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Protein & Cell

, Volume 1, Issue 8, pp 711–717 | Cite as

Mice-lacking LMP2, immuno-proteasome subunit, as an animal model of spontaneous uterine leiomyosarcoma

  • Takuma HayashiEmail author
  • Akiko Horiuchi
  • Kenji Sano
  • Nobuyoshi Hiraoka
  • Yae Kanai
  • Tanri Shiozawa
  • Susumu Tonegawa
  • Ikuo Konishi
Review

Abstract

Uterine tumors are the most common type of gynecologic neoplasm. Uterine leiomyosarcoma (LMS) is rare, accounting for 2% to 5% of tumors of the uterine body. Uterine LMS develops more often in the muscle tissue layer of the uterine body than in the uterine cervix. The development of gynecologic tumors is often correlated with female hormone secretion; however, the development of uterine LMS is not substantially correlated with hormonal conditions, and the risk factors are not yet known. Radiographic evaluation combined with PET/CT can be useless in the diagnosis and surveillance of uterine LMS. Importantly, a diagnostic biomarker, which distinguishes malignant LMS and benign tumor leiomyoma (LMA) is yet to be established. Accordingly, it is necessary to analyze risk factors associated with uterine LMS in order to establish a method of treatment. LMP2-deficient mice spontaneously develop uterine LMS, with a disease prevalence of ∼40% by 14 months of age. It is therefore of interest whether human uterine LMS shows a loss of LMP2 expression. We found LMP2 expression is absent in human LMS, but present in human LMA. Therefore, defective LMP2 expression may be one of the risk factors for LMS. LMP2 is potentially a diagnostic biomarker for uterine LMS, and gene therapy with LMP2-encording DNA may be a new therapeutic approach.

Keywords

LMP2 uterine leiomyosarcoma uterine leiomyoma diagnostic biomarker 

References

  1. Akhan, S.E., Yavuz, E., Tecer, A., Iyibozkurt, C.A., Topuz, S., Tuzlali, S., Bengisu, E., and Berkman, S. (2005). The expression of Ki-67, p53, estrogen and progesterone receptors affecting survival in uterine leiomyosarcomas. A clinicopathologic study. Gynecol Oncol 99, 36–42.CrossRefGoogle Scholar
  2. Amant, F., Coosemans, A., Debiec-Rychter, M., Timmerman, D., and Vergote, I. (2009). Clinical management of uterine sarcomas. Lancet Oncol 10, 1188–1198.CrossRefGoogle Scholar
  3. Brooks, S.E., Zhan, M., Cote, T., and Baquet, C.R. (2004). Surveillance, epidemiology, and end results analysis of 2677 cases of uterine sarcoma 1989–1999. Gynecol Oncol 93, 204–208.CrossRefGoogle Scholar
  4. Brucet, M., Marqués, L., Sebastián, C., Lloberas, J., and Celada, A. (2004). Regulation of murine Tap1 and Lmp2 genes in macrophages by interferon gamma is mediated by STAT1 and IRF-1. Genes Immun 5, 26–35.CrossRefGoogle Scholar
  5. Delp, K., Momburg, F., Hilmes, C., Huber, C., and Seliger, B. (2000). Functional deficiencies of components of the MHC class I antigen pathway in human tumors of epithelial origin. Bone Marrow Transplant 25, S88–S95.CrossRefGoogle Scholar
  6. Dunn, G.P., Bruce, A.T., Ikeda, H., Old, L.J., and Schreiber, R.D. (2002). Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 3, 991–998.CrossRefGoogle Scholar
  7. Dunn, G.P., Old, L.J., and Schreiber, R.D. (2004). The immunobiology of cancer immunosurveillance and immunoediting. Immunity 21, 137–148.CrossRefGoogle Scholar
  8. Dusenbery, K.E., Potish, R.A., and Judson, P. (2004). Limitations of adjuvant radiotherapy for uterine sarcomas spread beyond the uterus. Gynecol Oncol 94, 191–196.CrossRefGoogle Scholar
  9. Gaczynska, M., Rock, K.L., and Goldberg, A.L. (1993). γ-interferon and expression of MHC genes regulate peptide hydrolysis by proteasomes. Nature 365, 264–267.CrossRefGoogle Scholar
  10. Groettrup, M., Khan, S., Schwarz, K., and Schmidtke, G. (2001). Interferon-γ inducible exchanges of 20S proteasome active site subunits: why? Biochimie 83, 367–372.CrossRefGoogle Scholar
  11. Harada, H., Kitagawa, M., Tanaka, N., Yamamoto, H., Harada, K., Ishihara, M., and Taniguchi, T. (1993). Anti-oncogenic and oncogenic potentials of interferon regulatory factors-1 and -2. Science 259, 971–974.CrossRefGoogle Scholar
  12. Hayashi, T., and Faustman, D.L. (2002). Development of spontaneous uterine tumors in low molecular mass polypeptide-2 knockout mice. Cancer Res 62, 24–27.Google Scholar
  13. Hayashi, T., Kobayashi, Y., Kohsaka, S., and Sano, K. (2006). The mutation in the ATP-binding region of JAK1, identified in human uterine leiomyosarcomas, results in defective interferon-gamma inducibility of TAP1 and LMP2. Oncogene 25, 4016–4026.CrossRefGoogle Scholar
  14. Kanamori, T., Takakura, K., Mandai, M., Kariya, M., Fukuhara, K., Kusakari, T., Momma, C., Shime, H., Yagi, H., Konishi, M., et al. (2003). PEP-19 overexpression in human uterine leiomyoma. Mol Hum Reprod 9, 709–717.CrossRefGoogle Scholar
  15. Koepp, D.M., Schaefer, L.K., Ye, X., Keyomarsi, K., Chu, C., Harper, J.W., and Elledge, S.J. (2001). Phosphorylation-dependent ubiquitination of cyclin E by the SCFFbw7 ubiquitin ligase. Science 294, 173–177.CrossRefGoogle Scholar
  16. Lassot, I., Latreille, D., Rousset, E., Sourisseau, M., Linares, L.K., Chable-Bessia, C., Coux, O., Benkirane, M., and Kiernan, R.E. (2007). The proteasome regulates HIV-1 transcription by both proteolytic and nonproteolytic mechanisms. Mol Cell 25, 369–383.CrossRefGoogle Scholar
  17. Lin, J.F., and Slomovitz, B.M. (2008). Uterine sarcoma 2008. Curr Oncol Rep 10, 512–518.CrossRefGoogle Scholar
  18. Maniatis, T. (1999). A ubiquitin ligase complex essential for the NFkappaB, Wnt/Wingless, and Hedgehog signaling pathways. Genes Dev 13, 505–510.CrossRefGoogle Scholar
  19. Matsumoto, Y., and Maller, J.L. (2004). A centrosomal localization signal in cyclin E required for Cdk2-independent S phase entry. Science 306, 885–888.CrossRefGoogle Scholar
  20. Miettinen, M., and Fetsch, J.F. (2006). Evaluation of biological potential of smooth muscle tumours. Histopathology 48, 97–105.CrossRefGoogle Scholar
  21. Nakajima, C., Uekusa, Y., Iwasaki, M., Yamaguchi, N., Mukai, T., Gao, P., Tomura, M., Ono, S., Tsujimura, T., Fujiwara, H., et al. (2001). A role of interferon-γ (IFN-γ) in tumor immunity: T cells with the capacity to reject tumor cells are generated but fail to migrate to tumor sites in IFN-γ-deficient mice. Cancer Res 61, 3399–3405.Google Scholar
  22. Shankaran, V., Ikeda, H., Bruce, A.T., White, J.M., Swanson, P.E., Old, L.J., and Schreiber, R.D. (2001). IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 410, 1107–1111.CrossRefGoogle Scholar
  23. Sherr, C.J. (2000). The Pezcoller lecture: cancer cell cycles revisited. Cancer Res 60, 3689–3695.Google Scholar
  24. Tanaka, N., Ishihara, M., Lamphier, M.S., Nozawa, H., Matsuyama, T., Mak, T.W., Aizawa, S., Tokino, T., Oren, M., and Taniguchi, T. (1996). Cooperation of the tumour suppressors IRF-1 and p53 in response to DNA damage. Nature 382, 816–818.CrossRefGoogle Scholar
  25. Van Kaer, L., Ashton-Rickardt, P.G., Eichelberger, M., Gaczynska, M., Nagashima, K., Rock, K.L., Goldberg, A.L., Doherty, P.C., and Tonegawa, S. (1994). Altered peptidase and viral-specific T cell response in LMP2 mutant mice. Immunity 1, 533–541.CrossRefGoogle Scholar
  26. Wang, L., Felix, J.C., Lee, J.L., Tan, P.Y., Tourgeman, D.E., O’Meara, A.T., and Amezcua, C.A. (2003). The proto-oncogene c-kit is expressed in leiomyosarcomas of the uterus. Gynecol Oncol 90, 402–406.CrossRefGoogle Scholar
  27. Wu, T.I., Chang, T.C., Hsueh, S., Hsu, K.H., Chou, H.H., Huang, H.J., and Lai, C.H. (2006). Prognostic factors and impact of adjuvant chemotherapy for uterine leiomyosarcoma. Gynecol Oncol 100, 166–172.CrossRefGoogle Scholar
  28. Yanagi, S., Shimbara, N., and Tamura, T.A. (2000). Tissue and cell distribution of a mammalian proteasomal ATPase, MSS1, and its complex formation with the basal transcription factors. Biochem Biophys Res Commun 279, 568–573.CrossRefGoogle Scholar
  29. Ylisaukko-oja, S.K., Kiuru, M., Lehtonen, H.J., Lehtonen, R., Pukkala, E., Arola, J., Launonen, V., and Aaltonen, L.A. (2006). Analysis of fumarate hydratase mutations in a population-based series of early onset uterine leiomyosarcoma patients. Int J Cancer 119, 283–287.CrossRefGoogle Scholar
  30. Zaloudek, C., and Hendrickson, M.R. (2002) Mesenchymal tumors of the uterus, in Kurman RJ (ed): Blaustein’s Pathology of the Female Genital Tract (ed 5). New York, Springer-Verlag, pp561–578.Google Scholar
  31. Zhai, Y.L., Kobayashi, Y., Mori, A., Orii, A., Nikaido, T., Konishi, I., and Fujii, S. (1999). Expression of steroid receptors, Ki-67, and p53 in uterine leiomyosarcomas. Int J Gynecol Pathol 18, 20–28.CrossRefGoogle Scholar

Copyright information

© Higher Education Press and Springer-Verlag Berlin Heidelberg 2010

Authors and Affiliations

  • Takuma Hayashi
    • 1
    • 7
    Email author
  • Akiko Horiuchi
    • 2
  • Kenji Sano
    • 3
  • Nobuyoshi Hiraoka
    • 4
  • Yae Kanai
    • 4
  • Tanri Shiozawa
    • 2
  • Susumu Tonegawa
    • 5
  • Ikuo Konishi
    • 6
  1. 1.Department of Immunology and Infectious DiseaseShinshu University Graduate School of MedicineMatsumoto, NaganoJapan
  2. 2.Department of Obstetrics and GynecologyShinshu University School of MedicineMatsumoto, NaganoJapan
  3. 3.Department of Laboratory MedicineShinshu University HospitalMatsumoto, NaganoJapan
  4. 4.Pathology DivisionNational Cancer Center Research InstituteTokyoJapan
  5. 5.Picower Institution and Department of BiologyMassachusetts Institute of TechnologyCambridgeUSA
  6. 6.Department of Obstetrics and GynecologyKyoto University Graduate School of MedicineSakyo-ku, KyotoJapan
  7. 7.Promoting Business using Advanced TechnologyJapan Science and Technology Agency (JST)Kawaguchi-shi, SaitamaJapan

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