Kyong Wook Yi1, Sung Hoon Kim2, Hyo Jin Ihm3, Young Sang Oh3, Hee Dong Chae3, Chung-Hoon Kim3, Byung Moon Kang3. 1. Department of Obstetrics and Gynecology, College of Medicine, Korea University, Seoul, Republic of Korea. 2. Department of Obstetrics and Gynecology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea. Electronic address: kimsung@amc.seoul.kr. 3. Department of Obstetrics and Gynecology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
Abstract
OBJECTIVE: To investigate the expression of p21-activated kinase 4 (Pak4) in both adenomyotic foci and the eutopic endometrium of women with adenomyosis, and whether the activities of matrix metalloproteinases (MMPs)-2 and -9 are regulated by Pak4 in endometrial cells. DESIGN: Experimental study using human samples and cell lines. SETTING: University hospital. PATIENT(S): Thirty-nine patients with histologic evidence of adenomyosis, and 34 patients with carcinoma in situ of the uterine cervix without adenomyosis or endometriosis. INTERVENTION(S): Immunohistochemistry, zymography after transfection with Pak4 small interfering RNA (siRNA), and western blot analyses after nuclear factor kappa-B (NF-кB) inhibitor treatment. MAIN OUTCOME MEASURE(S): The Pak4 immunoreactivity of women with vs. without adenomyosis was compared semiquantitatively. The activities of MMP-2 and -9 were analyzed in eutopic endometrial stromal cells and Ishikawa cells after transfection with Pak4 siRNA. The Pak4 expression was evaluated in endometrial cells after treatment with NF-кB inhibitor. RESULT(S): Pak4 immunoreactivity was increased in adenomyotic foci and in the eutopic endometrium of women with adenomyosis. Transfection of endometrial cells with Pak4 siRNA led to significant decreases of MMP-2 and -9 activities. In vitro treatment of endometrial cells with tumor necrosis factor-alpha caused a significant increase of NF-кB activation and Pak4 expression, which was obviously decreased by the NF-кB inhibitor pyrrolidinedithiocarbamate. CONCLUSION(S): Our results suggest that Pak4 is regulated by NF-кB and that increased Pak4 expression can lead to development of adenomyosis by enhancing the invasiveness of endometrial cells through regulation of MMP-2 and -9 activities.
OBJECTIVE: To investigate the expression of p21-activated kinase 4 (Pak4) in both adenomyotic foci and the eutopic endometrium of women with adenomyosis, and whether the activities of matrix metalloproteinases (MMPs)-2 and -9 are regulated by Pak4 in endometrial cells. DESIGN: Experimental study using human samples and cell lines. SETTING: University hospital. PATIENT(S): Thirty-nine patients with histologic evidence of adenomyosis, and 34 patients with carcinoma in situ of the uterine cervix without adenomyosis or endometriosis. INTERVENTION(S): Immunohistochemistry, zymography after transfection with Pak4 small interfering RNA (siRNA), and western blot analyses after nuclear factor kappa-B (NF-кB) inhibitor treatment. MAIN OUTCOME MEASURE(S): The Pak4 immunoreactivity of women with vs. without adenomyosis was compared semiquantitatively. The activities of MMP-2 and -9 were analyzed in eutopic endometrial stromal cells and Ishikawa cells after transfection with Pak4 siRNA. The Pak4 expression was evaluated in endometrial cells after treatment with NF-кB inhibitor. RESULT(S): Pak4 immunoreactivity was increased in adenomyotic foci and in the eutopic endometrium of women with adenomyosis. Transfection of endometrial cells with Pak4 siRNA led to significant decreases of MMP-2 and -9 activities. In vitro treatment of endometrial cells with tumor necrosis factor-alpha caused a significant increase of NF-кB activation and Pak4 expression, which was obviously decreased by the NF-кB inhibitor pyrrolidinedithiocarbamate. CONCLUSION(S): Our results suggest that Pak4 is regulated by NF-кB and that increased Pak4 expression can lead to development of adenomyosis by enhancing the invasiveness of endometrial cells through regulation of MMP-2 and -9 activities.