Oncotarget

Research Papers:

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 and Hsuan-Ying Huang

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Oncotarget. 2014; 5:11428-11441. https://doi.org/10.18632/oncotarget.2552

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Abstract

Chien-Feng Li1,2,3,4,*, Fu-Min Fang5,*, Hsing-Jien Kung6, Li-Tzong Chen3,7, Jun-Wen Wang8, Jen-Wei Tsai9, Shih Chen Yu10, Yu-Hui Wang11, Shau-Hsuan Li12, Hsuan-Ying Huang10

1Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan

2Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan, Taiwan

3National Institute of Cancer Research National Health Research Institutes, Tainan, Taiwan

4Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

5Departments of Radiation Oncology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan

6Institute of Molecular and Genomic Medicine, National Health Research Institutes, Tainan, Taiwan

7Department of Internal Medicine and Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan

8Orthopedic Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan

9Department of Anatomic Pathology, E-Da Hospital, Kaohsiung, Tawian

10Department of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan

11Institute of Biosignal Transduction, National Cheng Kung University, Tainan, Taiwan

12Department of Internal Medicine, Division of Oncology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan

*These authors contributed equally to this work

Correspondence to:

Hsuan-Ying Huang, e-mail: a120600310@yahoo.com

Keywords: myxofibrosarcoma, MTAP, homozygous deletion, methylation

Received: August 03, 2014     Accepted: October 01, 2014     Published: October 24, 2014

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 MTAP-deficient cases, the homozygous deletion of MTAP predicted adverse outcome. In MTAP-deficient cells, MTAP reexpression inhibited cell migration and invasion, proliferation, 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.


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