Biological Significance of the Proteasome Subunit LMP2/b1i as a Tumor Suppressor in Human Uterine Leiomyosarcoma

Authors

  • Takuma Hayashi Dept. of Immunology and Infectious Disease, Shinshu University Graduate School of Medicine, Matsumoto-city, Nagano 390-8621, Japan
  • Akiko Horiuchi Department of Obstetrics and Gynecology, Shinshu University School of Medicine, Matsumoto-city, Nagano 390-8621, Japan
  • Kenji Sano Dept. of Laboratory Medicine, Shinshu University Hospital
  • Gal Gur Sigma-Aldrich Israel Ltd., Rehovot 76100, Israel
  • Hiroyuki Aburatani The Cancer System Laboratory, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo 153-9804 Japan
  • Osamu Ishiko Department of Obstetrics and Gynecology, Osaka City University Graduate School of Medicine, Osaka 545-8585 Japan
  • Nobuo Yaegashi Department of Obstetrics and Gynecology, Tohoku University Graduate School of Medicine, Miyagi 980-8574 Japan
  • Tanri Shiozawa Department of Obstetrics and Gynecology, Shinshu University School of Medicine, Matsumoto-city, Nagano 390-8621, Japan
  • Yae Kanai Pathology Division, National Cancer Center Research Institute, Tokyo 104-0045, Japan
  • Dorit Zharhary Promoting Business using Advanced Technology, Japan Science and Technology Agency (JST), Chiyoda-ku, Tokyo 102-8666, Japan
  • Susumu Tonegawa Picower Institution and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139-4307 USA
  • Ikuo Konishi Department of Obstetrics and Gynecology, Kyoto University Graduate School of Medicine, Kyoto-city, Kyoto 606-8507, Japan

DOI:

https://doi.org/10.6000/1929-2279.2012.01.02.4

Keywords:

LMP2/β1i, calponin h1, tumor-suppressor, leiomyosarcoma, leiomyoma, biomarker.

Abstract

 Uterine leiomyosarcoma (Ut-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 Ut-LMS is not substantially correlated with hormonal conditions, and the risk factors are not yet known. Importantly, a diagnostic-biomarker which distinguishes malignant Ut-LMS from other uterine mesenchymal tumors including leiomyoma (LMA) is yet to be established. Accordingly, it is necessary to analyze risk factors associated with Ut-LMS, to establish a clinical treatment method. Proteasome subunit, low-molecular mass polypeptide(LMP2)/b1i-deficient mice spontaneously develop Ut-LMS, with a disease prevalence of ~40% by 14 months of age. Recent experiments with human and mouse uterine tissues revealed defective LMP2/b1i expression in human Ut-LMS that was traced to the interferon (IFN)-g pathway and a specific effect of Janus kinase (JAK)-1 somatic mutations on LMP2/b1i transcriptional activation. Furthermore, analysis of a human Ut-LMS cell line clarified the biological significance of LMP2/b1i in malignant myometrium transformation and the cell cycle, thus implicating LMP2/b1i as an anti-tumorigenic candidate. Therefore, defective-LMP2/b1i expression may be a risk factor for human Ut-LMS. LMP2/b1i is a potential diagnostic-biomarker for Ut-LMS, and may be a targeted-molecule for a new clinical therapeutic approach.

References

Zaloudek C, Hendrickson MR. Mesenchymal tumors of the uterus, in Kurman RJ, Ed. Blaustein`s Pathology of the Female Genital Tract (ed 5). New York, Springer-Verlag 2002; 5: 561-578.

Perez EA, Pusztai L, Van de Vijver M. Improving patient care through molecular diagnostics. Semin Oncol 2004; 31: 14-20. http://dx.doi.org/10.1053/j.seminoncol.2004.07.017

Leitao MM, Soslow RA, Nonaka D, Olshen AB, Aghajanian C, Sabbatini P, et al. Tissue microarray immunohistochemical expression of estrogen, progesterone, and androgen receptors in uterine leiomyomata and leiomyosarcoma. Cancer 2004; 101: 1455-62. http://dx.doi.org/10.1002/cncr.20521

Wu TI, Chang TC, Hsueh S, Hsu KH, Chou HH, Huang HJ, et al. Prognostic factors and impact of adjuvant chemotherapy for uterine leiomyosarcoma. Gynecol Oncol 2006; 100: 166-72. http://www.sciencedirect.com/science/ article/pii/S0090825805007067 http://dx.doi.org/10.1016/j.ygyno.2005.08.010

http://cancer.gov/cancertopics/pdq/treatment/uterinesarcoma/HealthProfessional

Evans HL, Chawla SP, Simpson C, Finn KP. Smooth muscle neoplasms of the uterus other than ordinary leiomyoma. A study of 46 cases, with emphasis on diagnostic criteria and prognostic factors. Cancer 1988; 62: 2239-47. http://dx.doi.org/10.1002/1097-0142(19881115)62:10<2239::AID-CNCR2820621028>3.0.CO;2-Y

Kurma RJ. Pathology of the Female Genital Tract, 4th ed. New York, Springer-Verlag 2001; vol. 4: pp. 499.

Diagnostic Criteria for LMS, Adapted from 2003 WHO Guidelines: World Health Organization Classification of Tumours: Pathology and Genetics, Pathology and Genetics of Tumours of the Breast and Female Genital Organs. IARC Press, France 2003.

Miettinen M, Fetsch JF. Evaluation of biological potential of smooth muscle tumours. Histopathology 2006; 48: 97-105. http://dx.doi.org/10.1111/j.1365-2559.2005.02292.x

Lin JF, Slomovitz BM. Uterine sarcoma. Curr Oncol Rep 2008; 10: 512-18. http://dx.doi.org/10.1007/s11912-008-0077-9

Amant F, Coosemans A, Debiec-Rychter M, Timmerman D, Vergote I. Clinical management of uterine sarcomas. Lancet Oncol 2009; 10: 1188-98. http://dx.doi.org/10.1016/S1470-2045(09)70226-8

Peters JM, Franke WW, Kleinschmidt JA. Distinct 19S and 20S subcomplexes of the 26S proteasome and their distribution in the nucleus and the cytoplasm. J Biol Chem 1994; 269: 7709-18. http://www.jbc.org/content/269/10/ 7709.long

Lodish H, Berk A, Matsudaira P, Kaiser CA, Krieger M, Scott MP, et al. Mol Cell Biol (5th ed.). New York: W.H. Freeman and CO. 2004; vol. 5: pp. 66-72.

Higashitsuji H, Liu Y, Mayer RJ, Fujita J. The oncoprotein gankyrin negatively regulates both p53 and RB by enhancing proteasomal degradation. Cell Cycle 2005; 4: 1335-37. http://dx.doi.org/10.4161/cc.4.10.2107

Konstantinova IM, Tsimokha AS, Mittenberg AG. Role of proteasomes in cellular regulation. Int Rev Cell Mol Biol 2008; 267: 59-124. http://dx.doi.org/10.1016/S1937-6448(08)00602-3

Wang J, Maldonado MA. The Ubiquitin-Proteasome System and Its Role in Inflammatory and Autoimmune Diseases. Cell Mol Immunol 2006; 3: 255-61. http://www.cmi.ustc.edu.cn/ 3/4/255.pdf

Muchamuel T, Basler M, Aujay MA, Suzuki E, Kalim KW, Lauer C, et al. A selective inhibitor of the immunoproteasome subunit LMP7 blocks cytokine production and attenuates progression of experimental arthritis. Nature Med 2009; 15: 781-88. http://dx.doi.org/10.1038/nm.1978

Van Kaer L, Ashton-Rickardt PG, Eichelberger M, Gaczynska M, Nagashima K, Rock KL, et al. Altered peptidase and viral-specifi c T cell response in LMP2 mutant mice. Immunity 1994; 1: 533-41. http://dx.doi.org/10.1016/1074-7613(94)90043-4

Hayashi T, Faustman DL. Development of spontaneous uterine tumors in low molecular mass polypeptide-2 knockout mice. Cancer Res 202; 62: 24-27. http://cancerres. aacrjournals.org/content/62/1/24.long

http://www.informatics.jax.org/javawi2/servlet/WIFetch?page=alleleDetail&id=MGI:2152729#refs

Hayashi T, Horiuchi A, Sano K, Hiraoka N, Kanai Y, Shiozawa, T, et al. Molecular approach on uterine leiomyosarcoma: LMP2-deficient mice as an animal model of spontaneous uterine leiomyosarcoma. Sarcoma 2011: 476498. Epub 2011 Mar 8. http://www.hindawi.com/journals/ srcm/2011/476498/

Hayashi T, Kobayashi Y, Kohsaka S, Sano K. 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 2006; 25: 4016-26. http://dx.doi.org/10.1038/sj.onc.1209434

Hayashi T, Horiuchi A, Sano K, Hiraoka N, Kasai M, Ichimura T, et al. Potential role of LMP2 as tumor-suppressor defines new targets for uterine leiomyosarcoma therapy. Sci Rep 2001; 1: 180|DOI:10.1038/ srep00180 http://www.nature. com/srep/2011/111205/srep00180/full/srep00180.html

Zhai YL, Kobayashi Y, Mori A, Orii A, Nikaido T, Konishi I, et al. Expression of steroid receptors, Ki-67, and p53 in uterine leiomyosarcomas. Intl J Gynecol Pathol 1999; 18: 20-28. http://www.ncbi.nlm.nih.gov/pubmed/9891238 http://dx.doi.org/10.1097/00004347-199901000-00004

Hayashi T, Horiuchi A, Sano K, Hiraoka N, Kasai M, Ichimura T, et al. Potential role of LMP2 as an anti-oncogenic factor in human uterine leiomyosarcoma: morphological significance of calponin h1. FEBS Lett 2012; 586: 1824-31. http://www.sciencedirect.com/science/article/pii/S0014579312004048# http://dx.doi.org/10.1016/j.febslet.2012.05.029

Horiuchi A, Nikaido T, Ito K, Zhai YI, Orii A, Taniguchi S, et al. Reduced expression of calponin h1 in leiomyosarcoma of the uterus. Lab Invest 1998; 78: 839-46. http://www.ncbi.nlm. nih.gov/pubmed/9690561

Horiuchi A, Nikaido T, Taniguchi S, Fujii S. Possible role of calponin h1 as a tumor suppressor in human uterine leiomyosarcoma. J Natl Cancer Inst 1999; 91: 790-96. http://jnci.oxfordjournals.org/content/91/9/790.long http://dx.doi.org/10.1093/jnci/91.9.790

Winder SJ, Walsh MP, Vasulka C, Johnson JD. Calponin-calmodulin interaction: properties and effects on smooth and skeletal muscle actin biding and actomyosin ATPases. Biochemistry 1993; 32: 13327-3. http://dx.doi.org/10.1021/bi00211a046

Wills FL, McCubbin WD, Kay CM. Smooth muscle calponin-caltropin interaction: effect on biological activity and stability of calponin. Biochemistry 1994; 33: 5562-69. http://dx.doi.org/10.1021/bi00184a027

Wang HX, Wang HM, Li QL, Judoson PL. Expression of proteasome subunits low molecular mass polypeptide (LMP) 2 and LMP7 in the endometrium and placenta of rhesus monkey (Macaca mulatta) during early pregnancy. Biol Reprod 2004; 71: 1317-24. http://www.biolreprod.org/ content/71/4/1317.long http://dx.doi.org/10.1095/biolreprod.104.030213

Wang HX, Wang HM, Lin HY, Yang Q, Zhang H, Tsang BK, Zhu C. Proteasome subunit LMP2 is required for matrix metalloproteinase-2 and -9 expression and activities in human invasive extravillous trophoblast cell line. J Cell Physiol 2006; 206: 616-23. http://dx.doi.org/10.1002/jcp.20508

Fu JJ, Lin P, Lv XY, Yan XJ, Wang HX, Zhu C, et al. Low molecular mass polypeptide-2 in human trophoblast: over-expression in hydatidiform moles and possible role in trophoblast cell invasion. Placenta 2009; 30: 305-12. http://www.sciencedirect.com/science/article/pii/S0143400409000113 http://dx.doi.org/10.1016/j.placenta.2009.01.005

Sexl V, Kovacic B, Piekorz R, Moriggl R, Stoiber D, Hoffmeyer A, et al. Jak1 deficiency leads to enhanced Abelson-induced B-cell tumor formation. Blood 2003; 101: 4937-43. http://bloodjournal.hematologylibrary.org/content/ 101/12/4937.long http://dx.doi.org/10.1182/blood-2001-11-0142

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Published

2012-07-28

How to Cite

Takuma Hayashi, Akiko Horiuchi, Kenji Sano, Gal Gur, Hiroyuki Aburatani, Osamu Ishiko, Nobuo Yaegashi, Tanri Shiozawa, Yae Kanai, Dorit Zharhary, Susumu Tonegawa, & Ikuo Konishi. (2012). Biological Significance of the Proteasome Subunit LMP2/b1i as a Tumor Suppressor in Human Uterine Leiomyosarcoma . Journal of Cancer Research Updates, 1(2), 181–188. https://doi.org/10.6000/1929-2279.2012.01.02.4

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