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BMC Cancer
Published in: BMC Cancer 1/2008

Open Access 01-12-2008 | Research article

Skp2 expression is associated with high risk and elevated Ki67 expression in gastrointestinal stromal tumours

Authors: Dolores Di Vizio, Francesca Demichelis, Sara Simonetti, Guido Pettinato, Luigi Terracciano, Luigi Tornillo, Michael R Freeman, Luigi Insabato

Published in: BMC Cancer | Issue 1/2008

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Abstract

Background

Gastrointestinal stromal tumors (GIST) exhibit an unpredictable clinical course and can rapidly progress to lethality. Predictions about the biological behavior of GIST are based on a number of canonical clinical and pathologic parameters whose validity in distinguishing between a benign and a malignant tumour is still imperfect. The aim of our study was to investigate the role of morphologic parameters and expression of cells cycle regulators as prognosticators in GIST.

Methods

We performed an immunohistochemical analysis for Ki67, p27Kip1, Jab1, and Skp2, on a Tissue Microarray (TMA) containing 94 GIST. Expression of the above proteins was correlated to classically used prognosticators, as well as to risk groups. Clinical significance of histologic and immunohistochemical features were evaluated in 59 patients for whom follow-up information was available.

Results

Overexpression of Ki67 and Skp2, and p27Kip1 loss directly correlated with the high risk group (p = 0.03 for Ki67 and Skp2, p = 0.05 for p27Kip1). Jab1 expression did not exhibit correlation with risk. In 59 cases provided with clinical follow-up, high cellularity, presence of necrosis, and Ki67 overexpression were predictive of a reduced overall survival in a univariate model. The same parameters, as well as mitotic rate, tumour size, and p27Kip1 loss were indicative of a shortened relapse free survival interval. High cellularity, and high mitotic rate retained their prognostic significance by multivariate analysis.

Conclusion

Our data suggest that a number of histologic parameters in combination with immunohistochemical expression of cell cycle regulators can facilitate risk categorization and predict biologic behavior in GIST. Importantly this study demonstrates, for the first time, that Skp2 expression correlates with Ki67 expression and high risk in GIST.
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Literature
1.
Fletcher CD, Berman JJ, Corless C, Gorstein F, Lasota J, Longley BJ, Miettinen M, O'Leary TJ, Remotti H, Rubin BP, Shmookler B, Sobin LH, Weiss SW: Diagnosis of gastrointestinal stromal tumors: a consensus approach. Int J Surg Pathol. 2002, 10 (2): 81-89. 10.1177/106689690201000201.CrossRefPubMed
2.
Miettinen M, Lasota J: Gastrointestinal stromal tumors: review on morphology, molecular pathology, prognosis, and differential diagnosis. Arch Pathol Lab Med. 2006, 130 (10): 1466-1478.PubMed
3.
Tornillo L, Duchini G, Carafa V, Lugli A, Dirnhofer S, Di Vizio D, Boscaino A, Russo R, Tapia C, Schneider-Stock R, Sauter G, Insabato L, Terracciano LM: Patterns of gene amplification in gastrointestinal stromal tumors (GIST). Lab Invest. 2005, 85 (7): 921-931. 10.1038/labinvest.3700284.CrossRefPubMed
4.
Sun H, Lesche R, Li DM, Liliental J, Zhang H, Gao J, Gavrilova N, Mueller B, Liu X, Wu H: PTEN modulates cell cycle progression and cell survival by regulating phosphatidylinositol 3,4,5,-trisphosphate and Akt/protein kinase B signaling pathway. Proc Natl Acad Sci U S A. 1999, 96 (11): 6199-6204. 10.1073/pnas.96.11.6199.CrossRefPubMedPubMedCentral
5.
Di Vizio D, Cito L, Boccia A, Chieffi P, Insabato L, Pettinato G, Motti ML, Schepis F, D'Amico W, Fabiani F, Tavernise B, Venuta S, Fusco A, Viglietto G: Loss of the tumor suppressor gene PTEN marks the transition from intratubular germ cell neoplasias (ITGCN) to invasive germ cell tumors. Oncogene. 2005, 24 (11): 1882-1894. 10.1038/sj.onc.1208368.CrossRefPubMed
6.
Ricci R, Maggiano N, Castri F, Rinelli A, Murazio M, Pacelli F, Potenza AE, Vecchio FM, Larocca LM: Role of PTEN in gastrointestinal stromal tumor progression. Arch Pathol Lab Med. 2004, 128 (4): 421-425.PubMed
7.
Miettinen M, Lasota J: Gastrointestinal stromal tumors: pathology and prognosis at different sites. Semin Diagn Pathol. 2006, 23 (2): 70-83. 10.1053/j.semdp.2006.09.001.CrossRefPubMed
8.
Wong NA, Young R, Malcomson RD, Nayar AG, Jamieson LA, Save VE, Carey FA, Brewster DH, Han C, Al-Nafussi A: Prognostic indicators for gastrointestinal stromal tumours: a clinicopathological and immunohistochemical study of 108 resected cases of the stomach. Histopathology. 2003, 43 (2): 118-126. 10.1046/j.1365-2559.2003.01665.x.CrossRefPubMed
9.
Baghdassarian N, Ffrench M: Cyclin-dependent kinase inhibitors (CKIs) and hematological malignancies. Hematol Cell Ther. 1996, 38 (4): 313-323. 10.1007/s00282-996-0313-4.CrossRefPubMed
10.
Hershko DD, Shapira M: Prognostic role of p27Kip1 deregulation in colorectal cancer. Cancer. 2006, 107 (4): 668-675. 10.1002/cncr.22073.CrossRefPubMed
11.
Goto Y, Kawauchi S, Ihara K, Ikemoto K, Ohi R, Kawai S, Sasaki K: The prognosis in spindle-cell sarcoma depends on the expression of cyclin-dependent kinase inhibitor p27(Kip1) and cyclin E. Cancer Sci. 2003, 94 (5): 412-417. 10.1111/j.1349-7006.2003.tb01456.x.CrossRefPubMed
12.
Salerno G, Di Vizio D, Staibano S, Mottola G, Quaremba G, Mascolo M, Galli V, De Rosa G, Insabato L: Prognostic value of p27Kip1 expression in Basaloid Squamous Cell Carcinoma of the larynx. BMC Cancer. 2006, 6: 146-10.1186/1471-2407-6-146.CrossRefPubMedPubMedCentral
13.
Schneider-Stock R, Boltze C, Lasota J, Peters B, Corless CL, Ruemmele P, Terracciano L, Pross M, Insabato L, Di Vizio D, Iesalnieks I, Dirnhofer S, Hartmann A, Heinrich M, Miettinen M, Roessner A, Tornillo L: Loss of p16 protein defines high-risk patients with gastrointestinal stromal tumors: a tissue microarray study. Clin Cancer Res. 2005, 11 (2 Pt 1): 638-645.PubMed
14.
Ricci R, Arena V, Castri F, Martini M, Maggiano N, Murazio M, Pacelli F, Potenza AE, Vecchio FM, Larocca LM: Role of p16/INK4a in gastrointestinal stromal tumor progression. Am J Clin Pathol. 2004, 122 (1): 35-43. 10.1309/MJ4X-N2M5-7HNC-8X5H.CrossRefPubMed
15.
Nakamura N, Yamamoto H, Yao T, Oda Y, Nishiyama K, Imamura M, Yamada T, Nawata H, Tsuneyoshi M: Prognostic significance of expressions of cell-cycle regulatory proteins in gastrointestinal stromal tumor and the relevance of the risk grade. Hum Pathol. 2005, 36 (7): 828-837. 10.1016/j.humpath.2005.03.012.CrossRefPubMed
16.
Sabah M, Cummins R, Leader M, Kay E: Altered expression of cell cycle regulatory proteins in gastrointestinal stromal tumors: markers with potential prognostic implications. Hum Pathol. 2006, 37 (6): 648-655. 10.1016/j.humpath.2006.01.023.CrossRefPubMed
17.
Pruneri G, Mazzarol G, Fabris S, Del Curto B, Bertolini F, Neri A, Viale G: Cyclin D3 immunoreactivity in gastrointestinal stromal tumors is independent of cyclin D3 gene amplification and is associated with nuclear p27 accumulation. Mod Pathol. 2003, 16 (9): 886-892. 10.1097/01.MP.0000085026.38856.B9.CrossRefPubMed
18.
Shirin H, Kravtsov V, Shahmurov M, Shabat VS, Krinshpon I, Alin A, Avinoach I, Avni Y: The cyclin-dependent kinase inhibitor, p27, has no correlation with the malignant potential of GIST. Digestion. 2007, 75 (1): 4-9. 10.1159/000101457.CrossRefPubMed
19.
Tomoda K, Kubota Y, Arata Y, Mori S, Maeda M, Tanaka T, Yoshida M, Yoneda-Kato N, Kato JY: The cytoplasmic shuttling and subsequent degradation of p27Kip1 mediated by Jab1/CSN5 and the COP9 signalosome complex. J Biol Chem. 2002, 277 (3): 2302-2310. 10.1074/jbc.M104431200.CrossRefPubMed
20.
Goto A, Niki T, Moriyama S, Funata N, Moriyama H, Nishimura Y, Tsuchida R, Kato JY, Fukayama M: Immunohistochemical study of Skp2 and Jab1, two key molecules in the degradation of P27, in lung adenocarcinoma. Pathol Int. 2004, 54 (9): 675-681. 10.1111/j.1440-1827.2004.01679.x.CrossRefPubMed
21.
Pagano M, Tam SW, Theodoras AM, Beer-Romero P, Del Sal G, Chau V, Yew PR, Draetta GF, Rolfe M: Role of the ubiquitin-proteasome pathway in regulating abundance of the cyclin-dependent kinase inhibitor p27. Science. 1995, 269 (5224): 682-685. 10.1126/science.7624798.CrossRefPubMed
22.
Hulit J, Lee RJ, Li Z, Wang C, Katiyar S, Yang J, Quong AA, Wu K, Albanese C, Russell R, Di Vizio D, Koff A, Thummala S, Zhang H, Harrell J, Sun H, Muller WJ, Inghirami G, Lisanti MP, Pestell RG: p27Kip1 Repression of ErbB2-Induced Mammary Tumor Growth in Transgenic Mice Involves Skp2 and Wnt/{beta}-Catenin Signaling. Cancer Res. 2006, 66 (17): 8529-8541. 10.1158/0008-5472.CAN-06-0149.CrossRefPubMed
23.
Oliveira AM, Okuno SH, Nascimento AG, Lloyd RV: Skp2 protein expression in soft tissue sarcomas. J Clin Oncol. 2003, 21 (4): 722-727. 10.1200/JCO.2003.05.112.CrossRefPubMed
24.
Kouvaraki MA, Rassidakis GZ, Tian L, Kumar R, Kittas C, Claret FX: Jun activation domain-binding protein 1 expression in breast cancer inversely correlates with the cell cycle inhibitor p27(Kip1). Cancer Res. 2003, 63 (11): 2977-2981.PubMed
25.
Kouvaraki MA, Korapati AL, Rassidakis GZ, Tian L, Zhang Q, Chiao P, Ho L, Evans DB, Claret FX: Potential role of Jun activation domain-binding protein 1 as a negative regulator of p27kip1 in pancreatic adenocarcinoma. Cancer Res. 2006, 66 (17): 8581-8589. 10.1158/0008-5472.CAN-06-0975.CrossRefPubMedPubMedCentral
26.
Ozguc H, Yilmazlar T, Yerci O, Soylu R, Tumay V, Filiz G, Zorluoglu A: Analysis of prognostic and immunohistochemical factors in gastrointestinal stromal tumors with malignant potential. J Gastrointest Surg. 2005, 9 (3): 418-429. 10.1016/j.gassur.2004.07.003.CrossRefPubMed
27.
Daum O, Grossmann P, Vanecek T, Sima R, Mukensnabl P, Michal M: Diagnostic morphological features of PDGFRA-mutated gastrointestinal stromal tumors: molecular genetic and histologic analysis of 60 cases of gastric gastrointestinal stromal tumors. Ann Diagn Pathol. 2007, 11 (1): 27-33. 10.1016/j.anndiagpath.2006.10.002.CrossRefPubMed
28.
Bertin M, Angriman I, Scarpa M, Mencarelli R, Ranzato R, Ruffolo C, Polese L, Iacobone M, D'Amico DF: Prognosis of gastrointestinal stromal tumors. Hepatogastroenterology. 2007, 54 (73): 124-128.PubMed
29.
Penin RM, Fernandez-Figueras MT, Puig L, Rex J, Ferrandiz C, Ariza A: Over-expression of p45(SKP2) in Kaposi's sarcoma correlates with higher tumor stage and extracutaneous involvement but is not directly related to p27(KIP1) down-regulation. Mod Pathol. 2002, 15 (11): 1227-1235. 10.1097/01.MP.0000036589.99516.D6.CrossRefPubMed
30.
Li JQ, Wu F, Masaki T, Kubo A, Fujita J, Dixon DA, Beauchamp RD, Ishida T, Kuriyama S, Imaida K: Correlation of Skp2 with carcinogenesis, invasion, metastasis, and prognosis in colorectal tumors. Int J Oncol. 2004, 25 (1): 87-95.PubMed
31.
Gelen T, Elpek GO, Aksoy NH, Ogus M, Keles N: p27 Labeling index and proliferation in gastrointestinal stromal tumors: correlations with clinicopathologic factors and recurrence. Jpn J Clin Oncol. 2003, 33 (7): 346-352. 10.1093/jjco/hyg071.CrossRefPubMed
32.
Nemoto Y, Mikami T, Hana K, Kikuchi S, Kobayashi N, Watanabe M, Okayasu I: Correlation of enhanced cell turnover with prognosis of gastrointestinal stromal tumors of the stomach: relevance of cellularity and p27kip1. Pathol Int. 2006, 56 (12): 724-731. 10.1111/j.1440-1827.2006.02038.x.CrossRefPubMed
33.
Grimmler M, Wang Y, Mund T, Cilensek Z, Keidel EM, Waddell MB, Jakel H, Kullmann M, Kriwacki RW, Hengst L: Cdk-inhibitory activity and stability of p27Kip1 are directly regulated by oncogenic tyrosine kinases. Cell. 2007, 128 (2): 269-280. 10.1016/j.cell.2006.11.047.CrossRefPubMed
34.
Carrano AC, Eytan E, Hershko A, Pagano M: SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27. Nat Cell Biol. 1999, 1 (4): 193-199. 10.1038/12013.CrossRefPubMed
35.
Latres E, Chiarle R, Schulman BA, Pavletich NP, Pellicer A, Inghirami G, Pagano M: Role of the F-box protein Skp2 in lymphomagenesis. Proc Natl Acad Sci U S A. 2001, 98 (5): 2515-2520. 10.1073/pnas.041475098.CrossRefPubMedPubMedCentral
Metadata
Title
Skp2 expression is associated with high risk and elevated Ki67 expression in gastrointestinal stromal tumours
Authors
Dolores Di Vizio
Francesca Demichelis
Sara Simonetti
Guido Pettinato
Luigi Terracciano
Luigi Tornillo
Michael R Freeman
Luigi Insabato
Publication date
01-12-2008
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2008
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-8-134

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