title: Hepatocyte growth factor activator inhibitors (HAI-1 and HAI-2) are potential targets in uterine leiomyosarcoma.
abstract: 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.
authors.affiliation: Department of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan. k-nakamu@cc.okayama-u.ac.jp
authors.forename: Keiichiro
authors.initials: K
authors.lastname: Nakamura
authors.forename: Fernando
authors.initials: F
authors.lastname: Abarzua
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hongo
authors.forename: Junichi
authors.initials: J
authors.lastname: Kodama
authors.forename: Yasutomo
authors.initials: Y
authors.lastname: Nasu
authors.forename: Hiromi
authors.initials: H
authors.lastname: Kumon
authors.forename: Yuji
authors.initials: Y
authors.lastname: Hiramatsu
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism; D002449:Cell Aggregation / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D018572:Disease-Free Survival; D005260:Female; D016147:Genes, Tumor Suppressor; D006801:Humans; D007150:Immunohistochemistry; D007890:Leiomyosarcoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D053491:Proteinase Inhibitory Proteins, Secretory / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014594:Uterine Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; D008562:Membrane Glycoproteins; D053491:Proteinase Inhibitory Proteins, Secretory; C109149:SPINT1 protein, human; C109148:SPINT2 protein, human