Potential role of LMP2 as tumor-suppressor defines new targets for uterine leiomyosarcoma therapy

Abstract

Although the majority of smooth muscle neoplasms found in the uterus are benign, uterine leiomyosarcoma (LMS) is extremely malignant, with high rates of recurrence and metastasis. We earlier reported that mice with a homozygous deficiency for LMP2, an interferon (IFN)-γ-inducible factor, spontaneously develop uterine LMS. The IFN-γ pathway is important for control of tumor growth and invasion and has been implicated in several cancers. In this study, experiments with human and mouse uterine tissues revealed a defective LMP2 expression in human uterine LMS that was traced to the IFN-γ pathway and the specific effect of JAK-1 somatic mutations on the LMP2 transcriptional activation. Furthermore, analysis of a human uterine LMS cell line clarified the biological significance of LMP2 in malignant myometrium transformation and cell cycle, thus implicating LMP2 as an anti-tumorigenic candidate. This role of LMP2 as a tumor suppressor may lead to new therapeutic targets in human uterine LMS.

The Proteasome Subunit LMP2/b1i In the Female Genital System

“…A pathological examination of surgical samples revealed the presence of a mass measuring 3 cm in its largest diameter in the lumbar quadrate muscle without a fibrous capsule. All lymph nodes were negative for human Ut-LMS metastases, and immunohistological studies showed positivity for ki-67 and negativity for LMP2/β1i [37]. Histological findings were consistent with metastatic Ut-LMS for the skeletal muscle and rectum lesions [37].…”

“…2) (NOTE 1) . Of the 54 cases we examined with human Ut-LMS, 46 were negative for LMP2/β1i expression, 4 were focally positive, and 2 were partially positive [37]. Two Ut-LMS cases stained for LMP2/β1i.…”

“…Two Ut-LMS cases stained for LMP2/β1i. LMP2/β1i levels were also evaluated in skeletal muscle and rectum metastases from individual Ut-LMS patients [37,38]. A pathological examination of surgical samples revealed the presence of a mass measuring 3 cm in its largest diameter in the lumbar quadrate muscle without a fibrous capsule.…”

“…Furthermore, immunohistochemistry (IHC) revealed a serious loss in the ability to induce LMP2/β1i expression in human Ut-LMS tissue relative to that in LMA or a normal myometrium located in the same section [36,37] (Fig. 2) (NOTE 1) .…”

Mechanisms of tumour escape from immune surveillance

“…Furthermore, costimulatory molecules such as CD80 or CD86 are often absent from the surface of tumour cells, which makes activation of T lymphocytes impossible (37,46). Other molecules whose expression may be downregulated in tumour cells are latent membrane protein 2 (LMP2), latent membrane protein 7 (LMP7), transporter associated with antigen processing protein (TAP protein), and tapasin (17,23,32). Most tumour antigens that have been identified are proteins which are also found on other cells in the body, leading to the phenomenon of immune tolerance to tumour antigens (24).…”