Increased CDC20 expression is associated with pancreatic ductal adenocarcinoma differentiation and progression

Journal of Hematology & Oncology

Huamin Wang¹  Craig Logsdon⁵  James L Abbruzzese⁶  Patrick Hwu³  Yan Liu⁵  Baoan Ji⁵  Ying Ma²  David Z Chang⁴ 

[1] Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA;Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA;Melanoma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA;Virginia Oncology Associates, 1051 Loftis Blvd, Suite 100, Newport News, VA 23606, USA;Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA;Departments of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

关键词: Prognosis;    Progression;    Tumorigenesis;    Pancreatic cancer;    CDC20;   

Others  :  822522
DOI  :  10.1186/1756-8722-5-15

 received in 2012-02-01, accepted in 2012-04-04,  发布年份 2012

【 摘 要 】

Purpose

Cell division cycle 20 (CDC20) homolog is an anaphase-promoting complex activator that is essential for cell division, but whether its expression in pancreatic ductal adenocarcinoma (PDAC) is significant is unknown. In this retrospective study, we determined whether aberrant CDC20 expression can be used as a biomarker in pancreatic ductal adenocarcinoma (PDAC) tumorigenesis and whether its expression reflects clinical progression.

Experimental design

We compared CDC20 expression levels in normal, cancerous, and inflamed pancreatic tissues from stage II PDAC patients with clinical outcomes and determined CDC20 levels in seven PDAC cell lines. CDC20 was identified using a cDNA microarray database containing gene expression profiles for PDAC tissues and cell lines and chronic pancreatitis and normal pancreas tissues. Its expression was confirmed by real-time quantitative reverse-transcriptase-polymerase chain reaction (qRT-PCR). An immunohistochemical analysis of tissue microarrays from resected PDAC tumors and paired benign pancreatic tissues was done and CDC20 levels were correlated with clinical outcome.

Results

Fifty-six patients were included in this study. A microarray analysis revealed 5-fold higher CDC20 expression in PDAC tissue than in chronic pancreatitis tissue. A qRT-PCR analysis confirmed a mean 20-fold higher CDC20 level in PDAC tissue than in normal pancreas and pancreatitis tissue. RNA and protein CDC20 expression was detected in several PDAC cell lines. An immunohistochemical analysis revealed higher CDC20 protein expression levels in PDAC tissue than in normal pancreas tissue, and high CDC20 expression was associated with poor differentiation (P = 0.020) and a significantly lower 5-year recurrence-free survival rate (P = 0.039); we also found a trend toward a shorter overall survival duration.

Conclusions

Aberrant CDC20 expression may play an important role in PDAC tumorigenesis and progression and may thus be useful as a marker of disease progression and prognosis and as a therapeutic target.

【 授权许可】

   
2012 Chang et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

【 参考文献 】

• [1]Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ: Cancer statistics, 2007. CA Cancer J Clin 2007, 57:43-66.
• [2]American Cancer Society Cancer Facts & Figures 2007.
• [3]Carpelan-Holmstrom M, Nordling S, Pukkala E, Sankila R, Luttges J, Kloppel G, Haglund C: Does anyone survive pancreatic ductal adenocarcinoma? A nationwide study re-evaluating the data of the Finnish Cancer Registry. Gut 2005, 54:385-387.
• [4]Javle M, Hsueh CT: Recent advances in gastrointestinal oncology - updates and insights from the 2009 annual meeting of the American Society of Clinical Oncology. J Hematol Oncol 2010, 3:11. BioMed Central Full Text
• [5]Hu J, Zhao G, Wang HX, Tang L, Xu YC, Ma Y, Zhang FC: A meta-analysis of gemcitabine containing chemotherapy for locally advanced and metastatic pancreatic adenocarcinoma. J Hematol Oncol 2011, 4:11. BioMed Central Full Text
• [6]Zhang XJ, Ye H, Zeng CW, He B, Zhang H, Chen YQ: Dysregulation of miR-15a and miR-214 in human pancreatic cancer. J Hematol Oncol 2010, 3:46. BioMed Central Full Text
• [7]Kulke MH, Bendell J, Kvols L, Picus J, Pommier R, Yao J: Evolving Diagnostic and Treatment Strategies for Pancreatic Neuroendocrine Tumors. J Hematol Oncol 2011, 4:29. BioMed Central Full Text
• [8]Weinstein J, Jacobsen FW, Hsu-Chen J, Wu T, Baum LG: A novel mammalian protein, p55CDC, present in dividing cells is associated with protein kinase activity and has homology to the Saccharomyces cerevisiae cell division cycle proteins Cdc20 and Cdc4. Mol Cell Biol 1994, 14:3350-3363.
• [9]Fang G, Yu H, Kirschner MW: Direct binding of CDC20 protein family members activates the anaphase-promoting complex in mitosis and G1. Molec Cell 1998, 2:163-171.
• [10]Peters J-M: Cell biology: the checkpoint brake relieved. Nature 2007, 446:868-869.
• [11]Bharadwaj R, Yu H: The spindle checkpoint, aneuploidy, and cancer. Oncogene 2004, 23:2016-2027.
• [12]Banerjee T, Nath S, Roychoudhury S: DNA damage induced p53 downregulates Cdc20 by direct binding to its promoter causing chromatin remodeling. Nucleic Acids Res 2009, 37:2688-2698.
• [13]Iacomino G, Medici MC, Napoli D, Russo GL: Effects of histone deacetylase inhibitors on p55CDC/Cdc20 expression in HT29 cell line. J Cell Biochem 2006, 99:1122-1131.
• [14]Kim JMSH, Yoon SY, Oh JH, Yang JO, Kim JH, Song KS, Rho SM, Yoo HS, Kim YS, Kim JG, Kim NS: Identification of gastric cancer-related genes using a cDNA microarray containing novel expressed sequence tags expressed in gastric cancer cells. Clin Cancer Res 2005, 11:473-482.
• [15]Ouellet VGM, Le Page C, Filali-Mouhim A, Lussier C, Tonin PN, Provencher DM, Mes-Masson AM: Tissue array analysis of expression microarray candidates identifies markers associated with tumor grade and outcome in serous epithelial ovarian cancer. Int J Cancer 2006, 119:599-607.
• [16]Kidokoro T, Tanikawa C, Furukawa Y, Katagiri T, Nakamura Y, Matsuda K: CDC20, a potential cancer therapeutic target, is negatively regulated by p53. Oncogene 2008, 27:1562-1571.
• [17]Takahashi T, Haruki N, Nomoto S, Masuda A, Saji S, Osada H: Identification of frequent impairment of the mitotic checkpoint and molecular analysis of the mitotic checkpoint genes, hsMAD2 and p55CDC, in human lung cancers. Oncogene 1999, 18:4295-4300.
• [18]Saeki A, Tamura S, Ito N, Kiso S, Matsuda Y, Yabuuchi I, Kawata S, Matsuzawa Y: Frequent impairment of the spindle assembly checkpoint in hepatocellular carcinoma. Cancer 2002, 94:2047-2054.
• [19]Eytan E, Braunstein I, Ganoth D, Teichner A, Hittle JC, Yen TJ, Hershko A: Two different mitotic checkpoint inhibitors of the anaphase-promoting complex/cyclosome antagonize the action of the activator Cdc20. Proc Natl Acad Sci USA 2008, 105:9181-9185.
• [20]Fry AM, Yamano H: Under arrest in mitosis: Cdc20 dies twice. Nat Cell Biol 2008, 10:1385-1387.
• [21]Nilsson J, Yekezare M, Minshull J, Pines J: The APC/C maintains the spindle assembly checkpoint by targeting Cdc20 for destruction. Nat Cell Biol 2008, 10:1411-1420.
• [22]Thirthagiri E, Robinson CM, Huntley S, Davies M, Yap LF, Prime SS, Paterson IC: Spindle assembly checkpoint and centrosome abnormalities in oral cancer. Cancer Lett 2007, 258:276-285.
• [23]Liu B, Hong S, Tang Z, Yu H, Giam CZ: HTLV-I Tax directly binds the Cdc20-associated anaphase-promoting complex and activates it ahead of schedule. Proc Natl Acad Sci USA 2005, 102:63-68.
• [24]Li D, Zhu J, Firozi PF, Abbruzzese JL, Evans DB, Cleary K, Friess H, Sen S: Overexpression of oncogenic STK15/BTAK/Aurora A kinase in human pancreatic cancer. Clin Cancer Res 2003, 9:991-997.
• [25]Lee YJ, Kim EH, Jae SL, Jeoung D, Bae S, Seung HK, Lee YS: HSF1 as a mitotic regulator: Phosphorylation of HSF1 by Plk1 is essential for mitotic progression. Cancer Res 2008, 68:7550-7560.
• [26]Yuan Y, Liao YM, Hsueh CT, Mirshahidi HR: Novel targeted therapeutics: inhibitors of MDM2, ALK and PARP. J Hematol Oncol 2011, 4:16. BioMed Central Full Text