Downregulated MTAP expression in myxofibrosarcoma: A characterization of inactivating mechanisms, tumor suppressive function, and therapeutic relevance

Chien Feng Li, Fu Min Fang, Hsing-Jien Kung, Li Tzong Chen, Jun Wen Wang, Jen Wei Tsai, Shih Chen Yu, Yu Hui Wang, Shau Hsuan Li, Hsuan Ying Huang

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Myxofibrosarcomas are genetically complex and involve recurrently deleted chromosome 9p, for which we characterized the pathogenically relevant target(s) using genomic profiling. In 12 of the 15 samples, we detected complete or partial losses of 9p. The only aggressiveness-associated, differentially lost region was 9p21.3, spanning the potential inactivated methylthioadenosine phosphorylase (MTAP) that exhibited homozygous (4/15) or hemizygous (3/15) deletions. In independent samples, MTAP gene status was assessed using quantitative- and methylation-specific PCR assays, and immunoexpression was evaluated. We applied MTAP reexpression or knockdown to elucidate the functional roles of MTAP and the therapeutic potential of L-alanosine in MTAP-preserved and MTAP-deficient myxofibrosarcoma cell lines and xenografts. MTAP protein deficiency (37%) was associated with MTAP gene inactivation (P < 0.001) by homozygous deletion or promoter methylation, and independently portended unfavorable metastasis-free survival (P = 0.0318) and disease-specific survival (P = 0.014). Among the MTAPdeficient cases, the homozygous deletion of MTAP predicted adverse outcome. In MTAP-deficient cells, MTAP reexpression inhibited cell migration and invasionproliferation, and anchorage-independent colony formation and downregulated cyclin D1. This approach also attenuated the tube-forming abilities of human umbilical venous endothelial cells, attributable to the transcriptional repression of MMP-9, and abrogated the susceptibility to L-alanosine. The inhibiting effects of MTAP expression on tumor growth, angiogenesis, and the induction of apoptosis by L-alanosine were validated using MTAP-reexpressing xenografts and reverted using RNA interference in MTAP-preserved cells. In conclusion, homozygous deletion primarily accounts for the adverse prognostic impact of MTAP deficiency and confers the biological aggressiveness and susceptibility to L-alanosine in myxofibrosarcomas.

Original languageEnglish (US)
Pages (from-to)11428-11441
Number of pages14
JournalOncotarget
Volume5
Issue number22
StatePublished - 2014
Externally publishedYes

Keywords

  • Homozygous deletion
  • Methylation
  • MTAP
  • Myxofibrosarcoma

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    Li, C. F., Fang, F. M., Kung, H-J., Chen, L. T., Wang, J. W., Tsai, J. W., Yu, S. C., Wang, Y. H., Li, S. H., & Huang, H. Y. (2014). Downregulated MTAP expression in myxofibrosarcoma: A characterization of inactivating mechanisms, tumor suppressive function, and therapeutic relevance. Oncotarget, 5(22), 11428-11441.