Targeting self-renewal is an important goal in cancer therapy and recent studies have focused on Notch signalling in the maintenance of stemness of glioma stem cells (GSCs). Understanding cancer-specific Notch regulation would improve specificity of targeting this pathway. In this study, we find that Notch1 activation in GSCs specifically induces expression of the lncRNA, TUG1. TUG1 coordinately promotes self-renewal by sponging miR-145 in the cytoplasm and recruiting polycomb to repress differentiation genes by locus-specific methylation of histone H3K27 via YY1-binding activity in the nucleus. Furthermore, intravenous treatment with antisense oligonucleotides targeting TUG1 coupled with a drug delivery system induces GSC differentiation and efficiently represses GSC growth in vivo. Our results highlight the importance of the Notch-lncRNA axis in regulating self-renewal of glioma cells and provide a strong rationale for targeting TUG1 as a specific and potent therapeutic approach to eliminate the GSC population.

Recent studies have described the important multiple roles of long non‐coding RNAs (lncRNAs) during oncogenic transformation. Because the coding genome accounts for a small amount of total DNA, and many mutations leading to cancer occur in the non‐coding genome, it is plausible that the dysregulation of such non‐coding transcribes might also affect tumor phenotypes. Indeed, to date, lncRNAs have been reported to affect diverse biological processes through the regulation of mRNA stability, RNA splicing, chromatin structure, and miRNA‐mediated gene regulation by acting as miRNA sponges. Furthermore, accumulating studies have described the roles of lncRNAs in tumorigenesis; however, the precise mechanisms of many lncRNAs are still under investigation. Here, we discuss recently reported mechanistic insights into how lncRNAs regulate gene expression and contribute to tumorigenesis through interactions with other regulatory molecules. We especially highlight the role of taurine upregulated gene 1, which was recently reported to have biological functions related to gene regulation, and discuss the future clinical implications of lncRNAs in cancer treatments.

Emerging evidence, although currently very sparse, suggests the presence of ''lineage-specific dependency'' in the survival mechanisms of certain cancers. TTF-1 has a decisive role as a master regulatory transcription factor in lung development and in the maintenance of the functions of terminal respiratory unit (TRU) cells. We show that a subset of lung adenocarcinoma cell lines expressing TTF-1, which presumably represent those derived from the TRU lineage, exhibit marked dependence on the persistent expression of TTF-1. The inhibition of TTF-1 by RNA interference (RNAi) significantly and specifically induced growth inhibition and apoptosis in these adenocarcinoma cell lines. Furthermore, a fraction of TTF-1-expressing tumors and cell lines displayed an increase in the gene dosage of TTF-1 in the analysis of 214 patients with non-small-cell lung cancer, including 174 adenocarcinomas, showing a tendency of higher frequency of increased gene copies at metastatic sites than at primary sites (P = 0.07, by two-sided Fisher's exact test). These findings strongly suggest that in addition to the development and maintenance of TRU lineages in normal lung, sustained TTF-1 expression may be crucial for the survival of a subset of adenocarcinomas that express TTF-1, providing credence for the lineage-specific dependency model. [Cancer Res 2007; 67(13):6007-11]

We found that zaprinast, a well-known cyclic guanosine monophosphate-specific phosphodiesterase inhibitor, acted as an agonist for a G protein-coupled receptor, GPR35. In our intracellular calcium mobilization assay, zaprinast activated rat GPR35 strongly (geometric mean EC 50 value of 16 nM), whereas it activated human GPR35 moderately (geometric mean EC 50 value of 840 nM). We also demonstrated that GPR35 acted as a Ga i/o -and Ga 16 -coupled receptor for zaprinast when heterologously expressed in human embryonic kidney 293 (HEK 293) cells. These findings will facilitate the research on GPR35 and the drug discovery of the GPR35 modulators.

IntroductionProstaglandin E2 (PGE 2 ) is produced during inflammatory responses, and increased levels of PGE 2 help mediate some of the cardinal features of inflammation, including pain, edema, and fever (1, 2). PGE 2 exerts its effects through interactions with EP receptors, termed EP1-4 (3). Nonsteroidal anti-inflammatory drugs (NSAIDs) act by inhibiting cyclooxygenase (COX) enzymes and thereby inhibiting prostaglandin production. In the context of this putative mechanism of action, direct cause-and-effect relationships between interruption of specific receptor-mediated signaling pathways and therapeutic actions have not been firmly established. While NSAIDs are effective analgesic agents, certain NSAIDs have a number of troublesome side effects that are due in part to their broad inhibition of a variety of COX products (4,5).Defining the molecular mechanisms underlying both the therapeutic and adverse actions of NSAIDs should provide useful targets for new, more specific therapeutic strategies. Therefore, we focused on a receptor for one of the prostaglandins (PGE 2 ), the EP1 receptor (6). We generated EP1-deficient mice by gene targeting and compared their physiological responses to genetically matched wild-type controls. We find that EP1 -/-animals have reduced nociceptive pain perception as well as altered cardiovascular homeostasis. These results demonstrate the critical actions of EP1 receptors in two physiological functions: pain perception and blood pressure regulation. Methods EP1 targeting vector construction and production of EP1 -/-mice.Mouse genomic clones containing Ptgerep1, mouse gene symbol for EP1 receptor, were isolated from a DBA/1lacJ genomic λ-phage library (Stratagene, La Jolla, California, USA). Long-template PCR was used to amplify 5′and 3′ fragments of the clone using T3 or T7 and EP1-specific primers. A 4.5-kb 5′ fragment and 6.0-kb 3′ fragment were cloned into pCRII vector (Invitrogen Corp., San Diego, California, USA). These fragments were sequence confirmed and subcloned into pHok, a plasmid containing PGK-neo and PGK-thymidine kinase cassettes. The EP1 targeting vector was designed to replace 671 bp of coding sequence with the PGK-neo cassette. This 671-bp coding region was Received for publication March 9, 1999, and accepted in revised form December 6, 2000.The lipid mediator prostaglandin E2 (PGE 2 ) has diverse biological activity in a variety of tissues. Four different receptor subtypes (EP1-4) mediate these wide-ranging effects. The EP-receptor subtypes differ in tissue distribution, ligand-binding affinity, and coupling to intracellular signaling pathways. To identify the physiological roles for one of these receptors, the EP1 receptor, we generated EP1-deficient (EP1 -/-) mice using homologous recombination in embryonic stem cells derived from the DBA/1lacJ strain of mice. The EP1 -/-mice are healthy and fertile, without any overt physical defects. However, their pain-sensitivity responses, tested in two acute prostaglandin-dependent models, were reduced by approximately ...