Background: Early TIMP-1 accumulation may impede cancer progression, and cancer cells need to reduce the antiproteolytic burden. Results: Early overexpression and later aberrant glycosylation of TIMP-1 support tumor progression. Conclusion: Concomitant overexpression of TIMP-1 and GnT-V directs accelerated tumor growth and cancer progression in vivo and in vitro. Significance: An answer to the debate on whether TIMP-1 is pro-or anti-oncogenic is given.

TALE-nuclease chimeras (TALENs) can bind to and cleave specific genomic loci and, are used to engineer gene knockouts and additions. Recently, instead of using the FokI domain, epigenetically active domains, such as TET1 and LSD1, have been combined with TAL effector domains to regulate targeted gene expression via DNA and histone demethylation. However, studies of histone methylation in the TALE system have not been performed. Therefore, in this study, we established a novel targeted regulation system with a TAL effector domain and a histone methylation domain. To construct a TALE-methylation fusion protein, we combined a TAL effector domain containing an E-Box region to act as a Snail binding site and the SET domain of EHMT 2 to allow for histone methylation. The constructed TALE-SET module (TSET) repressed the expression of E-cadherin via by increasing H3K9 dimethylation. Moreover, the cells that overexpressed TSET showed increased cell migration and invasion. This is the first phenotype-based study of targeted histone methylation by the TALE module, and this new system can be applied in new cancer therapies to reduce side effects.

Abstract. Recent studies have demonstrated that the cell adhesion molecule, L1, is expressed in several malignant tumor types and its expression correlates with tumor progression and metastasis. However, the role of L1 in gallbladder carcinoma (GBC) remains unclear. Here, we demonstrate that L1 is expressed in GBC cells and plays an important role in the growth, motility, invasiveness, and adhesiveness of GBC cells. Specific depletion or overexpression of L1 in the GBC cell lines JCRB1033 and SNU-308, respectively, was achieved by lentivirus-mediated transduction and expression of an L1 mRNA-specific short hairpin RNA or full-length human L1. Stable depletion of L1 led to a significant decrease in GBC cell proliferation, migration and invasion, as well as decreased intracellular signaling through AKT and FAK. Overexpression of L1 in GBC cells enhanced these cellular activities. In a GBC xenograft nude mouse model, suppression of L1 markedly reduced tumor growth and increased the survival of tumorbearing mice whereas L1 overexpression stimulated tumorigenicity. Taken together, these results suggest that L1 plays a crucial role in GBC progression and may be a novel therapeutic target in GBC treatment. IntroductionGallbladder carcinoma (GBC) is the most common malignancy of the biliary tract. Although occurrence is rare compared to other gastrointestinal tract neoplasms such as gastric and colorectal cancers, GBC has a distinctly higher incidence in certain demographic groups and geographic areas (1,2). The prevalence of GBC in China, Thailand and Northern India is much higher than in the United States and Europe (3). Surgical resection is currently the most effective and potentially curative treatment for GBC. However, many patients present late in the course of the disease when surgical intervention is no longer effective; most patients with advanced GBC experience frequent recurrence after surgery. Therefore, the overall survival rate remains quite poor (4). Although the most important risk factor for the development of GBC is cholelithiasis (up to 95% of GBCs are associated with gallstones) (5), the molecular mechanisms involved in early carcinogenesis and the factors affecting disease progression remain unclear. Therefore, the identification of factors crucial for GBC progression is necessary for development of new therapeutic strategies.L1 is a transmembrane glycoprotein of 200-220 kDa that belongs to the immunoglobulin superfamily of cell adhesion molecules. It consists of six immunoglobulin-like domains and five fibronectin type III repeats in the extracellular region, a single-pass transmembrane domain and a cytoplasmic tail (6). L1 was originally described as a neural cell adhesion molecule and has been shown to initiate a variety of dynamic motile processes, including cerebellar cell migration and neurite extension in the central nervous system (7,8). L1 is also expressed in other cell types such as endothelial cells, certain epithelial cells, reticular fibroblasts, and cells of lymphoid and myelomonocyt...

Anoikis is a form of anchorage-dependent apoptosis, and cancer cells adopt anokis-resistance molecular machinery to conduct metastasis. Here, we report that N-acetylglucosaminyltransferase V gene expression confers anoikis resistance during cancer progression. Overexpression of N-acetylglucosaminyltransferase V protected detached cancer cells from apoptotic death, and suppression or knockout of the gene sensitized cancer cells to the apoptotic death. The gene expression also stimulated anchorage-dependent as well as anchorage-independent colony formation of cancer cells following anoikis stress treatments. Importantly, treatment with the lectin from Sambucus sieboldiana significantly sensitized anoikis-induced cancer cell deaths in vitro as well as in vivo. We propose that the lectin alone or an engineered form could offer a new therapeutic treatment option for cancer patients with advanced tumors.