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Hayashi TakumaCorresponding author Dept. of Obstetrics and Gynecology, Shinshu University School of Medicine, Japan,
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.
Hayashi TakumaCorresponding author Dept. of Immunology and Infectious Disease, Shinshu University, School of Medicine, Matsumoto, Nagano 390-8621, Japan
Sarcomas are neoplastic malignancies that typically arise in tissues of mesenchymal origin. The identification of novel molecular mechanisms leading to sarcoma formation and the establishment of new therapies has been hampered by several critical factors. Human uterine leiomyosarcoma (Ut-LMS) develops more frequently in the muscle tissue layer of the uterine body than in the uterine cervix. Although the development of gynecologic tumors is often correlated with the secretion of female hormones; that of human Ut-LMS does not and its risk factors remain unknown. Importantly, a diagnostic biomarker that can distinguish malignant Ut-LMS from benign tumor uterine leiomyoma (LMA) has yet to be established. Therefore the risk factor(s) associated with human Ut-LMS to establish a diagnosis and novel therapeutic method. Proteasome b-ring subunit LMP2/b1i-deficient mice spontaneously develop Ut-LMS, with a disease prevalence of ~40% by 14 months of age. We shown that LMP2/b1i expression was absent in human Ut-LMS, but present in other human uterine mesenchymal tumors including uterine LMA. Therefore, defective-LMP2/b1i expression may be one of the risk factors for human Ut-LMS. LMP2/b1i is a potential diagnostic biomarker for human Ut-LMS, and may be a targeted-molecule for a new therapeutic approach.