The association of microRNAs (miRs) with cancer progression has been established in many cancers including esophageal squamous cell carcinoma (ESCC). A public microarray database showed that the expression of miR-150 was lower in ESCC than in normal esophageal mucosa. Here, we focused on ZEB1, epithelial-mesenchymal-transition (EMT)-inducer, as a target gene of miR-150 based on in silico predictions. The purpose of this study was to clarify the clinicopathological significance of miR-150 in ESCC, and to investigate miR-150′s EMT-regulatory ability. Quantitative RT-PCR was used to evaluate miR-150 expression in 108 curative resected ESCC samples to determine the clinicopathological significance. Moreover, we examined the in vitro and in vivo function of miR-150 via degradation of ZEB1. MiR-150 expression was significantly lower in cancer tissues compared to adjacent non-cancerous tissues (P < 0.001). Low expression of miR-150 in ESCC contributed to malignant potential, such as tumor depth, lymph node metastasis, lymphatic invasion, venous invasion, clinical staging, and poor prognosis (P < 0.05). In vitro assays showed that EMT-inducer-ZEB1 is a new direct target of miR-150. Moreover, miR-150 induced MET-like changes in TE-8 cells through ZEB1 degradation (e.g., E-cadherin expression, vimentin repression, epithelial morphology, and suppression of migration ability), and significantly inhibited tumorigenicity and tumor growth in a mouse xenograft model. Analysis of the regulation of ZEB1 by miR-150 could provide new insights into preventing metastasis and also suggests novel targeted therapeutic strategies in ESCC. (Cancer Sci 2013; 104: 48-54) P rogress in perioperative management and definitive or adjuvant therapy has led to improved survival of esophageal squamous cell carcinoma (ESCC) patients. However, for patients with advanced disease, prognosis remains poor.(1-3) Local ESCCs directly invade other organs, presenting serious obstacles to radical resection, a characteristic which enhances local recurrence. Moreover, ESCCs cause early lymphatic and hematogenous disseminations more frequently compared to other solid gastrointestinal cancers.(4,5) Therefore, clinical indicators that accurately predict ESCC progression and prognosis are essential for improving patient survival.Recently, microRNAs (miRs) have attracted attention for their involvement in the regulation of gene expression. miRs are small non-coding RNAs, approximately 18-25 nucleotides in length, which partially bind to the 3′-untranslated region (3′-UTR) of target mRNAs, leading to mRNA degradation and/or translational repression.(6) Many miRs play an essential role in cellular processes, such as proliferation, differentiation, apoptosis, and cancer progression, depending on their specific gene targets. To find cancer-associated miRs in ESCC, we re-analyzed GSE6188 in the Gene Expression Omnibus public microarray database.(7) In this way, we detected five downregulated miRs in ESCC compared to normal esophageal mucosa (Fig. S1). First, we examin...

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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.

BACKGROUND:Metabolic tumor activity using 18F‐fluorodeoxyglucose positron emission tomography (FDG‐PET) was believed to have a predictive value for patient outcome in malignancies. The objective of the current study was to assess the prognostic effectiveness of the highest standardized uptake value (SUV) in the primary or regional area (peak SUV) and the number of PET‐positive lymph nodes in esophageal cancer.METHODS:The authors retrospectively reviewed their experience with 184 consecutive esophageal cancer patients imaged preoperatively using FDG‐PET scanning.RESULTS:The median peak SUV was 4.5 (range, 1.4‐21.9). The survival curve was analyzed using the median peak SUV as the cutoff value. Comparison of each group and clinicopathologic characteristics revealed significant associations between peak SUV and each of the following factors: tumor status (P < .001), lymph node status (P < .001), metastatic status (P < .05), stage of disease (P < .001), number of PET‐positive lymph nodes (P < .001), and the number of histologically positive lymph nodes (P < .001). The 5‐year overall survival (OS) rate for patients having FDG uptake with a peak SUV ≥4.5 was 47% and that for patients with a peak SUV <4.5 was 76% (P < .0001). On multivariate survival analysis using the Cox proportional hazards model, peak SUV and the number of PET‐positive lymph nodes were found to be independent predictive factors for OS. The number of PET‐positive lymph nodes was a single prognostic factor predicting both disease‐free survival and OS.CONCLUSIONS:Pretreatment PET cannot only potentially diagnose the extent of disease, but also may be predictive of patient survival after esophageal cancer resection. Cancer 2009. © 2009 American Cancer Society.

Carbonic anhydrase 9 (CA9) is a protein to be upregulated under exposure to hypoxic conditions. Hypoxic conditions are known to be associated with resistance to chemotherapy and radiotherapy, and with poor cancer prognosis. We examined CA9 expression in surgical specimens from oesophageal squamous cell carcinoma (ESCC) patients (n ¼ 127) using immunohistochemistry and real-time RT -PCR. We also examined CA9 expression and cell proliferation in ESCC cell lines (TE-2, TE-8 and TE-15) and an immortalised human oesophageal cell line (CHEK-1) using real-time RT -PCR, Western blotting, ELISA and MTT assay. Immunohistochemistry, high expression of CA9 was found in 63 of the 127 primary tumour specimens and was correlated with poor outcome (P ¼ 0.0003) and more aggressive/less favourable clinicopathological parameters (tumour size (P ¼ 0.0235), tumour depth (Po0.0001), regional lymph node metastasis (P ¼ 0.0031), distant lymph node metastasis (P ¼ 0.0077), stage (Po0.0001) and blood vessel invasion (P ¼ 0.006)). In vitro, CA9 expression in cultured cells and culture medium was also induced by hypoxia (Po0.01). CA9 is correlated with poor prognosis and malignant phenotype in patients with ESCC, and was upregulated by hypoxia. It is suggested that control of CA9 expression might improve the effectiveness of chemotherapy and radiotherapy in ESCC.

Our results suggest that TNFAIP8 might be an effective therapeutic target for ESCC in the future.

Esophageal cancer is one of the most difficult malignancies to cure, and identification of novel prognostic markers for patients with this disease is important. CD24 is a small highly glycosylated mucin-like protein. Several studies have shown that higher CD24 expression is significantly associated with shorter patient survival in various malignant tumors. However, the expression of CD24 and its clinicopathological significance in esophageal cancer remain largely unknown. Immunohistochemical analyses of CD24 and Ki-67 overexpression in 151 cases of esophageal squamous cell carcinoma were performed to examine the relationships of CD24 expression with clinicopathological parameters and patient survival. Five cell lines derived from esophageal cancer were subjected to Western blot analyses to evaluate CD24 expression. Immunohistochemically, CD24 expression was judged to be positive in 61 (40.4%) cases. CD24 expression was associated with lymph node metastasis (p = 0.005), pathologic stage (p = 0.018), number of nodal metastases (p = 0.003), lymphatic invasion (p = 0.002), venous invasion (p < 0.001), and Ki-67 labeling index (p < 0.001). The Pearson's correlation coefficient between the CD24 expression score and the Ki-67 labeling index was 0.404 (p < 0.001). CD24 expression was associated with disease-free survival (p < 0.001). A Cox multivariate regression analysis revealed that CD24 expression was an independent prognostic factor (p = 0.033). On Western blot analysis, CD24 was detected in all five cell lines. We conclude that overexpression of CD24, which was correlated with Ki-67 expression, is a novel independent prognostic marker for identifying patients with poor prognosis after curative resection of esophageal squamous cell carcinoma.

Abstract. The purpose of the present study was to assess the contribution of simultaneous functional/anatomical imaging using integrated 18 F-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT), compared with PET alone for the evaluation of initial lymph node staging in esophageal cancer. We studied 167 consecutive patients with thoracic esophageal squamous cell carcinoma (SCC) who had radical esophagectomy performed between January 1999 and April 2007. For individual nodal group evaluation, PET/CT showed 46.0% sensitivity (p<0.05 vs. PET), 99.4% specificity, 95.1% accuracy (p<0.05 vs. PET), 87.0% positive and 95.5% negative predictive values. PET showed 32.9% sensitivity, 98.9% specificity, 93.1% accuracy, 74.7% positive predictive value and 93.9% negative predictive value. Thus, the sensitivity and accuracy of PET/CT were significantly higher than those of PET. Comparisons between CT, PET and PET/CT in detecting lymph node metastasis by each region showed that PET/CT had a higher sensitivity in lower thoracic regions than PET and CT (p<0.05 vs. CT and PET). Lymph node staging (N0 vs. N1) was not significantly different, but staging per lymph nodal group was significantly better with PET/CT. Integrated PET/CT imaging with co-registration of anatomic and functional imaging data is useful in the initial lymph node staging of patients with operable esophageal cancer compared with PET alone.