Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related deaths. Deregulation of cell-cycle control is thought to be a crucial event in malignant transformation, and CDC25 phosphatases are a family of cyclin-dependent kinase activators, which act at different points of the cell cycle, including G1–S and G2–M transition. Here, we investigated the expression and functional significance of CDC25s in PDAC. CDC25B mRNA expression levels in human pancreatic tissue samples were analysed by cDNA array, quantitative PCR and Northern blotting. Immunohistochemistry was carried out to localize and quantify CDC25B expression. Two specific CDC25B inhibitors were utilized to determine the functional relevance of CDC25B. By quantitative RT–PCR, CDC25B mRNA was overexpressed in pancreatic cancer (7.5-fold) in comparison to the normal pancreas. Strong nuclear CDC25B immunoreactivity was present in both pancreatic and metastatic cancer samples, and there was a marked increase of the percentage of positive cells in primary cancer (48.6±16.3%) and metastatic tissues (71.7±3.1%) compared to normal samples (8.3±1.8%). Two CDC25B inhibitors reduced the growth of pancreatic cancer cell lines, resulting in the accumulation of phosphorylated CDC2 and G2/M arrest. These findings demonstrate an important role of CDC25B in cell-cycle progression, raising the possibility that inhibition of CDC25B may have therapeutic potential in pancreatic cancer.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Baldin V, Pelpel K, Cazales M, Cans C and Ducommun B . (2002). J. Biol. Chem., 277, 35176–35182.
Bardeesy N and DePinho RA . (2002). Nat. Rev. Cancer, 2, 897–909.
Broggini M, Buraggi G, Brenna A, Riva L, Codegoni AM, Torri V, Lissoni AA, Mangioni C and D'Incalci M . (2000). Anticancer Res., 20, 4835–4840.
Davezac N, Baldin V, Gabrielli B, Forrest A, Theis-Febvre N, Yashida M and Ducommun B . (2000). Oncogene, 19, 2179–2185.
DiMagno EP, Reber HA and Tempero MA . (1999). Gastroenterology, 117, 1464–1484.
Freeman JW, Mattingly CA and Strodel WE . (1995). J. Cell Physiol., 165, 155–163.
Friess H, Ding J, Kleeff J, Liao Q, Berberat PO, Hammer J and Buchler MW . (2001). Ann. Surg., 234, 769–778 discussion 778–779..
Friess H, Yamanaka Y, Buchler M, Ebert M, Beger HG, Gold LI and Korc M . (1993). Gastroenterology, 105, 1846–1856.
Gabrielli BG, De Souza CP, Tonks ID, Clark JM, Hayward NK and Ellem KA . (1996). J. Cell Sci., 109 (Part 5), 1081–1093.
Galaktionov K and Beach D . (1991). Cell, 67, 1181–1194.
Galaktionov K, Lee AK, Eckstein J, Draetta G, Meckler J, Loda M and Beach D . (1995). Science, 269, 1575–1577.
Gasparotto D, Maestro R, Piccinin S, Vukosavljevic T, Barzan L, Sulfaro S and Boiocchi M . (1997). Cancer Res., 57, 2366–2368.
Gudjonsson B . (1987). Cancer, 60, 2284–2303.
Hahn SA, Schutte M, Hoque AT, Moskaluk CA, da Costa LT, Rozenblum E, Weinstein CL, Fischer A, Yeo CJ, Hruban RH and Kern SE . (1996). Science, 271, 350–353.
Hernandez S, Bessa X, Bea S, Hernandez L, Nadal A, Mallofre C, Muntane J, Castells A, Fernandez PL, Cardesa A and Campo E . (2001). Lab. Invest., 81, 465–473.
Hernandez S, Hernandez L, Bea S, Pinyol M, Nayach I, Bellosillo B, Nadal A, Ferrer A, Fernandez PL, Montserrat E, Cardesa A and Campo E . (2000). Int. J. Cancer, 89, 148–152.
Hoffmann I, Clarke PR, Marcote MJ, Karsenti E and Draetta G . (1993). EMBO J., 12, 53–63.
Hoffmann I, Draetta G and Karsenti E . (1994). EMBO J., 13, 4302–4310.
Ito Y, Yoshida H, Nakano K, Kobayashi K, Yokozawa T, Hirai K, Matsuzuka F, Matsuura N, Kakudo K, Kuma K and Miyauchi A . (2002). Br. J. Cancer, 86, 1909–1913.
Jemal A, Thomas A, Murray T and Thun M . (2002). CA Cancer J. Clin., 52, 23–47.
Karlsson C, Katich S, Hagting A, Hoffmann I and Pines J . (1999). J. Cell Biol., 146, 573–584.
Kleeff J, Ishiwata T, Kumbasar A, Friess H, Buchler MW, Lander AD and Korc M . (1998). J. Clin. Invest., 102, 1662–1673.
Kleeff J, Ishiwata T, Maruyama H, Friess H, Truong P, Buchler MW, Falb D and Korc M . (1999a). Oncogene, 18, 5363–5372.
Kleeff J and Korc M . (1998). J. Biol. Chem., 273, 7495–7500.
Kleeff J, Maruyama H, Friess H, Buchler MW, Falb D and Korc M . (1999b). Biochem. Biophys. Res. Commun., 255, 268–273.
Kleeff J, Wildi S, Friess H and Korc M . (1999c). Pancreas, 18, 364–370.
Koliopanos A, Friess H, Kleeff J, Shi X, Liao Q, Pecker I, Vlodavsky I, Zimmermann A and Buchler MW . (2001). Cancer Res., 61, 4655–4659.
Kudo Y, Yasui W, Ue T, Yamamoto S, Yokozaki H, Nikai H and Tahara E . (1997). Jpn. J. Cancer Res., 88, 947–952.
Lal G, Liu L, Hogg D, Lassam NJ, Redston MS and Gallinger S . (2000). Genes Chromosomes Cancer, 27, 358–361.
Lammer C, Wagerer S, Saffrich R, Mertens D, Ansorge W and Hoffmann I . (1998). J. Cell Sci., 111 (Part 16), 2445–2453.
Lazo JS, Aslan DC, Southwick EC, Cooley KA, Ducruet AP, Joo B, Vogt A and Wipf P . (2001). J. Med. Chem., 44, 4042–4049.
Liao Q, Ozawa F, Friess H, Zimmermann A, Takayama S, Reed JC, Kleeff J and Buchler MW . (2001). FEBS Lett., 503, 151–157.
Miyata H, Doki Y, Yamamoto H, Kishi K, Takemoto H, Fujiwara Y, Yasuda T, Yano M, Inoue M, Shiozaki H, Weinstein IB and Monden M . (2001). Cancer Res., 61, 3188–3193.
Neoptolemos JP, Dunn JA, Stocken DD, Almond J, Link K, Beger H, Bassi C, Falconi M, Pederzoli P, Dervenis C, Fernandez-Cruz L, Lacaine F, Pap A, Spooner D, Kerr DJ, Friess H and Buchler MW . (2001a). Lancet, 358, 1576–1585.
Neoptolemos JP, Stocken DD, Dunn JA, Almond J, Beger HG, Pederzoli P, Bassi C, Dervenis C, Fernandez-Cruz L, Lacaine F, Buckels J, Deakin M, Adab FA, Sutton R, Imrie C, Ihse I, Tihanyi T, Olah A, Pedrazzoli S, Spooner D, Kerr DJ, Friess H and Buchler MW . (2001b). Ann. Surg., 234, 758–768.
Ngan ES, Hashimoto Y, Ma ZQ, Tsai MJ and Tsai SY . (2003). Oncogene, 22, 734–739.
Nicoletti I, Migliorati G, Pagliacci MC, Grignani F and Riccardi C . (1991). J. Immunol. Methods, 139, 271–279.
Ozawa F, Friess H, Tempia-Caliera A, Kleeff J and Buchler MW . (2001). Teratog. Carcinog. Mutagen., 21, 27–44.
Sasaki H, Yukiue H, Kobayashi Y, Tanahashi M, Moriyama S, Nakashima Y, Fukai I, Kiriyama M, Yamakawa Y and Fujii Y . (2001). Cancer Lett., 173, 187–192.
Sato Y, Sasaki H, Kondo S, Fukai I, Kiriyama M, Yamakawa Y and Fujii Y . (2001). Jpn. J. Clin. Oncol., 31, 428–431.
Schutte M, Hruban RH, Hedrick L, Cho KR, Nadasdy GM, Weinstein CL, Bova GS, Isaacs WB, Cairns P, Nawroz H, Sidransky D, Casero Jr RA, Meltzer PS, Hahn SA and Kern SE . (1996). Cancer Res., 56, 2527–2530.
Sebastian B, Kakizuka A and Hunter T . (1993). Proc. Natl. Acad. Sci. USA, 90, 3521–3524.
Sherr CJ . (1996). Science, 274, 1672–1677.
Takemasa I, Yamamoto H, Sekimoto M, Ohue M, Noura S, Miyake Y, Matsumoto T, Aihara T, Tomita N, Tamaki Y, Sakita I, Kikkawa N, Matsuura N, Shiozaki H and Monden M . (2000). Cancer Res., 60, 3043–3050.
Tsai RY and McKay RD . (2002). Genes Dev., 16, 2991–3003.
Tureci O, Ding J, Hilton H, Bian H, Ohkawa H, Braxenthaler M, Seitz G, Raddrizzani L, Friess H, Buchler M, Sahin U and Hammer J . (2003). FASEB J., 17, 376–385.
Ulloa L and Tabibzadeh S . (2001). J. Biol. Chem., 276, 21397–21404.
van Hemert MJ, Steensma HY and van Heusden GP . (2001). Bioessays, 23, 936–946.
Wagner M, Kleeff J, Lopez ME, Bockman I, Massaque J and Korc M . (1998). Int. J. Cancer, 78, 255–260.
Wu S and Wolgemuth DJ . (1995). Dev. Biol., 170, 195–206.
Acknowledgements
This work was supported, in part, by US Public Health Service Grant CA-40162 to M Korc.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Guo, J., Kleeff, J., Li, J. et al. Expression and functional significance of CDC25B in human pancreatic ductal adenocarcinoma. Oncogene 23, 71–81 (2004). https://doi.org/10.1038/sj.onc.1206926
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1206926
Keywords
This article is cited by
-
METTL3 modulates m6A modification of CDC25B and promotes head and neck squamous cell carcinoma malignant progression
Experimental Hematology & Oncology (2022)
-
THZ1 reveals CDK7-dependent transcriptional addictions in pancreatic cancer
Oncogene (2019)
-
Identification of the quinolinedione inhibitor binding site in Cdc25 phosphatase B through docking and molecular dynamics simulations
Journal of Computer-Aided Molecular Design (2017)
-
The BET bromodomain inhibitor JQ1 suppresses growth of pancreatic ductal adenocarcinoma in patient-derived xenograft models
Oncogene (2016)
-
The impact of MFG-E8 in chronic pancreatitis: potential for future immunotherapy?
BMC Gastroenterology (2013)