PMID- 22322669
OWN - NLM
STAT- MEDLINE
DCOM- 20120628
LR  - 20211203
IS  - 1557-3265 (Electronic)
IS  - 1078-0432 (Linking)
VI  - 18
IP  - 6
DP  - 2012 Mar 15
TI  - Characterization of gene amplification-driven SKP2 overexpression in 
      myxofibrosarcoma: potential implications in tumor progression and therapeutics.
PG  - 1598-610
LID - 10.1158/1078-0432.CCR-11-3077 [doi]
AB  - PURPOSE: Myxofibrosarcoma remains obscure in molecular determinants of clinical 
      aggressiveness, for which we elucidated implications of SKP2 amplification. 
      EXPERIMENTAL DESIGN: Array comparative genomic hybridization was applied on 
      samples and cell lines (NMFH-1 to OH931) to search causal genes of tumor 
      progression. SKP2 gene dosage was determined in 82 independent tumors for 
      clinical correlates. Stable SKP2 knockdown was achieved in myxofibrosarcoma cells 
      to assess its oncogenic attributes and candidate mediators in prometastatic 
      function. Pharmacologic assays were evaluated in vitro and in vivo for the 
      therapeutic relevance of bortezomib. RESULTS: DNA gains frequently involved 5p in 
      which three amplicons were differentially overrepresented in samples behaving 
      unfavorably, encompassing mRNA-upregulated TRIO, SKP2, and AMACR genes. Detected 
      in NMFH-1 cells and 38% of tumors, SKP2 amplification was associated with SKP2 
      immunoexpression and adverse prognosticators and independently predictive of 
      worse outcomes. Nevertheless, SKP2-expressing OH931 cells and 14% of such tumors 
      lacked gene amplification. Knockdown of SKP2 suppressed proliferation, 
      anchorage-independent growth, migration, and invasion of sarcoma cells and 
      downregulated motility-promoting genes, including ITGB2, ACTN1, IGF1, and ENAH. 
      In vitro, bortezomib downregulated SKP2 expression at the mRNA level with 
      p27(kip1) accumulation, induced caspase activation, and decreased cell viability 
      in myxofibrosarcoma cells but not in fibroblasts. In vivo, bortezomib inhibited 
      growth of NMFH-1 xenografts, the cells of which displayed decreased SKP2 
      expression but increased p27(kip1) and terminal deoxynucleotidyl 
      transferase-mediated dUTP nick end labeling (TUNEL). CONCLUSIONS: As a 
      predominant mechanism driving protein overexpression, SKP2 amplification confers 
      tumor aggressiveness in myxofibrosarcoma. The sensitivity of myxofibrosarcoma 
      cells to bortezomib with SKP2-repressing effect indicates the potentiality of 
      ubiquitin-proteasome pathway as a therapeutic target.
FAU - Li, Chien-Feng
AU  - Li CF
AD  - Department of Pathology, National Institute of Cancer Research, Taiwan.
FAU - Wang, Ju-Ming
AU  - Wang JM
FAU - Kang, Hong-Yo
AU  - Kang HY
FAU - Huang, Chiung-Kuei
AU  - Huang CK
FAU - Wang, Jun-Wen
AU  - Wang JW
FAU - Fang, Fu-Min
AU  - Fang FM
FAU - Wang, Yu-Hui
AU  - Wang YH
FAU - Wu, Wen-Ren
AU  - Wu WR
FAU - Li, Shau-Hsuan
AU  - Li SH
FAU - Yu, Shih-Chen
AU  - Yu SC
FAU - Lee, Jen-Chieh
AU  - Lee JC
FAU - Lan, Jui
AU  - Lan J
FAU - Shiue, Yow-Ling
AU  - Shiue YL
FAU - Wu, Li-Ching
AU  - Wu LC
FAU - Huang, Hsuan-Ying
AU  - Huang HY
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120209
PL  - United States
TA  - Clin Cancer Res
JT  - Clinical cancer research : an official journal of the American Association for 
      Cancer Research
JID - 9502500
RN  - 0 (Boronic Acids)
RN  - 0 (Guanine Nucleotide Exchange Factors)
RN  - 0 (Pyrazines)
RN  - 0 (RNA, Messenger)
RN  - 0 (S-Phase Kinase-Associated Proteins)
RN  - 69G8BD63PP (Bortezomib)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (TRIO protein, human)
RN  - EC 5.1.- (Racemases and Epimerases)
RN  - EC 5.1.99.4 (alpha-methylacyl-CoA racemase)
SB  - IM
MH  - Animals
MH  - Boronic Acids/pharmacology
MH  - Bortezomib
MH  - Cell Line, Tumor
MH  - Comparative Genomic Hybridization
MH  - Female
MH  - Fibrosarcoma/*genetics
MH  - *Gene Amplification
MH  - Gene Dosage
MH  - Guanine Nucleotide Exchange Factors/genetics
MH  - Humans
MH  - Male
MH  - Mice
MH  - Mice, SCID
MH  - Middle Aged
MH  - Prognosis
MH  - Protein Serine-Threonine Kinases/genetics
MH  - Pyrazines/pharmacology
MH  - RNA, Messenger/metabolism
MH  - Racemases and Epimerases/genetics
MH  - S-Phase Kinase-Associated Proteins/*genetics
MH  - Up-Regulation
MH  - Xenograft Model Antitumor Assays
EDAT- 2012/02/11 06:00
MHDA- 2012/06/29 06:00
CRDT- 2012/02/11 06:00
PHST- 2012/02/11 06:00 [entrez]
PHST- 2012/02/11 06:00 [pubmed]
PHST- 2012/06/29 06:00 [medline]
AID - 1078-0432.CCR-11-3077 [pii]
AID - 10.1158/1078-0432.CCR-11-3077 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2012 Mar 15;18(6):1598-610. doi: 10.1158/1078-0432.CCR-11-3077. 
      Epub 2012 Feb 9.