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.
Similar content being viewed by others
References
Jemal A, Siegel R, Ward E, et al. Cancer statistics. 2008. CA Cancer J Clin. 2008;58:71–96.
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.
Li C, Heidt DG, Dalerba P, et al. Identification of pancreatic cancer stem cells. Cancer Res. 2007;67:1030–7.
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.
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.
Mjaatvedt CH, Markwald RR. Induction of an epithelial-mesenchymal transition by an in vivo adheron-like complex. Dev Biol. 1989;136:118–28.
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.
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.
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.
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.
Thiery JP. Epithelial-mesenchymal transitions in development and pathologies. Curr Opin Cell Biol. 2003;15:740–6.
Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell. 2009;139:871–90.
Zeisberg M, Neilson EG. Biomarkers for epithelial-mesenchymal transitions. J Clin Invest. 2009;119:1429–37.
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.
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.
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.
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.
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.
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.
Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364:1817–25.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Reshmi G, Sona C, Pillai MR. Comprehensive patterns in microRNA regulation of transcription factors during tumor metastasis. J Cell Biochem. 2011;112:2210–7.
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.
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.
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.
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.
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.
Conflict of interest
The authors declare no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13577-015-0117-3