Shigemasa Suzuki

MiR‐150 is associated with poor prognosis in esophageal squamous cell carcinoma via targeting the EMT inducer ZEB1

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)

Stathmin1 regulates p27 expression, proliferation and drug resistance, resulting in poor clinical prognosis in cholangiocarcinoma

Patients with extrahepatic cholangiocarcinoma (EHCC) have a poor prognosis; postoperative survival depends on cancer progression and therapeutic resistance. The mechanism of EHCC progression needs to be clarified to identify ways to improve disease prognosis. Stathmin1 (STMN1) is a major cytosolic phosphoprotein that regulates microtubule dynamics and is associated with malignant phenotypes and chemoresistance in various cancers. Recently, STMN1 was reported to interact with p27, an inhibitor of cyclin‐dependent kinase complexes. Eighty EHCC cases were studied using immunohistochemistry and clinical pathology to determine the correlation between STMN1 and p27 expression; RNA interference to analyze the function of STMN1 in an EHCC cell line was also used. Cytoplasmic STMN1 expression correlated with venous invasion (P = 0.0021) and nuclear p27 underexpression (P = 0.0011). Patients in the high‐STMN1‐expression group were associated with shorter recurrence‐free survival and overall survival than those in the low‐expression group. An in vitro protein‐binding assay revealed that cytoplasmic STMN1 bound to p27 in the cytoplasm, but not in the nucleus of EHCC cells. Moreover, p27 accumulated in EHCC cells after STMN1 suppression. STMN1 knockdown inhibited proliferation and increased the sensitivity of EHCC cells to paclitaxel. STMN1 contributes to a poor prognosis and cancer progression in EHCC patients. Understanding the regulation of p27 by STMN1 could provide new insights for overcoming therapeutic resistance in EHCC.

Biological significance of fluorine-18- α -methyltyrosine (FAMT) uptake on PET in patients with oesophageal cancer

Purpose:18F-FAMT as an amino-acid tracer for positron emission tomography (PET) is useful for detecting human neoplasms. 18F-FAMT is accumulated in tumour cells solely via L-type amino-acid transporter 1 (LAT1). This study was conducted to investigate the biological significance of 18F-FAMT uptake in patients with oesophageal cancer.Methods:From April 2008 to December 2011, 42 patients with oesophageal cancer underwent both 18F-FAMT PET/CT and 18F-FDG PET/CT before surgical treatment. The immunohistochemical analysis of LAT1, CD98, Ki-67, CD34, p53, p-Akt and p-mTOR was performed on the primary lesions. In vitro experiments were performed to examine the mechanism of 18F-FAMT uptake.Results:High uptake of 18F-FAMT was significantly associated with advanced stage, lymph node metastasis and the expression of LAT1, CD98, Ki-67 and CD34. LAT1 expression yielded a statistically significant correlation with CD98 expression, cell proliferation, angiogenesis and glucose metabolism. In vitro experiments revealed that 18F-FAMT was specifically transported by LAT1.Conclusions:The uptake of 18F-FAMT within tumour cells is determined by the LAT1 expression and correlated with cell proliferation and angiogenesis in oesophageal cancer. The present experiments also confirmed the presence of LAT1 as an underlying mechanism of 18F-FAMT accumulation.

Significance of Lymph Node Capsular Invasion in Esophageal Squamous Cell Carcinoma

BackgroundExtranodal invasion (ENI) has been reported to be associated with a poor prognosis in several malignancies. However, previous studies have included perinodal fat tissue tumor deposits in their definitions of ENI. To investigate the precise nature of ENI in esophageal squamous cell carcinoma (ESCC), we excluded these tumor deposits from our definition of ENI and defined tumor cell invasion through the lymph node capsule and into the perinodal tissues as lymph node capsular invasion (LNCI). The aim of the current study was to elucidate the significance of LNCI in ESCC.MethodsWe investigated the associations between LNCI and other clinicopathologic features in 139 surgically resected ESCC. We also investigated the prognostic significance of LNCI in ESCC.ResultsLNCI was detected in 35 (25.2%) of 139 patients. The overall survival rate of the ESCC patients with LNCI was significantly lower than that of the ESCC patients with lymph node metastasis who were negative for LNCI. The survival difference between the patients with 1–3 lymph node metastases without LNCI and those with no lymph node metastasis was not significant. LNCI was significantly associated with distant organ recurrence. LNCI was also found to be an independent predictor of overall survival in addition to the number of lymph node metastases.ConclusionsLNCI in ESCC patients is an indicator of distant organ recurrence and a worse prognosis. LNCI could be used as a candidate marker for designing more precise staging and therapeutic strategies for ESCC.

An Individual with Gastric Schwannoma with Pathologically Malignant Potential Surviving Two Years after Laparoscopy-Assisted Partial Gastrectomy

Schwannomas are a kind of neurogenic tumor. They are generally benign and originate primarily from the central and peripheral nerve. They rarely develop in the gastrointestinal tract: gastric schwannomas make up 0.2% of gastric neoplasms. A malignant gastric schwannoma is a comparatively rare tumor, a few cases have been reported until now. We present the case of a 34-year-old male patient diagnosed during medical examination. The patient was treated with surgical resection, and 2 years passed without recurrence.

High stathmin 1 expression is associated with poor prognosis and chemoradiation resistance in esophageal squamous cell carcinoma

Stathmin 1 (STMN1) is a major cytosolic phosphoprotein regulating microtubule dynamics, thereby playing an important role in cancer progression and resistance to microtubule-binding anticancer agents. We assessed the prognostic significance of STMN1 expression and STMN1-associated resistance to docetaxel and radiation in esophageal squamous cell carcinoma (ESCC) patients. STMN1 expression was evaluated by immunohistochemistry in 172 surgical specimens. The association of STMN1 expression with chemoradiation resistance using docetaxel was examined by comparing expression in 15 biopsy specimens obtained before neoadjuvant therapy to histological grades of post-therapy surgically resected tumors. We also evaluated the effects of STMN1 on sensitivity to docetaxel and radiation in ESCC cell lines. High STMN1 immunoexpression was significantly associated with tumor depth, lymph node metastasis, lymphatic invasion and venous invasion. Survival rates were significantly lower in ESCC patients with high STMN1 expression than in those with low STMN1 expression. Multivariable analysis showed that high STMN1 expression was an independent factor for poor survival. High STMN1 expression was also associated with poor response to neoadjuvant chemoradiotherapy using docetaxel. Knockdown of STMN1 expression enhanced ESCC cell line sensitivity to docetaxel and radiation. STMN1 appears critical for ESCC invasiveness and predicts an unfavorable prognosis in ESCC.

Liver Hemorrhage Due to Idiopathic Peliosis Hepatis Successfully Treated With Hepatic Artery Embolization

Peliosis hepatis is an extremely rare condition that may cause fatal hepatic hemorrhage and liver failure. We report a case of liver hemorrhage due to idiopathic peliosis hepatis. A 60-year-old woman was admitted to our hospital with slight right hypochondriac pain. She went into hemorrhagic shock, and computed tomography (CT) showed multiple low-density areas in the right liver with massive subcapsular blood collection. Selective transfemoral arteriography of the celiac artery revealed no signs of vascular malformation or tumor stain, but showed signs of pooling in the right posterior segmental artery. The artery was embolized with particles of gelatin sponge, and hemostatic control was successful. Although peliosis hepatis is extremely rare, the diagnosis is significant because of its urgent clinical status, and transarterial embolization is a useful and minimally invasive procedure for liver hemorrhage due to peliosis hepatis.

Molecular characterization of antitumor effects of the rhizome extract from Curcuma zedoaria on human esophageal carcinoma cells

Curcuma zedoaria has been used as a traditional agent against malignant diseases. To elucidate detailed mechanisms producing such an activity, characterization and determination of molecular mechanisms of its antitumor effects was conducted. Inhibiting activities against cell proliferation, invasion and colony formation, and expression levels of corresponding molecules were investigated using human esophageal cancer TE-8 cells treated with the rhizome extract from C. zedoaria. Antitumor effect of the extract administered orally was also examined in tumor-bearing mice. The extract possessed strong anti-proliferation and invasion activities against TE-8 cells. Further, upregulated PTEN and downregulated phosphorylated Akt, mTOR and STAT3 expressions in the cells were induced shortly after treatment with the extract, followed by attenuation of FGFR1 and MMP-2, activation of caspase-9, caspase-3 and PARP, and suppression of Bcl-2 expressions, which led the cells to apoptotic cell death. Furthermore, tumor formation in mice was significantly suppressed through the oral administration of the extract. Taken together, these results suggest that the C. zedoaria extract could be a promising agent against esophageal cancer.

Correlation between high FBXW7 expression in pretreatment biopsy specimens and good response to chemoradiation therapy in patients with locally advanced esophageal cancer: A retrospective study: GOMBODORJ et al.

Esophageal squamous cell carcinoma (ESCC) exhibits good reactivity to chemoradiation therapy (CRT). The dysregulation of F‐Box and WD Repeat Domain Containing 7 (FBXW7) is associated with therapeutic resistance in cancer cells. However, the correlation between FBXW7 expression and CRT sensitivity in patients with clinical ESCC has been investigated only in few studies. Therefore, this study aimed to elucidate the significance of FBXW7 expression in pretreatment biopsy specimens from patients with ESCC receiving CRT.

18F-FAMT-PET is useful for judging clinical complete response in advanced esophageal cancer patients who have received definitive chemoradiotherapy

Abstract Background: We developed 18F-FAMT as an amino acid tracer for PET imaging. In esophageal cancer, 18F-FAMT PET was significantly higher than that of 18F-FDG PET and CT in the evaluation of individual lymph node groups. Definitive CRT has been considered to be a potentially curative treatment for locoregional esophageal cancer and may achieve the same survival benefits as surgical resection. Clinical evaluation of complete response (CR) is important using several modalities. Patients and Methods: We evaluated 6 patients who had been diagnosed with clinical CR by FAMT-PET following definitive CRT for esophageal SCC between June 2008 and July 2012. Treatment evaluation of 18F-FAMT was performed following CRT, and approximately 1 month later. Results: In primary tumors, 66.7% of patients (4/6) showed FDG uptake following CRT, whereas that of FAMT was 33.3% (2/6). In lymph node metastases, 50% of patients (3/6) showed FDG uptake following CRT, whereas that of FAMT was 0% (0/6). In the present study, FA...