Hepatocyte growth factor activator inhibitors (HAI-1 and HAI-2) are Kunitz-type serine protease inhibitors that have a broad inhibitory spectrum against serine proteases. This study examined the role of HAI-1 and HAI-2 in uterine leiomyosarcoma (LMS) patients, and in vitro. HAI-1 and HAI-2 was examined in uterine normal smooth muscle, leiomyoma and LMS specimens using immunohistochemistry. We investigated biological functions and inhibitory effects of HAI-1 and HAI-2 using uterine LMS cell line SK-LMS-1 and SKN. The expression levels of HAI-1 and HAI-2 were significantly decreased in uterine LMS specimens relative to corresponding uterine normal smooth muscle and leiomyoma specimens. Furthermore, the low HAI-1 and HAI-2 expression was a significant predictor for poor prognosis when compared with high HAI-1 and HAI-2 expression (disease-free survival rate; p=0.024 and p=0.045, overall survival rate; p=0.043 and p=0.009). HAI-1 and HAI-2 showed potential inhibitory effects that mediated cell proliferation, migration and cellular invasion which led to apoptosis and necrosis through a reduction of HGFA, matriptase and hepsin expression. These findings indicate that HAI-1 and HAI-2 may be possible tumor suppressor genes for uterine LMS and thus, both could be considered therapeutic agents for the treatment of LMS.

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