Abstract 2306: Overexpression of microRNA-223 regulates the ubiquitin ligase FBXW7 in esophageal squamous cell carcinoma

Abstract

Abstract Background: F-box and WD repeat domain-containing 7 (FBXW7) is a cell cycle regulatory gene whose protein product ubiquitinates positive cell cycle regulators such as c-Myc, cyclin E and c-Jun, thereby acting as a tumor-suppressor gene. This study focused on microRNA-223 (miR-223), which is a candidate regulator of FBXW7 mRNA. The aim of this study was to clarify the clinical significance of miR-223 and FBXW7 in esophageal squamous cell carcinoma (ESCC) patients and to elucidate the mechanism by which FBXW7 is regulated by miR-223. Methods: The expression levels of miR-223 and the expression of FBXW7 protein was examined using 109 resected specimens to determine the clinicopathological significance. The expression levels of miR-223 were determined by qRT-PCR. The immunohistochemical studies for FBXW7 were performed on formalin-fixed paraffin-embedded surgical sections obtained from 109 patients with ESCC. We also investigated the role of miR-223 in the regulation of FBXW7 expression in ESCC cell lines in an in vitro analysis. Results: We found that the mean expression levels of miR-223 in cancerous tissue specimens were significantly higher than those in non-cancerous tissues (p <0.001). We divided the 109 ESCC patients into two groups according to the ratio of their cancer/normal tissue expression levels of miR-223, as α1.0 or <1.0 for the cancer/noncancerous tissues expression levels of miR-223. There were 74 cases (67.9%) in the high miR-223 group and 35 cases (32.1%) in the low miR-223 expression group. There were significant differences in gender (p = 0.008), tumor size (p = 0.042), and depth of tumor invasion (p = 0.030) between the groups. There was a significant inverse relationship between the expression levels of miR-223 and FBXW7 protein. High levels of miR-223 were associated with low FBXW7 expression (Pearson correlation, r = −0.336; p<0.01). Moreover, patients with high miR-223 expression demonstrated a significantly poorer prognosis than those with low expression (p=0.034). Based on a series of gain-of-function and loss-of-function investigation in vitro, we found that these effects may be due to the downregulation of the tumor-suppressor FBXW7, which was targeted by miR-223. Conclusions: Our present study indicates that high expression of miR-223 had a significant adverse impact on the survival of esophageal squamous cell carcinoma patients through repression of the function of FBXW7. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2306. doi:1538-7445.AM2012-2306