Expression of P-REX2a is associated with poor prognosis in endometrial malignancies
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Sho Takeshita1, Yoriko Yamashita2, Kosuke Shiomi2, Nako Suzuki2, Jun Yoshida2, Aya Naiki-Ito2, Shugo Suzuki2, Shinya Akatsuka3, Shinya Toyokuni3, Takashi Takahashi4, Shoko Mase1, Atsushi Arakawa1, Mayumi Sugiura-Ogasawara1 and Satoru Takahashi2
1Department of Obstetrics and Gynecology, Nagoya City University Graduate School of Medicical Sciences, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
2Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
3Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, 466-8550, Japan
4Division of Molecular Carcinogenesis, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, 466-8550, Japan
Yoriko Yamashita, email: firstname.lastname@example.org
Keywords: endometrial neoplasms; GTP/GDP exchange factors; immunohistochemistry; prognosis; PTEN
Received: December 09, 2017 Accepted: April 24, 2018 Published: May 15, 2018
P-REX2a is a PTEN inhibitor that also activates Rac 1. No associations with P-REX2a and human endometrial cancers have been reported to date. In this study, we immunohistochemically analyzed 155 uterine endometrial malignancies for P-REX2a expression. The P-REX2a-positive tumors displayed worse prognosis independent of PTEN expression. Then, we transduced either P-REX2a expression vector or short hairpin RNAs targeting P-REX2a into 2 uterine endometrioid carcinoma cell lines, OMC-2 and JHUEM-14. Ectopic expression of P-REX2a led to increased cell proliferation only in the PTEN-expressing OMC-2 cells but did not show any change in the PTEN-negative JHUEM-14 cells or the P-REX2a-knockdown cells. Induction of P-REX2a increased and knockdown of P-REX2a decreased cell migration in both cell lines. Then, we performed expression microarray analysis using these cells, and pathway analysis revealed that the expression of members of the GPCR downstream pathway displayed the most significant changes induced by the knockdown of P-REX2a. Immunohistochemical analysis revealed that Vav1, a member of the GPCR downstream pathway, was expressed in 139 of the 155 endometrial tumors, and the expression levels of Vav1 and P-REX2a showed a positive correlation (r = 0.44, p < 0.001). In conclusion, P-REX2a enhanced cell motility via the GPCR downstream pathway independently of PTEN leading to progression of uterine endometrioid malignancies and poor prognosis of the patients.
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