laboratory for their help and technical support with this project. This study was supported by the National Natural Science Foundation of China (No. 81160311); and the International Science & Technology Cooperation Program of China (No. 2014DFA31420); and the Outstanding Young Training Project of Science and Education of Guizhou Province (No. [2012]177).

Conflict of interest

We certify that regarding this paper, no actual or potential conflicts of interests exist; the work is original, has not been accepted for publication nor is concurrently under consideration elsewhere, and will not be published elsewhere without the permission of the Editor, and that all the authors have contributed directly to the planning, execution, or analysis of the work reported or to the writing of the paper.

References

  1. 1.
    Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62:10–29.PubMedCrossRefGoogle Scholar
  2. 2.
    Arslan AA, Helzlsouer KJ, Kooperberg C, Shu XO, Steplowski E, Bueno-de-Mesquita HB, Fuchs CS, Gross MD, Jacobs EJ, Lacroix AZ, Petersen GM, Stolzenberg-Solomon RZ, Zheng W, Albanes D, Amundadottir L, Bamlet WR, Barricarte A, Bingham SA, Boeing H, Boutron-Ruault MC, Buring JE, Chanock SJ, Clipp S, Gaziano JM, Giovannucci EL, Hankinson SE, Hartge P, Hoover RN, Hunter DJ, Hutchinson A, Jacobs KB, Kraft P, Lynch SM, Manjer J, Manson JE, McTiernan A, McWilliams RR, Mendelsohn JB, Michaud DS, Palli D, Rohan TE, Slimani N, Thomas G, Tjonneland A, Tobias GS, Trichopoulos D, Virtamo J, Wolpin BM, Yu K, Zeleniuch-Jacquotte A, Patel AV. Anthropometric measures, body mass index, and pancreatic cancer: a pooled analysis from the Pancreatic Cancer Cohort Consortium (PanScan). Arch Intern Med. 2010;170:791–802.PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Kim SS, Chen YM, O’Leary E, Witzgall R, Vidal M, Bonventre JV. A novel member of the RING finger family, KRIP-1, associates with the KRAB-A transcriptional repressor domain of zinc finger proteins. Proc Natl Acad Sci USA. 1996;93:15299–304.PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Friedman JR, Fredericks WJ, Jensen DE, Speicher DW, Huang XP, Neilson EG, Rauscher FJ 3rd. KAP-1, a novel corepressor for the highly conserved KRAB repression domain. Genes Dev. 1996;10:2067–78.PubMedCrossRefGoogle Scholar
  5. 5.
    Agata Y, Matsuda E, Shimizu A. Two novel Kruppel-associated box-containing zinc-finger proteins, KRAZ1 and KRAZ2, repress transcription through functional interaction with the corepressor KAP-1 (TIF1beta/KRIP-1). J Biol Chem. 1999;274:16412–22.PubMedCrossRefGoogle Scholar
  6. 6.
    Wang C, Ivanov A, Chen L, Fredericks WJ, Seto E, Rauscher FJ 3rd, Chen J. MDM2 interaction with nuclear corepressor KAP1 contributes to p53 inactivation. EMBO J. 2005;24:3279–90.PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Lee YK, Thomas SN, Yang AJ, Ann DK. Doxorubicin down-regulates Kruppel-associated box domain-associated protein 1 sumoylation that relieves its transcription repression on p21WAF1/CIP1 in breast cancer MCF-7 cells. J Biol Chem. 2007;282:1595–606.PubMedCrossRefGoogle Scholar
  8. 8.
    Ryan RF, Schultz DC, Ayyanathan K, Singh PB, Friedman JR, Fredericks WJ, Rauscher FJ 3rd. KAP-1 corepressor protein interacts and colocalizes with heterochromatic and euchromatic HP1 proteins: a potential role for Kruppel-associated box-zinc finger proteins in heterochromatin-mediated gene silencing. Mol Cell Biol. 1999;19:4366–78.PubMedCentralPubMedGoogle Scholar
  9. 9.
    Lechner MS, Begg GE, Speicher DW, Rauscher FJ 3rd. Molecular determinants for targeting heterochromatin protein 1-mediated gene silencing: direct chromoshadow domain-KAP-1 corepressor interaction is essential. Mol Cell Biol. 2000;20:6449–65.PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Ziv Y, Bielopolski D, Galanty Y, Lukas C, Taya Y, Schultz DC, Lukas J, Bekker-Jensen S, Bartek J, Shiloh Y. Chromatin relaxation in response to DNA double-strand breaks is modulated by a novel ATM- and KAP-1 dependent pathway. Nat Cell Biol. 2006;8:870–6.PubMedCrossRefGoogle Scholar
  11. 11.
    Venkov CD, Link AJ, Jennings JL, Plieth D, Inoue T, Nagai K, Xu C, Dimitrova YN, Rauscher FJ, Neilson EG. A proximal activator of transcription in epithelial-mesenchymal transition. J Clin Investig. 2007;117:482–91.PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Lee JM, Dedhar S, Kalluri R, Thompson EW. The epithelial-mesenchymal transition: new insights in signaling, development, and disease. J Cell Biol. 2006;172:973–81.PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Wolf D, Goff SP. TRIM28 mediates primer binding site-targeted silencing of murine leukemia virus in embryonic cells. Cell. 2007;131:46–57.PubMedCrossRefGoogle Scholar
  14. 14.
    Nakajima S, Doi R, Toyoda E, Tsuji S, Wada M, Koizumi M, Tulachan SS, Ito D, Kami K, Mori T, Kawaguchi Y, Fujimoto K, Hosotani R, Imamura M. N-cadherin expression and epithelial-mesenchymal transition in pancreatic carcinoma. Clin Cancer Res. 2004;10:4125–33.PubMedCrossRefGoogle Scholar
  15. 15.
    Ellenrieder V, Hendler SF, Ruhland C, Boeck W, Adler G, Gress TM. TGF-beta-induced invasiveness of pancreatic cancer cells is mediated by matrix metalloproteinase-2 and the urokinase plasminogen activator system. Int J Cancer. 2001;93:204–11.PubMedCrossRefGoogle Scholar
  16. 16.
    Peinado H, Olmeda D, Cano A. Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev. 2007;7:415–28.CrossRefGoogle Scholar
  17. 17.
    Kang Y, Massague J. Epithelial-mesenchymal transitions: twist in development and metastasis. Cell. 2004;118:277–9.PubMedCrossRefGoogle Scholar
  18. 18.
    Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, Brooks M, Reinhard F, Zhang CC, Shipitsin M, Campbell LL, Polyak K, Brisken C, Yang J, Weinberg RA. The epithelial–mesenchymal transition generates cells with properties of stem cells. Cell. 2008;133:704–15.PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Seki Y, Kurisaki A, Watanabe-Susaki K, Nakajima Y, Nakanishi M, Arai Y, Shiota K, Sugino H, Asashima M. TIF1beta regulates the pluripotency of embryonic stem cells in a phosphorylation-dependent manner. Proc Natl Acad Sci USA. 2010;107:10926–31.PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Yokoe T, Toiyama Y, Okugawa Y, Tanaka K, Ohi M, Inoue Y, Mohri Y, Miki C, Kusunoki M. KAP1 is associated with peritoneal carcinomatosis in gastric cancer. Ann Surg Oncol. 2010;17:821–8.PubMedCrossRefGoogle Scholar
  21. 21.
    Soumaoro LT, Uetake H, Higuchi T, et al. Cyclooxygenase-2 expression: a significant prognostic indicator for patients with colorectal cancer. Clin Cancer Res. 2004;10:8465–71.PubMedCrossRefGoogle Scholar
  22. 22.
    Chen PN, Hsieh YS, Chiang CL, Chiou HL, Yang SF, Chu SC. Silibinin inhibits invasion of oral cancer cells by suppressing the MAPK pathway. J Dent Res. 2006;85:220–5.PubMedCrossRefGoogle Scholar
  23. 23.
    Choi W, Gerner EW, Ramdas L, Dupart J, Carew J, Proctor L, Huang P, Zhang W, Hamilton SR. Combination of 5-fluorouracil and N1, N11-diethylnorspermine markedly activates spermidine/spermine N1-acetyltransferase expression, depletes polyamines, and synergistically induces apoptosis in colon carcinoma cells. J Biol Chem. 2005;280:3295–304.PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Radisky DC. Epithelial–mesenchymal transition. J Cell Sci. 2005;118:4325–6.PubMedCrossRefGoogle Scholar
  25. 25.
    Thiery JP. Epithelial–mesenchymal transitions in tumour progression. Nat Rev Cancer. 2002;2:442–54.PubMedCrossRefGoogle Scholar
  26. 26.
    Desmouliere A. Factors influencing myofibroblast differentiation during wound healing and fibrosis. Cell Biol Int. 1995;19:471–6.PubMedCrossRefGoogle Scholar
  27. 27.
    Peter ME. Let-7 and miR-200 microRNAs: guardians against pluripotency and cancer progression. Cell Cycle (Georgetown, Tex). 2009;8:843–52.CrossRefGoogle Scholar
  28. 28.
    Yang J, Weinberg RA. Epithelial–mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell. 2008;14:818–29.PubMedCrossRefGoogle Scholar
  29. 29.
    Li Y, VandenBoom TG, Kong D, Wang Z, Ali S, Philip PA, et al. Up-regulation of miR-200 and let-7 by natural agents leads to the reversal of epithelial-to-mesenchymal transition in gemcitabineresistant pancreatic cancer cells. Cancer Res. 2009;69:6704–12.PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Arumugam T, Ramachandran V, Fournier KF, Wang H, Marquis L, Abbruzzese JL, et al. Epithelial to mesenchymal transition contributes to drug resistance in pancreatic cancer. Cancer Res. 2009;69:5820–8.PubMedCrossRefGoogle Scholar
  31. 31.
    Javle MM, Gibbs JF, Iwata KK, Pak Y, Rutledge P, Yu J, et al. Epithelial-mesenchymal transition (EMT) and activated extracellular signal-regulated kinase (p-Erk) in surgically resected pancreatic cancer. Ann Surg Oncol. 2007;14:3527–33.PubMedCrossRefGoogle Scholar
  32. 32.
    Nakajima S, Doi R, Toyoda E, Tsuji S, Wada M, Koizumi M, et al. N-cadherin expression and epithelial-mesenchymal transition in pancreatic carcinoma. Clin Cancer Res. 2004;10:4125–33.PubMedCrossRefGoogle Scholar
  33. 33.
    Moustakas A, Heldin CH. Signaling networks guiding epithelial–mesenchymal transitions during embryogenesis and cancer progression. Cancer Sci. 2007;98:1512–20.PubMedCrossRefGoogle Scholar
  34. 34.
    Okamoto K, Kitabayashi I, Taya Y. KAP1 dictates p53 response induced by chemotherapeutic agents via Mdm2 interaction. Biochem Biophys Res Commun. 2006;351:216–22.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Chao Yu
    • 1
  • Lei Zhan
    • 1
  • Jianxin Jiang
    • 1
  • Yaozhen Pan
    • 1
  • Hong Zhang
    • 1
  • Xu Li
    • 2
  • Feng Pen
    • 2
  • Min Wang
    • 2
  • Renyi Qin
    • 2
  • Chenyi Sun
    • 1
    Email author
  1. 1.Department of Biliary-Hepatic SurgeryAffiliated Hospital of Guiyang Medical CollegeGuiyangChina
  2. 2.Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina

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