Characterized by a wide histological spectrum, myxofibrosarcoma ranges from deceptively bland-appearing lesions to frankly pleomorphic sarcomas, representing a suitable model to elucidate the molecular aberrations in multistep disease progression. Using genome-wide array comparative genomic hybridization, we have profiled DNA copy number alterations in myxofibrosarcoma samples and cell lines in coupled with expression profiling data and identified prominent SKP2 amplification on 5p, frequent homozygous deletion of MTAP on 9p, as well as loss expression of ASS1, a candidate tumor suppressor.
As a predominant driving mechanism, SKP2 gene amplification was detected in one-third of cases in independent cohort validation and associated with SKP2 immunohistochemical expression, adverse prognosticators, and worse patient survival. Besides the classical attribute in promoting cell proliferation and tumor growth, we have confirmed the pro-metastatic oncogenic function of SKP2 and identified differentially expressed motility-promoting genes as its potential mediators, including ITGB2, ACTN1, IGF1, and ENAH.
Since MTAP and ASS1 are key enzymes in either salvage pathway of nucleologenesis and amino acid biosynthesis, their deficiency suggests alterations involving metabolic homeostasis is important in sarcomagenesis. We in our studies not only validated their deletion and/or epigenetic silencing in myxofibrosaroma, evaluating the therapeutic responses of L-alanosine and ADI-PEG20 in MTAP or ASS1 deficient cells in vitro and in vivo, but also confirmed their tumor suppressor functions with special focus on tumor angiogenesis.
Our study provides further insight into the molecular pathogenesis in tumor progression and highlights the prognostic, biological, and potential therapeutic relevance in myxofibrosarcoma.
| Identifer | oai:union.ndltd.org:NSYSU/oai:NSYSU:etd-0905112-105211 |
| Date | 05 September 2012 |
| Creators | Li, Chien-Feng |
| Contributors | Li-Tzon Chen, Yow-Ling Shiue, Jim Jinn-Chyuan Sheu, Long-sen Chang, Ching-Cherng Tzeng |
| Publisher | NSYSU |
| Source Sets | NSYSU Electronic Thesis and Dissertation Archive |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0905112-105211 |
| Rights | user_define, Copyright information available at source archive |
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