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FAM3B mRNA has been predicted to have multiple splicing forms. Its secretory form PANDER is decreased in gastric cancers with high invasiveness and metastasis. Here we found that its non-secretory form FAM3B-258 was highly expressed in most colon cancer cell lines and colorectal adenocarcinoma tissues but not hepatocellular carcinoma, lung carcinoma and pancreatic adenocarcinoma cell lines. Elevation of FAM3B-258 was associated with poor cancer cell differentiation. Stable overexpression of FAM3B-258 in colon cancer cells downregulated adhesion proteins, upregulated Slug and Cdc42, promoted cell migration and invasion in vitro and metastasis in nude mice. Slug mediated FAM3B-258-induced downregulation of adhesion molecules, upregulation of Cdc42, and invasion of colon cancer cells. The expression of FAM3B-258 in human colorectal adenocarcinomas was positively correlated with Slug. These results suggest that FAM3B-258 promotes colon cancer cell invasion and metastasis through upregulation of Slug.

Amylin is the major component of pancreatic amyloid, which is implicated in the development of type 2 diabetes. It is costored with insulin in the secretory granules of pancreatic ␤-cells and cosecreted with insulin following stimulation with glucose. Here, we investigate the effect of fatty acids (FAs) on amylin expression and secretion by ␤-cells and explore the underlying mechanisms. Palmitate and oleate dose-dependently induced amylin mRNA accumulation in murine pancreatic ␤-cell line MIN6 and primary pancreatic islets. the inductive effect of FAs on amylin expression is independent of glucose concentration. FAs upregulated amylin expression at the transcriptional level, and FAs must be metabolized to induce amylin expression. FAs also significantly induced human amylin promoter activation. Pretreatment of MIN6 cells with Ca 2ϩ chelator (EGTA, BAPTA-AM) PKC inhibitor Gö-6976 or protein synthesis inhibitor cycloheximide significantly inhibited FA-induced amylin mRNA expression. Transcription factors cAMP-responsive element-binding protein, pancreatic and duodenal homeobox factor-1, and peroxisome proliferator-activated receptor were not involved in FA-induced amylin expression. Palmitate and oleate both increased amylin and insulin release from MIN6 cells and stimulated amylin expression but had no effect on insulin expression. Mice refed with Intralipid had significantly higher levels of plasma FFA, amylin, and insulin than those refed with saline. These data demonstrate that FAs differently regulate amylin and insulin expression and induce both amylin and insulin release. Ca 2ϩ and PKC signaling pathways and de novo-synthesized protein(s) were involved in FA-induced amylin expression. Induction of amylin production and release by FA may contribute to its biological functions under physiological conditions. pancreas; islet amyloid polypeptide; insulin; gene expression; signal transduction; high-lipid diet AMYLOID DEPOSITION IS A COMMON FEATURE in individuals with type 2 diabetes (30). Amylin, also known as islet amyloid polypeptide, is the most abundant component of pancreatic amyloid (6,49). Amylin is a 37-amino acid peptide of the calcitonin gene family. Amylin has been suggested to be toxic to ␤-cells and to be involved in the development of type 2 diabetes (30, 31). It has been proposed that overexpression of amylin contributes to pancreatic amyloid formation and development of type 2 diabetes, a view supported by transgenic mouse and rat studies involving the overexpression of human amylin in islets of Langerhans (31). Therefore, elucidation of the mechanisms controlling amylin gene expression in pancreatic ␤-cells may contribute to a better understanding of the physiological functions of amylin and prove relevant to the pathogenesis of type 2 diabetes.In pancreatic ␤-cells, amylin is costored with insulin in the secretory granules and cosecreted in a regulated manner following stimulation with glucose and a variety of other secretagogues (5, 22). Glucose stimulates amylin mRNA expression and protein re...

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Human formylpeptide receptor 2 (FPR2) and its mouse homologue mFPR2 belong to the G protein-coupled, seven-transmembrane receptor superfamily. Both FPR2 and mFPR2 recognize a variety of exogenous and host-derived chemotactic peptides associated with proinflammatory conditions. Since endothelial cells actively participate in inflammation, we investigated whether microvascular endothelial cells express mFPR2 and its regulation by proinflammatory factors. We found that resting primary mouse microvascular endothelial cells and a cell line bEnd.3 expressed low levels of mFPR2 at both mRNA and protein levels, which was markedly enhanced by two key proinflammatory stimulants, lipopolysaccharide (LPS) and interleukin (IL)-1β. While the inductive effect of LPS was dependent on the JNK MAP kinase, both JNK and ERK MAP kinases were utilized by IL-1β to enhance mFPR2 expression. Overexpression of dominant-negative IκBα attenuated LPS- and IL-1β-induced mFPR2 expression, indicating an essential role for NF-κB in regulating mFPR2 expression in endothelial cells by proinflammatory stimulants. Our results suggest that upregulated mFPR2 in vascular endothelial cells under inflammatory conditions may mediate cell responses in diseases in which mFPR2 agonists are elevated.

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Objective Heat shock factor 1 (HSF1), a transcriptional regulator of heat shock proteins (HSPs), is an attractive therapeutic target for cancer. However, only a few HSF1 inhibitors have been identified so far. Methods The mRNA and protein levels of HSF1, HSPs, cleaved PARP, and phosphorylated HSF1 were examined by real-time PCR and Western blot. Forced expression, RNA interference, and immunofluorescence assay were used for mechanistic studies. Cell viability and apoptosis were measured by WST-8 assay and flow cytometry, respectively. Xenograft studies were performed in nude mice to evaluate the effect of dorsomorphin and an HSP90 inhibitor on tumor growth. Results Dorsomorphin suppressed multiple stimuli-induced and constitutive HSPs expression in cancer cells. Mechanistic studies revealed that dorsomorphin reduced heat-induced HSP expression independent of adenosine monophosphate activated protein kinase. Dorsomorphin reduced heat-stimulated HSF1 Ser320 phosphorylation and nuclear translocation, as well as resting nuclear HSF1 levels in cancer cells. Dorsomorphin induced cancer cell apoptosis by inhibiting HSF1 expression. A structure-activity study revealed that the 4-pyridyl at the 3-site of the pyrazolo [1, 5-a]pyrimidine ring is critical for the anti-HSF1 activities of dorsomorphin. Dorsomorphin sensitized cancer cells to HSP90 and proteasome inhibitors and inhibited HSP70 expression induced by these inhibitors in vitro . In tumor-bearing nude mice, dorsomorphin enhanced HSP90 inhibitor-induced cancer cell apoptosis, tumor growth inhibition, and HSP70 expression. Conclusions Dorsomorphin is an HSF1 inhibitor. It induces cancer cell apoptosis, sensitizes cancer cells to both HSP90 and proteasome inhibitors, and suppresses HSP upregulation by these drugs, which may prevent the development of drug resistance. Hence, dorsomorphin and its derivates may serve as potential precursors for developing drugs against cancer.

The grain size composition and distribution of river sediments are important for understanding regional geomorphological evolution, source-sink processes and drainage ecology. The Shiyang River basin, an inland river system in northwestern China, provides an environmental context within which to investigate the relationship between sediment particle size and environmental factors. Based on the analysis of the grain size characteristics of modern riverbed sediments, basin geomorphological parameters and lithology, it is found that the median grain size (Md) of river sediments shows a decrease trend from upstream to downstream in the basin. One of the tributaries named the Jinta River shows an obvious downstream fining trend (exponentially decreasing) of Md, which is related to the old geomorphological development stages and relatively homogeneous lithology in the basin. The downstream fining trend of Md along the Xiying River, another tributary, shows complex fluctuations, which might be affected by the tectonically active, young geomorphic development stage, complex lithology of the basin, and the sediment confluence of tributaries. The gravel-sand transition zone occurs in the plain section of the river about 28 km out of the mountain, which is related to the combination of regional geomorphological features, river morphology and hydraulic sorting.