Mice null for the deubiquitinase USP18 spontaneously develop leiomyosarcomas
| Autor: | Masanori Kawakami, Wendy A. Wells, Aarti Sanglikar, Alexander J. Lazar, Vincent A. Memoli, Ethan Dmitrovsky, Fadzai Chinyengetere, Elizabeth G. Demicco, Keila E. Torres, David Sekula, Sarah J. Freemantle, Andrew J. Giustini, Burton L. Eisenberg, Yun Lu, Sandra Burkett, P. J. Hoopes, Tian Ma |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Leiomyosarcoma
Cancer Research ISG15 Carcinogenesis Aneuploidy medicine.disease_cause Metastasis Chromosome 15 Mice Surgical oncology Genetics medicine Animals Humans Neoplasm Metastasis Mice Knockout business.industry medicine.disease 3. Good health body regions Gene Expression Regulation Neoplastic Disease Models Animal USP18 Oncology Murine cancer model Uterine Neoplasms Cancer research Immunohistochemistry Female Sarcoma Tumor Suppressor Protein p53 business Ubiquitin Thiolesterase Research Article |
| Zdroj: | BMC Cancer |
| ISSN: | 1471-2407 |
| Popis: | Background USP18 (ubiquitin-specific protease 18) removes ubiquitin-like modifier interferon stimulated gene 15 (ISG15) from conjugated proteins. USP18 null mice in a FVB/N background develop tumors as early as 2 months of age. These tumors are leiomyosarcomas and thus represent a new murine model for this disease. Methods Heterozygous USP18 +/− FVB/N mice were bred to generate wild-type, heterozygous and homozygous cohorts. Tumors were characterized immunohistochemically and two cell lines were derived from independent tumors. Cell lines were karyotyped and their responses to restoration of USP18 activity assessed. Drug testing and tumorigenic assays were also performed. USP18 immunohistochemical staining in a large series of human leiomyosacomas was examined. Results USP18 −/− FVB/N mice spontaneously develop tumors predominantly on the back of the neck with most tumors evident between 6–12 months (80 % penetrance). Immunohistochemical characterization of the tumors confirmed they were leiomyosarcomas, which originate from smooth muscle. Restoration of USP18 activity in sarcoma-derived cell lines did not reduce anchorage dependent or independent growth or xenograft tumor formation demonstrating that these cells no longer require USP18 suppression for tumorigenesis. Karyotyping revealed that both tumor-derived cell lines were aneuploid with extra copies of chromosomes 3 and 15. Chromosome 15 contains the Myc locus and MYC is also amplified in human leiomyosarcomas. MYC protein levels were elevated in both murine leiomyosarcoma cell lines. Stabilized P53 protein was detected in a subset of these murine tumors, another feature of human leiomyosarcomas. Immunohistochemical analyses of USP18 in human leiomyosarcomas revealed a range of staining intensities with the highest USP18 expression in normal vascular smooth muscle. USP18 tissue array analysis of primary leiomyosarcomas from 89 patients with a clinical database revealed cases with reduced USP18 levels had a significantly decreased time to metastasis (P = 0.0441). Conclusions USP18 null mice develop leiomyosarcoma recapitulating key features of clinical leiomyosarcomas and patients with reduced-USP18 tumor levels have an unfavorable outcome. USP18 null mice and the derived cell lines represent clinically-relevant models of leiomyosarcoma and can provide insights into both leiomyosarcoma biology and therapy. Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-1883-8) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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