Mice-lacking LMP2, immuno-proteasome subunit, as an animal model of spontaneous uterine leiomyosarcoma

Abstract

Uterine tumors are the most common type of gynecologic neoplasm. Uterine leiomyosarcoma (LMS) is rare, accounting for 2% to 5% of tumors of the uterine body. Uterine LMS develops more often in the muscle tissue layer of the uterine body than in the uterine cervix. The development of gynecologic tumors is often correlated with female hormone secretion; however, the development of uterine LMS is not substantially correlated with hormonal conditions, and the risk factors are not yet known. Radiographic evaluation combined with PET/CT can be useless in the diagnosis and surveillance of uterine LMS. Importantly, a diagnostic biomarker, which distinguishes malignant LMS and benign tumor leiomyoma (LMA) is yet to be established. Accordingly, it is necessary to analyze risk factors associated with uterine LMS in order to establish a method of treatment. LMP2-deficient mice spontaneously develop uterine LMS, with a disease prevalence of~40% by 14 months of age. It is therefore of interest whether human uterine LMS shows a loss of LMP2 expression. We found LMP2 expression is absent in human LMS, but present in human LMA. Therefore, defective LMP2 expression may be one of the risk factors for LMS. LMP2 is potentially a diagnostic biomarker for uterine LMS, and gene therapy with LMP2-encording DNA may be a new therapeutic approach.

Characteristic of Uterine Rhabdomyosarcoma by Algorithm of Potential Biomarkers for Uterine Mesenchymal Tumor

“…Strong expression of cyclin E and Ki-67, biomarker candidates for malignant mesenchymal tumors, was also observed in the uterine leiomyosarcoma and uterine tumors (Figure 1, Figure 2). Previous studies have indicated that the spontaneous onset of uterine leiomyosarcoma is observed in LMP2/β1i-deficient mice, which is one of the subunits of the immunoproteasome (12,13). In human uterine leiomyosarcoma, the expression of LMP2/β1i is significantly reduced (12,13,14).…”

“…Previous research studies have indicated that the spontaneous onset of uterine leiomyosarcoma is observed in mice lacking LMP2/β1i, which is a subunit of the immunoproteasome (12,13,14). In human uterine leiomyosarcoma, the expression of LMP2/β1i is significantly reduced (12,13,14).…”

“…Previous research studies have indicated that the spontaneous onset of uterine leiomyosarcoma is observed in mice lacking LMP2/β1i, which is a subunit of the immunoproteasome (12,13,14). In human uterine leiomyosarcoma, the expression of LMP2/β1i is significantly reduced (12,13,14). However, as with normal uterine smooth muscle tissue and uterine leiomyoma, strong expression of LMP2/β1i was observed in the patient's uterine rhabdomyosarcoma (Figure 1, Figure 2, Table 1).…”

Malignant tumors of the uterine corpus: molecular background of their origin

“…On the other hand, BCl-2 is underexpressed [51]. Furthermore, experimentally, using knockout mice models, the potential of BRCA1 in formation of leiomyosarcoma [52] was proven or lack of the LMP2 gene probably spontaneously develops this disease [53].…”

Identification of Prognostic Genes in Leiomyosarcoma by Gene Co-Expression Network Analysis

“…Although many genes and signaling pathways have been identified to improve detection and treatment of LMS, surgical removal of tumors is currently the most effective way to treat leiomyosarcoma. Poor prognosis of LMS is related to a higher degree of malignancy, larger tumor volume, and deeper tumor site (Hayashi et al, 2010;Ognjanovic et al, 2012;Croce and Chibon, 2015). Therefore, identification of new biomarkers to assess malignancy and prognosis of LMS is essential.…”