VOL. 4, No. 1, January 2008

T. Hayashi, et al. [2008] Med. Hypotheses Res. 4: 11‒20.

Molecular Mechanisms of Uterine Leiomyosarcomas:
Involvement of Defective LMP2 Activation

Takuma Hayashi*, Yukihiro Kobayashi, Akiko Horiuchi,
Nobuyoshi Hiraoka, Noriko Kubota, Yae Kanai, Hiroyuki Aburatani,
Ikuo Konishi and Kenji Sano

Department of Immunology and Infectious Disease, Shinshu University Graduate School of
Medicine, Department of Laboratory Medicine, Shinshu University Hospital, Department of
Obstetrics and Gynecology, Shinshu University Medical School, Pathology Division,
National Cancer Center Research Institute, Department of Clinical Pathology, Nagano
Children’s Hospital, The Cancer System Laboratory, Research Center for Advanced Science
and Technology, The University of Tokyo, and Japan Science and Technology Agency,
Nagano 390-8621 Japan

Abstract. Patients with uterine leiomyosarcoma (LMS) typically present with vaginal
bleeding, pain, and a pelvic mass. Typical presentations with hypercalcemia or eosinophilia
have been reported. Radiographic evaluation with combined positron emission
tomography/computed tomography may assist in the diagnosis and surveillance of women
with uterine LMS. Stage and tumor grade continue to appear to be valid prognostic
indicators. A recently developed risk-assessment index is highly predictive of disease-specific
survival. Ovarian preservation does not appear to negatively impact outcome, and the
addition of adjuvant therapy after surgical treatment do not seem to improve survival. It is
noteworthy that LMP2-deficient mice exhibit spontaneous development of uterine LMS with
a disease prevalence of ~37% by 12 months of age. Furthermore, a recent report
demonstrated the loss of ability to induce LMP2 expression, which is an interferon-γ (IFN-γ)
inducible factor, in human uterine LMS tissues. We analyzed human uterine LMS for genetic
mutation in the IFN-γ signal cascade and found serious mutations in three genes. Molecular
experiments demonstrated cytokine differential expression, especially IL-8, which directly
regulated tumor cell migration or invasion, by LMP2 expression. The discovery of this
mutational activation of a key cell-signaling pathway and cytokine differential expressions
may provide new targets for diagnostic approaches and therapeutic intervention.

* Correspondence: Dr. Takuma Hayashi, Department of Immunology and Infectious
Disease, Shinshu University Graduate School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano
390-8621, Japan Tel: +81-263-37-2611 Fax: +81-263-37-2613.
E-Mail: takuma-h@sch.

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