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The stem cell marker nestin is an intermediate filament protein that plays an important role in cell integrity, migration, and differentiation. Nestin expression occurs in approximately one third of pancreatic ductal adenocarcinoma (PDAC), and its expression strongly correlates with tumor staging and metastasis. Little is known about the mechanisms by which nestin influences PDAC progression. Here, nestin overexpression in PDAC cells increased cell motility and drove phenotypic changes associated with the epithelial-mesenchymal transition (EMT) in vitro; conversely, knockdown of endogenous nestin expression reduced the migration rate and reverted cells to a more epithelial phenotype. Mouse xenograft studies showed that knockdown of nestin significantly reduced tumor incidence and volume. Nestin protein expression was associated with Smad4 status in PDAC cells; hence, nestin expression might be regulated by the TGF-b1/Smad4 pathway in PDAC. We examined nestin expression after TGF-b1 treatment in human pancreatic cancer PANC-1 and PANC-1 shSmad4 cells. The TGF-b1/Smad4 pathway induced nestin protein expression in PDAC cells in a Smad4-dependent manner. Moreover, increased nestin expression caused a positive feedback regulator of the TGF-b1 signaling system. In addition, hypoxia was shown to induce nestin expression in PDAC cells, and the hypoxiainduced expression of nestin is mediated by the TGF-b1/Smad4 pathway. Finally, the antimicrotubule inhibitors, cytochalasin D and withaferin A, exhibited anti-nestin activity; these inhibitors might be potential antimetastatic drugs. Our findings uncovered a novel role of nestin in regulating TGF-b1-induced EMT. Antinestin therapeutics may serve as a potential treatment for PDAC metastasis. Mol Cancer Res; 11(7); 768-79. Ó2013 AACR. IntroductionThe incidence of pancreatic ductal adenocarcinoma (PDAC) is rising to the fifth leading cause of cancerrelated mortality. The condition is associated with the poorest prognosis among all gastrointestinal cancers, with a 5-year survival rate less than 4% (1, 2). A main reason for this extremely poor prognosis is the cancer's tendency to invade adjacent tissues and metastasize to regional lymph at a relatively early stage. Patients with PDAC frequently

Background and Aim: It is known that ultrasonography (US) cannot differentiate between non-alcoholic fatty liver disease (NAFLD) and steatohepatitis. However, US can accurately estimate the severity of the steatosis. The clinical significance of severe hepatic fatty change by US has not been explored. The aim of this study was to investigate the relationship between the severity of the fatty liver, classified by US, and the degree of metabolic disorders with insulin resistance. Methods: In 16 486 Taiwanese patients, severity of fatty change on US was classified as follows: group A (n = 6950), absence of fatty change; group B (n = 8694), mild; and group C (n = 842), severe fatty liver change. Biometabolic parameters included body mass index (BMI), blood pressure (BP), fasting plasma glucose, triglycerides, cholesterol, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and serum creatinine. Nominal logistic regression analysis was used to estimate the odds ratio for different degrees of fatty liver. Results: The frequencies of obesity, hypertension, glucose intolerance and hypertriglyceridemia were all significantly higher in group C than in group A or B (P < 0.0001), and the mean values of BMI, BP, fasting glucose, triglyceride and ALT were also higher in group C (P < 0.0001). High BMI (Ն30 kg/m