Increased expression of p21 activated kinase 4 in adenomyosis and its regulation of matrix metalloproteinase 2 and 9 in endometrial cells

Capsule:
The present study showed that increased Pak4 expression can lead to the development of adenomyosis by enhancing the invasiveness of endometrial cells through regulating MMP-2 and -9 activities.

Authors:
Kyong Wook Yi, M.D., Ph.D., Sung Hoon Kim, M.D., Ph.D., Hyo Jin Ihm, M.S., Young Sang Oh, M.S., Hee Dong Chae, M.D., Ph.D., Chung-Hoon Kim, M.D., Ph.D., Byung Moon Kang, M.D., Ph.D.

Volume 103, Issue 4, Pages 1089-1097

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.

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