Epithelial cell adhesion molecule (EpCAM) is overexpressed in most solid cancers and is an ideal antigen for clinical applications in cancer diagnosis, prognosis, imaging, and therapy. Currently, most of the EpCAM-based diagnostic, prognostic, and therapeutic strategies rely on the anti-EpCAM antibody. However, the use of EpCAM antibody is restricted due to its large size and instability. In this study, we have successfully identified DNA aptamers that selectively bind human recombinant EpCAM protein. The aptamers can specifically recognize a number of live human cancer cells derived from breast, colorectal, and gastric cancers that express EpCAM but not bind to EpCAM-negative cells. Among the aptamer sequences identified, a hairpin-structured sequence SYL3 was optimized in length, resulting in aptamer sequence SYL3C. The Kd values of the SYL3C aptamer against breast cancer cell line MDA-MB-231 and gastric cancer cell line Kato III were found to be 38 ± 9 and 67 ± 8 nM, respectively, which are better than that of the full-length SYL3 aptamer. Flow cytometry analysis results indicated that the SYL3C aptamer was able to recognize target cancer cells from mixed cells in cell media. When used to capture cancer cells, up to 63% cancer cell capture efficiency was achieved with about 80% purity. With the advantages of small size, easy synthesis, good stability, high binding affinity, and selectivity, the DNA aptamers reported here against cancer biomarker EpCAM will facilitate the development of novel targeted cancer therapy, cancer cell imaging, and circulating tumor cell detection.

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Liver kinase B1 (LKB1) has important roles in governing energy homeostasis by regulating the activity of the energy sensor kinase AMP-activated protein kinase (AMPK). The regulation of LKB1 function, however, is still poorly understood. Here we demonstrate that the orphan nuclear receptor Nur77 binds and sequesters LKB1 in the nucleus, thereby attenuating AMPK activation. This Nur77 function is antagonized by the chemical compound ethyl 2-[2,3,4-trimethoxy-6-(1-octanoyl)phenyl]acetate (TMPA), which interacts with Nur77 with high affinity and at specific sites. TMPA binding of Nur77 results in the release and shuttling of LKB1 to the cytoplasm to phosphorylate AMPKα. Moreover, TMPA effectively reduces blood glucose and alleviates insulin resistance in type II db/db and high-fat diet- and streptozotocin-induced diabetic mice but not in diabetic littermates with the Nur77 gene knocked out. This study attains a mechanistic understanding of the regulation of LKB1-AMPK axis and implicates Nur77 as a new and amenable target for the design and development of therapeutics to treat metabolic diseases.

Genomic ablation of hepatocyte-specific fibroblast growth factor receptor (FGFR)4 in mice revealed a role of FGF signaling in cholesterol and bile acid metabolism and hepatolobular restoration in response to injury without effect on liver development or hepatocyte proliferation. Although the potential role of all 23 FGF polypeptides in the liver is still unclear, the most widely studied prototypes, FGF1 and FGF2, are present and have been implicated in liver cell growth and function in vitro. To determine whether FGF1 and FGF2 play a role in response to injury and fibrosis, we examined the impact of both acute and chronic exposure to carbon tetrachloride (CCl 4 ) in the livers of FGF1-and FGF2-deficient mice. After acute CCl 4 exposure, FGF1(؊/؊)FGF2(؊/؊) mice exhibited an accelerated release of serum alanine aminotransferase similar to FGFR4 deficiency, but no effect on overall hepatolobular restoration or bile acid metabolism. The fibroblast growth factors (FGFs) comprise a family of 23 reported members that have varying affinities for variants of four different FGF receptor kinases (FGFR1 to FGFR4). 1-3 FGF1 and FGF2, the first two cloned members of the FGF family, 4,5 have received the most study, are widely expressed, and thus, predicted to be involved in tissue-specific functions and associated pathologies at their site of expression. 6,7 In vitro FGF1 affects cells of multiple origin whereas activity of FGF2 appears more limited to cells derived from mesenchyme and neuroectoderm. 8 FGF1 and FGF2 have been implicated in derivation of the liver from foregut endoderm. 9 However, mice lacking FGF1, FGF2, or both FGF1 and FGF2 are viable, fertile, and grossly indistinguishable from wild type (WT) except for modest defects in cardiovascular tissue, healing of skin wounds, and neuronal tissue. 3,10,11 This suggests that FGF1 and FGF2 alone are not essential for embryonic development or are compensated by other members of the extensive FGF ligand family. Consequently, FGF1-and FGF2-deficient animals are available for study of the role of the two factors in adult tissue homeostasis. Despite their ubiquity, little has emerged except for the modest effects of ablation of FGF1 and FGF2 in the cardiovascular, skin, and nervous systems.Although the levels of mRNA transcripts are low, longlived FGF1 and FGF2 polypeptides are present in the resting liver at significant levels. 12 This suggests that a significant reservoir of both ligands is present in the resting liver in an inactive state before activation and