https://scholars.lib.ntu.edu.tw/handle/123456789/473710
標題: | Characterization of gene amplification-driven SKP2 overexpression in myxofibrosarcoma: Potential implications in tumor progression and therapeutics | 作者: | Li C.-F. Wang J.-M. Kang H.-Y. Huang C.-K. Wang J.-W. Fang F.-M. Wang Y.-H. Wu W.-R. Li S.-H. Yu S.-C. JEN-CHIEH LEE Lan J. Shiue Y.-L. Wu L.-C. Huang H.-Y. |
公開日期: | 2012 | 卷: | 18 | 期: | 6 | 起(迄)頁: | 1598-1610 | 來源出版物: | Clinical Cancer Research | 摘要: | 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 OH931cells and14% 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. ?2012 AACR. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-84863253129&doi=10.1158%2f1078-0432.CCR-11-3077&partnerID=40&md5=7f6400c18079b3b6827650a734e0f382 https://scholars.lib.ntu.edu.tw/handle/123456789/473710 |
ISSN: | 1078-0432 | DOI: | 10.1158/1078-0432.CCR-11-3077 | SDG/關鍵字: | bortezomib; caspase; cyclin dependent kinase inhibitor 1B; DNA; messenger RNA; S phase kinase associated protein 2; ACTN1 gene; adult; AMACR gene; amplicon; anchorage independent growth; animal experiment; animal model; animal tissue; article; cancer cell culture; cancer inhibition; cancer invasion; carcinogenesis; cell migration; cell proliferation; cell viability; chromosome 5p; comparative genomic hybridization; controlled study; down regulation; drug efficacy; drug sensitivity; embryo; ENAH gene; enzyme activation; female; fibroblast; fibromyxosarcoma; gene; gene amplification; gene dosage; gene overexpression; gene silencing; human; human cell; human tissue; IGF1 gene; in vitro study; in vivo study; ITGB2 gene; major clinical study; male; mouse; nonhuman; prediction; priority journal; prognosis; SKP2 gene; soft tissue sarcoma; TRIO gene; tumor growth; tumor xenograft; Animals; Boronic Acids; Cell Line, Tumor; Comparative Genomic Hybridization; Female; Fibrosarcoma; Gene Amplification; Gene Dosage; Guanine Nucleotide Exchange Factors; Humans; Male; Mice; Mice, SCID; Middle Aged; Prognosis; Protein-Serine-Threonine Kinases; Pyrazines; Racemases and Epimerases; RNA, Messenger; S-Phase Kinase-Associated Proteins; Up-Regulation; Xenograft Model Antitumor Assays |
顯示於: | 病理學科所 |
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