Decreased expression of 14-3-3σ is predictive of poor prognosis for patients with human uterine papillary serous carcinoma.

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.

MicroRNA-34b functions as a potential tumor suppressor in endometrial serous adenocarcinoma.

Endometrial serous adenocarcinoma (ESC) is aggressive and carries a poor prognosis. p53 is frequently mutated in ESC. microRNAs (miRNAs) are a direct p53 target and have been implicated in cancer cell behavior. In this study, we compared miRNA expression levels in ESC with the levels in endometrial endometrioid adenocarcinoma (EEC) and normal endometria. Six miRNAs were identified as having aberrant down-regulation specific to ESC with miR-34b being most pronounced. miR-34b was found to have promoter hypermethylation, which when reversed, restored miR-34b expression in the cell lines treated with 5-aza-2' deoxycytidine (DAC). Ectopic expression of miR-34b in turn inhibited cell growth, migration and most notably invasion. Our findings suggest a relationship among p53 mutation, miR-34b promoter methylation and tumor cell behavior. These effects are likely mediated by the downstream target of miR-34b, the proto-oncogene mesenchymal-epithelial transition factor (MET), a known prognostic factor in endometrial carcinomas. The expression of MET was reduced following the restoration of miR-34b in cell lines. In summary, our data suggest that miR-34b plays a role in the molecular pathogenesis of endometrial cancer.

Changes in microRNA expression levels correlate with clinicopathological features and prognoses in endometrial serous adenocarcinomas.

This study aimed to determine the expression profiles of microRNAs (miRNAs) in endometrial serous adenocarcinoma and to examine the association between miRNA expression and clinical outcomes. Twenty-one patients diagnosed with endometrial serous adenocarcinoma between January 2001 and December 2006 were enrolled. miRNA expression profiles were examined using miRNA microarray and qRT-PCR. miRNA expression levels were correlated with clinicopathological variables and survival rates. A total of 120 miRNAs were differentially expressed in endometrial serous adenocarcinoma compared to normal endometria. Of these, 54 miRNAs were down-regulated (>2-fold), including miR-101, miR-10b*, miR-152, and miR-29b, and the remainder were up-regulated (>2-fold), including miR-200a, miR-200b, and miR-205. Decreased expression of miR-10b*, miR-29b, and miR-455-5p was correlated with vascular invasion (P = 0.048, P = 0.013, and P = 0.032, respectively). Univariate analysis revealed that lower expression of miR-101, miR-10b*, miR-139-5p, miR-152, miR-29b, and miR-455-5p was significantly correlated with poor overall survival (P < 0.05), and reduced expression of miR-152, miR-29b, and miR-455-5p was significantly correlated with poor disease-free survival (P < 0.05). Multivariate analysis demonstrated that decreased expression of miR-152 (P = 0.021) was a statistically independent risk factor for overall survival, and decreased expression levels of miR-101 (P = 0.016) and miR-152 (P = 0.010) were statistically independent risk factors for disease-free survival. In addition, transfection of miR-101 or miR-152 precursors into an endometrial serous carcinoma cell line inhibited cell growth (P < 0.0001 and P = 0.01, respectively). Moreover, strong positive immunoreactivity of cyclooxygenase-2 (COX-2) was significantly correlated with down-regulation of miR-101 (P = 0.035). These findings suggest that the dysregulation of miRNAs is associated with the poor prognosis in endometrial serous adenocarcinoma patients.

Recurrent Crow-Fukase syndrome associated with increased serum levels of vascular endothelial growth factor: a case report and review of the literature.

Crow-Fukase syndrome (CFS) is a rare multi-system disorder, characterized by polyneuropathy, organomegaly, endocrinopathy, M-proteins, skin changes and anasarca, with or without myeloma. The pathophysiology, diagnosis, and treatment of CFS are controversial. CFS may be associated with the overproduction of vascular endothelial growth factor (VEGF). However, there have been no reports of monitoring the serum VEGF level after recurrence, to the best of our knowledge. We report a 54-year-old man with CFS presenting with a 3-year history of ascites, anasarca, weakness of the lower extremities, and plasmacytoma in the scapula. At the initial examination, the VEGF level was 1,590 pg/ml (the VEGF level of a healthy control, 78.4 +/- 75.2 pg/ml). After initial treatment with chemotherapy and irradiation of the affected shoulder, the VEGF level decreased to 154 pg/ml and the symptoms disappeared. Twenty one months later, gate disturbance and anasarca recurred, and the VEGF level was over 2,000 pg/dl. After total scaplectomy, the VEGF level decreased to 730 pg/dl and the symptoms disappeared. The serum level of VEGF well correlated to the clinical course of the patient. In conclusion, measurement of the VEGF level is useful for diagnosing CFS and for monitoring its clinical course.