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

• 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

 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.

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