Skp2 overexpression is highly representative of intrinsic biological aggressiveness and independently associated with poor prognosis in primary localized myxofibrosarcomas.
OBJECTIVE
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.


METHODS
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 (> or =10%), cyclin A (> or =10%), and Mcm2 (> or =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.
Huang
Hsuan-Ying
HY
Departments of Pathology and Radiation Oncology and Graduate institute of Clinical Medical Science, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Chang Gung University, 123 Ta-Pei Road, Niao-Sung, Kaohsiung County, Taiwan.
Kang
Hong-Yo
HY
Li
Chien-Feng
CF
Eng
Hock-Liew
HL
Chou
Shih-Cheng
SC
Lin
Ching-Nan
CN
Hsiung
Ching-Yeh
CY
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D042846:CDC2-CDC28 Kinases; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D019925:Cyclin A / Q000235:genetics / Q000378:metabolism; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D005354:Fibrosarcoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D019394:Ki-67 Antigen / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D064111:Minichromosome Maintenance Complex Component 2; D009236:Myxosarcoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012189:Retrospective Studies; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D015996:Survival Rate
D014408:Biomarkers, Tumor; C436291:CDKN1B protein, human; C093090:CKS1B protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D019925:Cyclin A; D019927:Cyclin E; D047908:Intracellular Signaling Peptides and Proteins; D019394:Ki-67 Antigen; D009687:Nuclear Proteins; D012333:RNA, Messenger; D044786:S-Phase Kinase-Associated Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D042846:CDC2-CDC28 Kinases; D018844:Cyclin-Dependent Kinases; C084859:MCM2 protein, human; D064111:Minichromosome Maintenance Complex Component 2