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Slug contributes to gemcitabine resistance through epithelial-mesenchymal transition in CD133+ pancreatic cancer cells

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Abstract

CD133-positive pancreatic cancer is correlated with unfavorable survival despite current development of therapy. Slug acts as a master regulator of epithelial-mesenchymal transition (EMT) which is the essential process in cancer progression. The aim of this study was to investigate the role of Slug in gemcitabine treatment for CD133-positive pancreatic cancer cells. We used a previously established pancreatic cancer cell line expressing high level of CD133 (Capan-1M9), which also expresses high level of Slug. We generated Slug knock-down subclone (shSlug M9) from this cell line, and compared expression of EMT-related genes, migration, invasion and gemcitabine resistance between two cell lines. Slug knock-down in CD133-positive pancreatic cancer cell line led to the reduction of migration and invasion ability. Furthermore, Slug knock-down sensitized CD133-positive pancreatic cancer cell line to gemcitabine. These results suggest that Slug plays an important role in not only invasion ability through EMT but also gemcitabine resistance of CD133-positive pancreatic cancer cells.

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References

  1. Jemal A, Siegel R, Ward E, et al. Cancer statistics. 2008. CA Cancer J Clin. 2008;58:71–96.

    Article  PubMed  Google Scholar 

  2. Takao S, Ding Q, Matsubara S. Pancreatic cancer stem cells: regulatory networks in the tumor microenvironment and targeted therapy. J Hepatobiliary Pancreat Sci. 2012;19:614–20.

    Article  PubMed  Google Scholar 

  3. Li C, Heidt DG, Dalerba P, et al. Identification of pancreatic cancer stem cells. Cancer Res. 2007;67:1030–7.

    Article  CAS  PubMed  Google Scholar 

  4. Hermann PC, Huber SL, Herrler T, et al. Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell. 2007;1:313–23.

    Article  CAS  PubMed  Google Scholar 

  5. Maeda S, Shinchi H, Kurahara H, et al. CD133 expression is correlated with lymph node metastasis and vascular endothelial growth factor-C expression in pancreatic cancer. Br J Cancer. 2008;98:1389–97.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Mjaatvedt CH, Markwald RR. Induction of an epithelial-mesenchymal transition by an in vivo adheron-like complex. Dev Biol. 1989;136:118–28.

    Article  CAS  PubMed  Google Scholar 

  7. Thompson EW, Torri J, Sabol M, et al. Oncogene-induced basement membrane invasiveness in human mammary epithelial cells. Clin Exp Metastasis. 1994;12:181–94.

    Article  CAS  PubMed  Google Scholar 

  8. Rosivatz E, Becker I, Specht K, et al. Differential expression of the epithelial-mesenchymal transition regulators snail, SIP1, and twist in gastric cancer. Am J Pathol. 2002;161:1881–91.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Arumugam T, Ramachandran V, Fournier KF, et al. Epithelial to mesenchymal transition contributes to drug resistance in pancreatic cancer. Cancer Res. 2009;69:5820–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Wang Z, Li Y, Kong D, et al. Acquisition of epithelial-mesenchymal transition phenotype of gemcitabine-resistant pancreatic cancer cells is linked with activation of the notch signaling pathway. Cancer Res. 2009;69:2400–7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Thiery JP. Epithelial-mesenchymal transitions in development and pathologies. Curr Opin Cell Biol. 2003;15:740–6.

    Article  CAS  PubMed  Google Scholar 

  12. Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell. 2009;139:871–90.

    Article  CAS  PubMed  Google Scholar 

  13. Zeisberg M, Neilson EG. Biomarkers for epithelial-mesenchymal transitions. J Clin Invest. 2009;119:1429–37.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Mancini M, Petta S, Iacobucci I, Salvestrini V, Barbieri E, Santucci MA. Zinc-finger transcription factor slug contributes to the survival advantage of chronic myeloid leukemia cells. Cell Signal. 2010;22:1247–53.

    Article  CAS  PubMed  Google Scholar 

  15. Guo Y, Zi X, Koontz Z, et al. Blocking Wnt/LRP5 signaling by a soluble receptor modulates the epithelial to mesenchymal transition and suppresses met and metalloproteinases in osteosarcoma Saos-2 cells. J Orthop Res. 2007;25:964–71.

    Article  CAS  PubMed  Google Scholar 

  16. Jethwa P, Naqvi M, Hardy RG, et al. Overexpression of Slug is associated with malignant progression of esophageal adenocarcinoma. World J Gastroenterol. 2008;14:1044–52.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Come C, Magnino F, Bibeau F, et al. Snail and slug play distinct roles during breast carcinoma progression. Clin Cancer Res. 2006;12:5395–402.

    Article  CAS  PubMed  Google Scholar 

  18. Burris HA 3rd, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997;15:2403–13.

    CAS  PubMed  Google Scholar 

  19. Moore MJ, Goldstein D, Hamm J, et al. National Cancer Institute of Canada Clinical Trials, Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007;25:1960–6.

    Article  CAS  PubMed  Google Scholar 

  20. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364:1817–25.

    Article  CAS  PubMed  Google Scholar 

  21. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369:1691–703.

    Article  Google Scholar 

  22. Ding Q, Yoshimitsu M, Kuwahata T, et al. Establishment of a highly migratory subclone reveals that CD133 contributes to migration and invasion through epithelial-mesenchymal transition in pancreatic cancer. Hum Cell. 2012;25:1–8.

    Article  PubMed  Google Scholar 

  23. Peinado H, Olmeda D, Cano A. Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer. 2007;7:415–28.

    Article  CAS  PubMed  Google Scholar 

  24. Ding Q, Miyazaki Y, Tsukasa K, Matsubara S, Yoshimitsu M, Takao S. CD133 facilitates epithelial-mesenchymal transition through interaction with the ERK pathway in pancreatic cancer metastasis. Mol Cancer. 2014;13:15.

    Article  PubMed Central  PubMed  Google Scholar 

  25. Yang AD, Fan F, Camp ER, et al. Chronic oxaliplatin resistance induces epithelial-to-mesenchymal transition in colorectal cancer cell lines. Clin Cancer Res. 2006;12:4147–53.

    Article  CAS  PubMed  Google Scholar 

  26. Quint K, Tonigold M, Di Fazio P, et al. Pancreatic cancer cells surviving gemcitabine treatment express markers of stem cell differentiation and epithelial-mesenchymal transition. Int J Oncol. 2012;41:2093–102.

    CAS  PubMed  Google Scholar 

  27. Cheng GZ, Chan J, Wang Q, Zhang W, Sun CD, Wang LH. Twist transcriptionally up-regulates AKT2 in breast cancer cells leading to increased migration, invasion, and resistance to paclitaxel. Cancer Res. 2007;67:1979–87.

    Article  CAS  PubMed  Google Scholar 

  28. Kajiyama H, Shibata K, Terauchi M, et al. Chemoresistance to paclitaxel induces epithelial-mesenchymal transition and enhances metastatic potential for epithelial ovarian carcinoma cells. Int J Oncol. 2007;31:277–83.

    CAS  PubMed  Google Scholar 

  29. Kurrey NK, Jalgaonkar SP, Joglekar AV, et al. Snail and slug mediate radioresistance and chemoresistance by antagonizing p53-mediated apoptosis and acquiring a stem-like phenotype in ovarian cancer cells. Stem Cells. 2009;27:2059–68.

    Article  CAS  PubMed  Google Scholar 

  30. Haslehurst AM, Koti M, Dharsee M, et al. EMT transcription factors snail and slug directly contribute to cisplatin resistance in ovarian cancer. BMC Cancer. 2012;12:91.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Tamura D, Arao T, Nagai T, et al. Slug increases sensitivity to tubulin-binding agents via the downregulation of betaIII and betaIVa-tubulin in lung cancer cells. Cancer Med. 2013;2:144–54.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Reshmi G, Sona C, Pillai MR. Comprehensive patterns in microRNA regulation of transcription factors during tumor metastasis. J Cell Biochem. 2011;112:2210–7.

    Article  CAS  PubMed  Google Scholar 

  33. Wang J, Haubrock M, Cao KM, et al. Regulatory coordination of clustered microRNAs based on microRNA-transcription factor regulatory network. BMC Syst Biol. 2011;5:199.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Moes M, Le Bechec A, Crespo I, et al. A novel network integrating a miRNA-203/SNAI1 feedback loop which regulates epithelial to mesenchymal transition. PLoS ONE. 2012;7:e35440.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Liu YN, Yin JJ, Abou-Kheir W, et al. MiR-1 and miR-200 inhibit EMT via Slug-dependent and tumorigenesis via Slug-independent mechanisms. Oncogene. 2013;32:296–306.

    Article  CAS  PubMed  Google Scholar 

  36. Bracken CP, Gregory PA, Kolesnikoff N, et al. A double-negative feedback loop between ZEB1-SIP1 and the microRNA-200 family regulates epithelial-mesenchymal transition. Cancer Res. 2008;68:7846–54.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We thank Ms. Miho Hachiman for her assistance with shSlugM9-GFP cell line established by lentiviral transduction, Mr. Toru Obara and Ms. Shoko Ueno for their assistance with the pathological analysis, Ms. Ryoko Imakiire for her gene profiling analysis, and Miss Hiromi Tokushige and Ms. Yoshiko Setogawa for their clerical assistance. This work was supported by JSPS KAKENHI (Grant-in-Aid for Scientific Research (B)) Grant Number 25293288 (to S.T.) from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

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The authors declare no conflict of interest.

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Authors and Affiliations

  1. Division of Cancer and Regenerative Medicine, Frontier Biomedical Science and Swine Research Center, Kagoshima University, 8-35-1, Sakuragaoka, Kagoshima, 890-8520, Japan

    Koichiro Tsukasa, Qiang Ding, Yumi Miyazaki, Shyuichiro Matsubara & Sonshin Takao

  2. Keenan Research Centre of the Li Ka Shing Knowledge Institute of St. Michael’s Hospital, Tronto, Canada

    Qiang Ding

  3. Department of Hematology and Immunology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1, Sakuragaoka, Kagoshima, 890-8520, Japan

    Makoto Yoshimitsu

Authors
  1. Koichiro Tsukasa
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  2. Qiang Ding
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  3. Makoto Yoshimitsu
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  4. Yumi Miyazaki
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  5. Shyuichiro Matsubara
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  6. Sonshin Takao
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Corresponding author

Correspondence to Sonshin Takao.

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Tsukasa, K., Ding, Q., Yoshimitsu, M. et al. Slug contributes to gemcitabine resistance through epithelial-mesenchymal transition in CD133+ pancreatic cancer cells. Human Cell 28, 167–174 (2015). https://doi.org/10.1007/s13577-015-0117-3

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  • DOI: https://doi.org/10.1007/s13577-015-0117-3

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