The role of hepatocyte growth factor activator inhibitor (HAI)‐1 and HAI‐2 in endometrial cancer

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 is the first study to investigate the role of HAI‐1 and HAI‐2 in endometrial cancer. We investigated the biological functions of HAI‐1 and HAI‐2 using KLE and HEC‐251 endometrial cancer cell lines, thus HAI‐1 and HAI‐2 were examined in uterine normal endometrium, endometrial hyperplasia and cancer specimens by immunohistochemistry. HAI‐1 and HAI‐2 showed potential inhibitory effects on cell proliferation, migration and cellular invasion by reduction of matriptase and hepsin expression. This in turn led to an increase in the levels of E‐cadherin and Slug, and a reduction in the levels of Vimentin, SIP1, Snail and Twist, and hence ER and PR signal transduction in endometrial cancer cells. The levels of HAI‐1 and HAI‐2 expression were significantly decreased in endometrial cancer specimens relative to the corresponding normal endometrium specimens. Low HAI‐1 and HAI‐2 expression was a significant predictor for a poor prognosis compared with high HAI‐1 and HAI‐2 expression. These findings indicate that HAI‐1 and HAI‐2 could be considered as therapeutic targets and used as favorable prognosis markers for endometrial cancer.