Because of the early onset of local invasion and distant metastasis, pancreatic ductal adenocarcinoma (PDAC) is the most lethal human malignant tumor, with a 5-year survival rate of less than 5%. In this study, we investigated the role of fascin, a prometastasis actin-bundling protein, in PDAC progression, invasion, and the molecular mechanisms underlying fascin overexpression in PDAC. Our data showed that the expression levels of fascin were higher in cancer tissues than in normal tissues, and fascin overexpression correlated with the PDAC differentiation and prognosis. Fascin overexpression promoted PDAC cell migration and invasion by elevating matrix metalloproteinase-2 (MMP-2) expression. Fascin regulated MMP-2 expression through protein kinase C and extracellular signal-regulated kinase. Importantly, our data showed that hypoxia induced fascin overexpression in PDAC cells by promoting the binding of hypoxia-inducible factor-1 (HIF-1) to a hypoxia response element on the fascin promoter and transactivating fascin mRNA transcription. Intriguingly, HIF-1a expression levels in PDAC patient specimens significantly correlated with fascin expression. Moreover, immunohistochemistry staining of consecutive sections demonstrated colocalization between HIF-1a and fascin in PDAC specimens, suggesting that hypoxia and HIF-1a were responsible for fascin overexpression in PDAC. When ectopically expressed, fascin was able to rescue PDAC cell invasion after HIF-1a knockdown. Our results demonstrated that fascin is a direct target gene of HIF-1. Our data suggested that the hypoxic tumor microenvironment in PDAC might promote invasion and metastasis by inducing fascin overexpression, and fascin might be targeted to block PDAC progression. Cancer Res; 74(9);

Treatment outcome of acute myeloid leukemia (AML) in elderly patients remains unsatisfactory. It has been shown that the infusion of granulocyte colony-stimulating factor-mobilized donor peripheral blood stem cells (G-PBSCs) can enhance graftversus-leukemia effects and speed hematopoietic recovery. Fifty-eight AML patients aged 60-88 years were randomly assigned to receive induction chemotherapy with cytarabine and mitoxantrone (control group; n ‫؍‬ 28) or it plus human leukocyte antigen-mismatched G-PBSCs

In Alzheimer's disease, microtubule-associated protein tau is hyperphosphorylated by an unknown mechanism and is aggregated into paired helical filaments. Hyperphosphorylation causes loss of tau function, microtubule instability, and neurodegeneration. Glycogen synthase kinase-3␤ (GSK3␤) has been implicated in the phosphorylation of tau in normal and Alzheimer's disease brain. The molecular mechanism of GSK3␤-tau interaction has not been clarified. In this study, we find that when microtubules are disassembled, microtubuleassociated GSK3␤ dissociates from microtubules. From a gel filtration column, the dissociated GSK3␤ elutes as an ϳ400-kDa complex. When fractions containing the ϳ400-kDa complex are chromatographed through an anti-GSK3␤ immunoaffinity column, tau co-elutes with GSK3␤. From fractions containing the ϳ400-kDa complex, both tau and GSK3␤ co-immunoprecipitate with each other. GSK3␤ binds to nonphosphorylated tau, and the GSK3␤-binding region is located within the N-terminal projection domain of tau. In vitro, GSK3␤ associates with microtubules only in the presence of tau. From brain extract, ϳ6-fold more GSK3␤ co-immunoprecipitates with tau than GSK3␣. These data indicate that, in brain, GSK3␤ is bound to tau within a ϳ400-kDa microtubule-associated complex, and GSK3␤ associates with microtubules via tau.