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Skp2 Overexpression Is Highly Representative of Intrinsic Biological Aggressiveness and Independently Associated with Poor Prognosis in Primary Localized Myxofibrosarcomas

Authors' Affiliations: Departments of ¹ Pathology and ² Radiation Oncology and ³ Graduate institute of Clinical Medical Science, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Chang Gung University, Kaohsiung, Taiwan; ⁴ Department of Pathology, Chi-Mei Foundation Medical Center, Tainan, Taiwan; and ⁵ Department of Pathology and Laboratory Medicine, Veterans General Hospital-Kaohsiung, Kaohsiung, Taiwan

Requests for reprints: Ching-Yeh Hsiung, Department of Radiation Oncology, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Chang Gung University, 123, Ta-Pei Road, Niao-Sung, Kaohsiung County, Taiwan. Phone: 11-886-7-7317123-2537; Fax: 11-886-7-7333198; E-mail: a120600310{at}yahoo.com.

Purpose: Two SCF^Skp2 ubiquitin ligase–related proteins, Skp2 and cyclin-dependent kinase subunit 1 (Cks1), are involved in posttranscriptional degradation of p27^Kip1 tumor suppressor. We analyzed the prognostic utility of p27^Kip1 and its interacting cell cycle regulators in myxofibrosarcomas.

Experimental Design: Clinicopathologic features and tissue microarray–based immunohistochemical expression of p27^Kip1, Skp2, Cks1, cyclin E, cyclin A, Ki-67, and minichromosome maintenance protein 2 (Mcm2) were assessed in 70 primary myxofibrosarcomas and correlated with clinical outcomes. Skp2 mRNA expression and the relationship between Skp2 and p27^Kip1 proteins were examined in six cases by semiquantitative reverse transcription-PCR and Western blotting, respectively.

Results: High indices of Skp2 (10%), cyclin A (10%), and Mcm2 (50%) were adverse prognosticators at the univariate level. Furthermore, co-overexpression of Skp2 and cyclin A identified highly lethal cases in the entire cohort [P < 0.0001 for disease-specific survival (DSS), P = 0.0004 for overall survival (OS)] and the lower-grade subset (Fédération Nationale des Centres de Lutte Contre le Cancer grade 1 and 2; P = 0.0006 for DSS, P = 0.0093 for OS). In multivariate analyses, Skp2 overexpression overshadowed most intrinsic clinicopathologic factors and independently correlated with worse metastasis-free survival (P = 0.0012), DSS (P = 0.0234), and OS (P = 0.0056). Notably, positive margins independently predicted inferior local recurrence-free survival (P = 0.0012) and also negatively affected metastasis-free survival (P = 0.0471), DSS (P = 0.0152), and OS (P = 0.0173). Reverse transcription-PCR showed up-regulation of Skp2 mRNA in four cases and Western blotting displayed a matched expression pattern of Skp2.

Conclusions: Margin status and intrinsic property of myxofibrosarcomas both affect patient survival. Skp2 overexpression is highly representative of the biological aggressiveness of myxofibrosarcomas and plays an important prognostic role.

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