title: Induction of p53-independent apoptosis by ectopic expression of HOXA5 in human liposarcomas.
abstract: Dedifferentiated liposarcoma (DDLPS) is a highly malignant subtype of human liposarcoma (LPS), whose genomic profile is characterized by chromosomal amplification at 12q13-q22. miR-26a-2 is one of the most frequently amplified genes in the region, and inhibition of its downstream target genes likely contributes to LPS tumorigenesis. Our previous study of LPS predicted homeobox protein A5 (HOXA5) as a target of miR-26a-2, and here we explored further the function of HOXA5, and its relationship with miR-26a-2 in DDLPS cells. Compared to normal human adipocytes, all LPS cell lines showed significant downregulation of HOXA5 (p = 0.046), and inhibition of miR-26a-2 using anti-miR-26a-2 substantially upregulated HOXA5 expression in these LPS cells. Interestingly, overexpression of HOXA5 alone induced very strong apoptotic response of LPS cells. HOXA5-induced apoptosis was p53-independent and caspase-dependent. Surprisingly, overexpression of HOXA5 induced nuclear translocation of RELA (p65), which was not associated with the transcriptional activity of RELA. Rather, nucleolar sequestration of RELA was observed. Overall, our study demonstrated for the first time that the downregulation of HOXA5 in LPS cells, partly by overexpression of miR-26a-2 in DDLPS, confers LPS cells resistance to apoptotic death. Further studies are required to understand the relationship of HOXA5 and the NFκB pathway in LPS cells.
authors.affiliation: Division of Hematology and Oncology, Departments of Surgery,Biomedical Sciences and Pathology and Laboratory Medicine, Samuel Oschin Comprehensive Cancer Institute,Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Dhong Hyun
authors.initials: DH
authors.lastname: Lee
authors.affiliation: Division of Hematology and Oncology, Departments of Surgery,Biomedical Sciences and Pathology and Laboratory Medicine, Samuel Oschin Comprehensive Cancer Institute,Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Forscher
authors.affiliation: 1] Division of Cancer Biology and Therapeutics, Departments of Surgery, Biomedical Sciences and Pathology and Laboratory Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA [2] The Urological Diseases Research Center; Boston Children's Hospital, Boston, MA, Department of Surgery, Harvard Medical School, Boston, MA, USA.
authors.forename: Dolores
authors.initials: D
authors.lastname: Di Vizio
authors.affiliation: 1] Division of Hematology and Oncology, Departments of Surgery,Biomedical Sciences and Pathology and Laboratory Medicine, Samuel Oschin Comprehensive Cancer Institute,Cedars-Sinai Medical Center, Los Angeles, CA, USA [2] National Cancer Institute and Cancer Science Institute, National University of Singapore, Singapore.
authors.forename: H Phillip
authors.initials: HP
authors.lastname: Koeffler
mesh_terms: D017209:Apoptosis / Q000235:genetics*; D063646:Carcinogenesis / Q000235:genetics; D020169:Caspases / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000235:genetics; D000066630:Ectopic Gene Expression / Q000235:genetics*; D005784:Gene Amplification / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008080:Liposarcoma / Q000235:genetics*; D035683:MicroRNAs / Q000235:genetics; D016328:NF-kappa B / Q000235:genetics; D015533:Transcriptional Activation / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics
chemical_list: D020169:Caspases; D018398:Homeodomain Proteins; D035683:MicroRNAs; D016328:NF-kappa B; D016159:Tumor Suppressor Protein p53; C489213:HOXA5 protein, human; C528163:MIRN26 microRNA, human; C495901:TP53 protein, human