title: Downregulated MTAP expression in myxofibrosarcoma: A characterization of inactivating mechanisms, tumor suppressive function, and therapeutic relevance.
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.
authors.affiliation: Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan. Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan, Taiwan. National Institute of Cancer Research National Health Research Institutes, Tainan, Taiwan. Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Chien-Feng
authors.initials: CF
authors.lastname: Li
authors.affiliation: Departments of Radiation Oncology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Fu-Min
authors.initials: FM
authors.lastname: Fang
authors.affiliation: Institute of Molecular and Genomic Medicine, National Health Research Institutes, Tainan, Taiwan.
authors.forename: Hsing-Jien
authors.initials: HJ
authors.lastname: Kung
authors.affiliation: National Institute of Cancer Research National Health Research Institutes, Tainan, Taiwan. Department of Internal Medicine and Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Li-Tzong
authors.initials: LT
authors.lastname: Chen
authors.affiliation: Orthopedic Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Jun-Wen
authors.initials: JW
authors.lastname: Wang
authors.affiliation: Department of Anatomic Pathology, E-Da Hospital, Kaohsiung, Tawian.
authors.forename: Jen-Wei
authors.initials: JW
authors.lastname: Tsai
authors.affiliation: Department of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Shih Chen
authors.initials: SC
authors.lastname: Yu
authors.affiliation: Institute of Biosignal Transduction, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Yu-Hui
authors.initials: YH
authors.lastname: Wang
authors.affiliation: Department of Internal Medicine, Division of Oncology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Shau-Hsuan
authors.initials: SH
authors.lastname: Li
authors.affiliation: Department of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Hsuan-Ying
authors.initials: HY
authors.lastname: Huang
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D005354:Fibrosarcoma / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D064593:Heterografts; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016019:Survival Analysis
chemical_list: C530104:CCND1 protein, human; D019938:Cyclin D1; C000082:alanosine; D011683:Purine-Nucleoside Phosphorylase; C021784:5'-methylthioadenosine phosphorylase; D000409:Alanine