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Human uterine leiomyosarcoma (LMS) is neoplastic malignancy that typically arises in tissues of mesenchymal origin. The identification of novel molecular mechanism leading to human uterine LMS formation and the establishment of new therapies has been hampered by several critical points. We earlier reported that mice with a homozygous deficiency for proteasome beta subunit 9 (PSMB9)/b1i, an interferon (IFN)-g inducible factor, spontaneously develop uterine LMS. The use of research findings of the experiment with mouse model has been successful in increasing our knowledge and understanding of how alterations, in relevant oncogenic, tumour suppressive, and signaling pathways directly impact sarcomagenesis. The IFN-g pathway is important for control of tumour growth and invasion and, has been implicated in several malignant tumours. In this study, experiments with human tissues revealed a defective PSMB9/b1i expression in human uterine LMS that was traced to the IFN-g pathway and the specific effect of somatic mutations of Janus kinase (JAK1) molecule or promoter region on the transcriptional activation of PSMB9/b1i gene. Understanding the molecular mechanisms of human uterine LMS may lead to identification of new diagnostic candidates or therapeutic targets in human uterine LMS. DOI : 10.14302/issn2572-3030.jcgb-16-1276 Freely Available Online www.openaccesspub.org | JCGB CC-license DOI : 10.14302/issn2572-3030.jcgb-16-1276 Vol-1 Issue 1 Pg. no.30 Introduction Uterine mesenchymal tumours have been traditionally divided into benign tumour leiomyomas (LMA) and malignant tumour leiomyosarcomas (LMS) based on cytological atypia, mitotic activity and other criteria. Uterine LMS, which are some of the most common neoplasms of the female genital tract, are relatively rare uterine mesenchymal tumour, having an estimated annual incidence of 0.64 per 100,000 women (1). They account for approximately one-third of uterine sarcomas, of only 53% for tumours confined to the uterus (2,3). Generally, patients with uterine LMS typically present with vaginal bleeding, pain, and a pelvic mass. Gynecological cancer, for instance breast cancer and endometrial carcinomas, are strongly promoted by female hormones, but the rate of hormone receptor expression is reported to be significantly less in human uterine LMS compared with normal myometrium. These low receptor expressions were found to not correlate with the promotion of initial disease development or with the overall survival of patients with uterine LMS. As uterine LMS is resistant to chemotherapy and radiotherapy, and thus surgical intervention is virtually the only means of treatment for this disease (4,5,6), however, molecular targeting therapies against tumours have recently shown remarkable achievements (7,8). It is noteworthy that, when adjusting for stage and mitotic count, uterine LMS has a significantly worse prognosis than carcinosarcoma (9); developing an efficient adjuvant therapy is expected to improve the prognosis of the disease. A trend towards prolonged disease-free survival is seen in patients with matrix metalloproteinase (MMP)-2-negative tumours (10). Although typical presentations with hypercalcemia or eosinophilia have been reported, this clinical abnormality is not an initial risk factor for uterine LMS. To the best of our knowledge, little is known regarding the biology of uterine LMS; therefore, the risk factors that promote the initial development of uterine LMS and regulate their growth in vivo remain poorly understood. The mice with a targeted disruption of proteasome beta subunit 9 (PSMB9)/b1i, which is interferon (IFN)-g -inducible proteasome subunit, exhibited a defect in tissueand substratedependent proteasome function, and female PSMB9-deficient mice shown to develop uterine LMS, with a disease prevalence of 37% by 14 months of age (11,12). Defective PSMB9/b1i expression is likely to be one of the risk factors for the development of human uterine LMS, as it is in PSMB9/b1i-deficient mice (12). Recent report shows that stable PSMB9/b1i expression contributes to cell proliferation, which directly correlates to the progressive deterioration with increasing stage and grade of the tumour. As the importance and involvement of the IFN-g signal pathway in the transcriptional regulation of the transporter associated with antigen processing (TAP1) and PSMB9/b1i promoter have been established, it is demonstrated that the defective PSMB9/b1i expression was attributable to G871E somatic mutation in the ATPbinding region of JAK1 molecule in SKN cell line, which is established from patient with uterine LMS. It is (Continued on page 31) Corresponding Author: Takuma Hayashi, Dept. of Obstetrics and Gynecology, Shinshu University School of Medicine, Japan, 3-1-1, Asahi, Matsumoto, Nagano 390-8621, Japan. Tel: 81-263-37-2719, e-mail: takumah@shinshu-u.ac.jp

The Identification Of Somatic Mutations In Interferon-g Signal Molecules In Human Uterine Leiomyosarcoma