Focal adhesion kinase (p125 FAK ; 'FAK') is a tyrosine kinase that is localised to cellular focal adhesions and is associated with a number of other proteins, such as integrin adhesion receptors. We performed an immunohistochemical analysis of FAK protein expression to determine the relationship between FAK overexpression and clinicopathological factors in oesophageal squamous cell carcinoma (ESCC). We examined tissue specimens that had been removed from 91 patients with thoracic oesophageal cancer who had undergone surgery between 1983 and 2001. Immunohistochemical staining was performed by the standard streptavidin -biotin method. Seven human ESCC cell lines -TE-1, TE-2, TE-8, TE-13, TE-15, TT, and TTn -and one immortalized human keratinocyte cell line -HaCaT -were used in Western blot analysis. Immunostaining of FAK was seen in the cytoplasm of cancer cells, particularly in cells located in the invasive fronts of cancer nests. FAK overexpression was detected in 54 of the 91 patients (59.3%). Significant correlations were observed between FAK overexpression and cell differentiation (P ¼ 0.0057), depth of tumour invasion (P ¼ 0.0023), presence of regional lymph node metastasis (P ¼ 0.0097), number of lymph node metastases (P ¼ 0.0026), and disease stage (P ¼ 0.012). The survival rates of patients with FAK-overexpressing cancer were significantly lower than those of patients without FAK-overexpression cancer (P ¼ 0.006). The 5-year survival rate of patients without FAK overexpression was 69%, whereas that of patients with FAK overexpression was 38%. On Western blot analysis, FAK was expressed at a high level in TE-1, TE-8, TE-15, and TT cells, at a moderate level in TE-2 and TTn cells, and at a low level in TE13 and HaCaT cells. FAK phosphorylation at tyrosine 397 was demonstrated in proportion to the intensity of FAK in all cell lines except TE15 and HaCaT. In conclusion, FAK overexpression of ESCC was related to cell differentiation, tumour invasiveness, and lymph node metastasis. Consequently, patients with ESCC who had FAK overexpression had a poor prognosis.

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BACKGROUNDThe purpose of the current study was to assess whether [18F]fluorodeoxyglucose positron emission tomography (FDG‐PET) provides incremental value (e.g., additional information on lymph node involvement or the presence of distant metastases) compared with computed tomography (CT) in patients with esophageal carcinoma.METHODSThe authors examined 149 consecutive patients with thoracic esophageal carcinoma. Eighty‐one patients underwent radical esophagectomy without pretreatment, 17 received chemoradiotherapy followed by surgery, 3 underwent endoscopic mucosal resection, and the remaining 48 patients received definitive radiotherapy and chemotherapy. The diagnostic accuracy of FDG‐PET and CT was evaluated at the time of diagnosis.RESULTSThe primary tumor was visualized using FDG‐PET in 119 (80%) of 149 patients. Regarding lymph node metastases, FDG‐PET had 32% sensitivity, 99% specificity, and 93% accuracy for individual lymph node group evaluation and 55% sensitivity, 90% specificity, and 72% accuracy for lymph node staging evaluation. PET exhibited incremental value over CT with regard to lymph node status in 14 of 98 patients who received surgery: 6 patients with negative CT findings were eventually shown to have lymph node metastases (i.e., they had positive PET findings and a positive reference standard [RS]); 6 patients with positive CT findings were shown not to have lymph node metastases (i.e., they had negative PET findings and a negative RS); and 2 patients were shown to have cervical lymph node metastases in addition to mediastinal or abdominal lymph node metastases. Among the remaining patients, PET showed incremental value over CT with regard to distant organ metastases in six patients. The overall incremental value of PET compared with CT with regard to staging accuracy was 14% (20 of 149 patients).CONCLUSIONSFDG‐PET provided incremental value over CT in the initial staging of esophageal carcinoma. At present, combined PET‐CT may be the most effective method available for the preoperative staging of esophageal tumors. Cancer 2005. © 2004 American Cancer Society.

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...

Transforming growth factor-␤ (TGF-␤) regulates cell growth inhibition, and inactivation of the TGF-␤ signaling pathway contributes to tumor development. In our previous study, altered expression of TGF-␤, TGF-␤-specific receptors and Smad4 was shown to correlate with tumor progression in esophageal squamous cell carcinoma (SCC). These components, however, were maintained normally in some patients with esophageal SCC. In our study, the mechanism by which aggressive esophageal SCC maintains these components was investigated, with particular emphasis on the par-

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Esophageal cancer is a common malignancy with a striking variation in geographical distribution; a reflection of exposure to specific environmental factors, which are still poorly defined. We discuss the recent progress made in the investigation of the molecular biology of esophageal cancer, addressing the topics of genetic alterations, methylation, overexpression of molecules thought to cause malignant transformation, carcinogenesis, invasion, and metastasis. We review six aspects of the research literature on esophageal cancer: epidemiology and etiology, epidermal growth factor receptor and related growth factor receptors, cell cycle regulatory proteins, transforming growth factor-beta/Smad proteins, mismatch repair genes, and other genes. This article provides a conceptual basis for evaluating studies on the molecular mechanism of esophageal carcinogenesis and for devising therapeutic and preventive strategies based on molecular biology. We hope that in the near future, the clinical outcome of patients with esophageal carcinoma will be improved by a better understanding of the basic mechanisms of carcinogenesis.

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.