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. 2008 Jul 22:2:297-305.
doi: 10.4137/grsb.s470.

Molecular mechanisms of uterine leiomyosarcomas: involvement of defect in LMP2 expression

Takuma Hayashi  1 , Yuto Shimamura, Taro Saegusa, Akiko Horiuchi, Yukihiro Kobayashi, Nobuyoshi Hiraoka, Yae Kanai, Hiroyuki Aburatani, Kenji Sano, Ikuo Konishi
Affiliations

Molecular mechanisms of uterine leiomyosarcomas: involvement of defect in LMP2 expression

Takuma Hayashi et al. Gene Regul Syst Bio. .

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. 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 does not seem to improve survival. It is noteworthy that LMP2-deficient mice exhibit spontaneous development of uterine LMS with a disease prevalence of approximately 37% by 12 months of age. The LMP2 gene is transcribed from a promoter containing an interferon (IFN)-gamma-response factor element; thus, the IFN-gamma-signal strongly induces LMP2 expression. Furthermore, a recent report demonstrated the loss of ability to induce LMP2 expression, which is an interferon (IFN)-gamma-inducible factor, in human uterine LMS tissues and cell lines. Analysis of human uterine LMS shows somatic mutations in the IFN gamma signalling pathway, thus the loss of LMP2 induction is attributable to a defect in the earliest steps of the IFN-gamma signalling pathway. The discovery of an impaired key cell-signalling pathway may provide new targets for diagnostic approaches and therapeutic intervention.

Keywords: IFN-γ signalling pathway; leiomyosarcoma; lmp2; uterus.

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Figures

Figure 1
Figure 1
Development of uterine neoplasms in LMP2−/− mice. Uterine neoplasms in LMP2−/− mice. a and e, abdominal cavities of female C57BL/6 (a) and LMP2−/− (e) mice, showing a uterine tumor (outlined by yellow arrowheads) in the latter. b and f, female genital organs of C57BL/6 (b) and LMP2−/− (f) mice, showing a uterine neoplasm in the latter. c, d, g, h, histologycal analysis showing the normal smooth muscle cells of the uterus of C67BL/6 mice (c and d) and the abnormal cells of a leiomyosarcoma of the uterus of LMP2−/− mice (g and h). c,g, × 200; d,h, × 400.
Figure 2
Figure 2
The interferon-γ signaling pathway and mutations in its components found in human uterine leiomyosarcoma. After binding of interferon-γ (IFN-γ) to the type II IFN receptor, Janus activated kinase 1 (JAK1) and JAK2 are activated and phosphorylate STAT1 (signal transducer and activator of transcription 1) on the tyrosine residue at position 701 (Tyr701). The tyrosine-phosphorylated form of STAT1 forms homodimers that translocate to the nucleus and bind GAS (IFN-γ-activated site) elements, which are present in the promoters of IFN-γ-regulated genes. The IFN-γ-activated JAKs also regulate, through as-yet-unknown intermediates, activation of the catalytic subunit (p110) of phosphatidylinositol 3-kinase (PI3K). The activation of PI3K ultimately results in downstream activation of protein kinase C-δ (PKC-δ), which in turm regulates phosphorylation of STAT1 on the serine residue at position 727 (Ser727). The phosphorylation of Ser727 is not essential for the translocation of STAT1 to the nucleus or for the binding of STAT1 to DNA, but it is required for full transcriptional activation. IFNGR1, IFN-γ receptor subunit 1; IFNGR2, IFN-γ receptor subunit 2. Investigation of human uterine LMS tissues (total of 14 cases of LMS tissue sections and normal tissue sections located in same tissue) for somatic mutations in the IFN-γ signal cascade, JAK1, JAK2, STAT1 and Lmp2 promoter region.
Figure 3
Figure 3
Model for the initiation of uterine leiomyosarcoma tumorgenesis. The initiation of uterine leimyosarcoma development is attributed to defect in LMP2 expression, which results in marked cell proliferation.
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