Candidate Molecules as Tumor Suppressor for Human Uterine Mesenchymal Tumor

Uterine leiomyosarcoma (Ut-LMS) develops more often in myometrium 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 Ut-LMS is not substantially correlated with hormonal conditions, and the risk factor(s) are not yet known. Importantly, a diagnostic-biomarker, which distinguishes malignant tumor Ut-LMS from benign tumor leiomyoma (LMA), is yet to be established. Accordingly, it is necessary to examine risk factor(s) associated with Ut-LMS, to establish a diagnosis and a clinical treatment method. The mice with a homozygous deficiency for proteasome -ring subunit, low-molecular mass polypeptide (LMP)2/1i spontaneously develop Ut-LMS, with a disease prevalence of ~37% by 12 months of age. In the recent study, we found LMP2/1i expression to be absent in human Ut-LMS, but clearly present in other human uterine mesenchymal tumors including uterine LMA. Further analyses with clinical materials and the gene-modified mice have not clarified the biological significance of the TP53 and retinoblastoma (Rb) pathway in malignant myometrium transformation, thus implicating LMP2/1i as an anti-tumorigenic candidate. This role of LMP2/1i as a tumor suppressor may lead to new therapeutic targets in human Ut-LMS. (191 words)