CD47 to evade the tumor immunosurveillance system (9-11). Overexpression of CD47 correlates with poor prognosis in acute myeloid leukemia (12), acute lymphoblastic leukemia (13) and breast cancer (14). However, the clinicopathological and prognostic significance of CD47 expression in ESCC

CD47 inhibits phagocytosis and its overexpression is correlated with poor prognosis in patients with several types of cancer. It has also been reported that CD47 expression in multiple sclerosis is regulated by microRNAs. However, the regulatory mechanism of CD47 in cancer tissues has not been yet clarified. Re-analysis of a public microarray database revealed that miR-133a is downregulated in esophageal squamous cell carcinoma (ESCC). Moreover, in silico algorithms predicted that miR-133a is a regulator of CD47. The purpose of this study was to clarify the clinical significance of CD47 and its regulatory mechanism by miR-133a in ESCC. Quantitative real-time RT-PCR was used to evaluate CD47 and miR-133a expression in 102 cases of curative resected ESCC and adjacent non-cancerous tissue. The regulation of CD47 by miR-133a was examined with precursor miR-133a-transfected cells. A mouse xenograft model was used to investigate the ability of miR-133a to suppress tumor progression. High expression levels of CD47 were associated with lymph node metastasis (P=0.049). Multivariate analysis showed that CD47 expression was an independent prognostic factor (P=0.045). miR-133a expression was significantly lower in cancer tissues compared to adjacent non-cancerous tissues (P<0.001). In vitro assays showed that miR-133a is a direct regulator of CD47. miR-133a significantly inhibited tumorigenesis and growth in vivo. CD47 expression is a novel prognostic marker in ESCC that is directly inhibited by the miR-133a tumor suppressor. This correlation could provide new insight into the mechanism of cancer progression and a promising candidate for target therapy in ESCC. Introduction Esophageal squamous cell carcinoma (ESCC) has one of the highest mortality rates among patients with solid tumors due to the fact that it is a highly aggressive malignancy with early lymphatic and hematogenous dissemination (1,2). Recent advances in perioperative management, combined with chemotherapy or chemoradiotherapy, have led to improved survival rates. However, the prognosis for patients with advanced disease remains poor and unsatisfactory (3-5). Discovering suitable biomarkers of malignancy could enhance monitoring for cancer recurrence, and the development of new therapeutic approaches is essential for the improvement of survival rates. CD47 is a widely expressed transmembrane protein that has been implicated in multiple cellular processes, including a function as a ‘do not eat me’ signal inhibiting macrophage activity by binding the signal regulatory protein α, which is expressed on phagocytes (6-8). Whereas this function is partly attributed to ‘self recognition’ in normal physiological conditions, several human cancers appear to upregulate CD47 to evade the tumor immunosurveillance system (9-11). Overexpression of CD47 correlates with poor prognosis in acute myeloid leukemia (12), acute lymphoblastic leukemia (13) and breast cancer (14). However, the clinicopathological and prognostic significance of CD47 expression in ESCC remains unclear. It was reported that CD47 expression in multiple sclerosis is regulated by microRNAs (miRNAs) including miR-34a, miR-155 and miR-326 (15). However, the mechanism of CD47 regulation in cancer tissues has not yet been clarified. miRNAs are small non-coding RNAs of 18-25 nucleotides that partially bind the 3' untranslated region (3'-UTR) of their target mRNA, resulting in mRNA degradation and/or translational repression (16). By downregulating their target gene expression, miRNAs play an essential role in several cellular processes, such as proliferation, differentiation and apoptosis (17,18). Moreover, miRNAs also function as oncogenes or tumor suppressors depending on their targets. Therefore, miRNA has garnered attention as a new diagnostic and therapeutic tool for human malignancies (19,20). CD47 expression regulated by the miR-133a tumor suppressor is a novel prognostic marker in esophageal squamous cell carcinoma SHIGEMASA SUZUKI1, TAKEHIKO YOKOBORI1, NARITAKA TANAKA1, MAKOTO SAKAI1, AKIHIKO SANO1, TAKANORI INOSE1, MAKOTO SOHDA1, MASANOBU NAKAJIMA2, TATSUYA MIYAZAKI1, HIROYUKI KATO2 and HIROYUKI KUWANO1 1Department of General Surgical Science, Gunma University, Graduate School of Medicine, Gunma 371-8511; 2Department of Surgical Oncology, Dokkyo Medical University, Tochigi 321-0293, Japan Received January 4, 2012; Accepted March 2, 2012 DOI: 10.3892/or.2012.1831 Correspondence to: Dr Shigemasa Suzuki, Department of General Surgical Science, Gunma University, Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan E-mail: [email protected]