Decreased Expression of 14-3-3σ Is Predictive of Poor Prognosis for Patients with Human Uterine Papillary Serous Carcinoma

Decreased Expression of 14-3-3σ Is Predictive of Poor Prognosis for Patients with Human Uterine Papillary Serous Carcinoma

FUMIHIKO SUZUKI,¹ SATORU NAGASE,¹ KICHIYA SUZUKI,^1,3 ETSUKO OBA,¹ ERI HIROKI,¹ YUKIKA MATSUDA,¹ JUN-ICHI AKAHIRA,^1,2 HIDEKAZU NISHIGORI,¹ TAKASHI SUGIYAMA,¹ TAKEO OTSUKI,¹ KOUSUKE YOSHINAGA,¹ TADAO TAKANO,¹ HITOSHI NIIKURA,¹ KIYOSHI ITO,^1,4 HIRONOBU SASANO² and NOBUO YAEGASHI^1,3

¹Department of Obstetrics and Gynecology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
²Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
³Tohoku Medical Megabank Organization (ToMMo), Tohoku University, Sendai, Miyagi, Japan
⁴International Research Institute of Disaster Science (IRIDeS), Tohoku University, Sendai, Miyagi, Japan

Uterine papillary serous carcinoma (UPSC) morphologically resembles ovarian serous carcinoma and is categorized as a type II endometrial cancer. UPSC comprises about 10% of all types of endometrial cancer and has an aggressive clinical course and a poor prognosis. The 14-3-3σ gene was originally discovered as a p53-inducible gene; its expression is induced by DNA damage in a p53-dependent manner, which leads to G2 arrest and repair of damaged DNA. Moreover, it has been reported that expression of 14-3-3σ is frequently lost in various types of human cancer, including ovarian cancer. We therefore examined the association between 14-3-3σ expression determined by immunohistochemistry and clinical outcomes of 51 patients with UPSC. UPSC was considered positive for 14-3-3σ when > 30% of tumor cells were stained with a specific antibody. Of these patients, 29 (58.7%) showed positive immunoreactivity for 14-3-3σ and 22 (41.3%) had decreased 14-3-3σ staining. Decreased immunoreactivity for 14-3-3σ was associated with stage (P = 0.001) and lymphovascular space involvement (P = 0.005). Moreover, decreased 14-3-3σ expression was an independent risk factor for reduced overall survival (P = 0.0416) in multivariate analysis. Direct bisulfite sequencing was performed to evaluate the methylation status of the 27 CpG islands in the promoter region and first exon of the 14-3-3σ gene. These CpG islands were hypermethylated in 30% of 14-3-3σ-positive UPSC and 80% of 14-3-3σ-negative UPSC, although the difference was not statistically significant. These findings suggest that decreased expression of immunoreactive 14-3-3σ may be a predictor of poor prognosis in patients with UPSC.

keywords —— 14-3-3σ; immunohistochemistry; prognostic factor; uterine cancer; uterine papillary serous carcinoma

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Tohoku J. Exp. Med., 2013, 231, 193-199

Correspondence: Satoru Nagase, M.D., Ph.D., Department of Obstetrics and Gynecology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan.

e-mail: nagases@med.tohoku.ac.jp