miR-331-3p regulates expression of neuropilin-2 in glioblastoma.

Aberrant expression of microRNAs (miRNAs), a class of small non-coding regulatory RNAs, has been implicated in the development and progression of high-grade gliomas. However, the precise mechanistic role of many miRNAs in this disease remains unclear. Here, we investigate the functional role of miR-331-3p in glioblastoma multiforme (GBM).

Loss of the nuclear receptor corepressor SLIRP compromises male fertility.

Nuclear receptors (NRs) and their coregulators play fundamental roles in initiating and directing gene expression influencing mammalian reproduction, development and metabolism. SRA stem Loop Interacting RNA-binding Protein (SLIRP) is a Steroid receptor RNA Activator (SRA) RNA-binding protein that is a potent repressor of NR activity. SLIRP is present in complexes associated with NR target genes in the nucleus; however, it is also abundant in mitochondria where it affects mitochondrial mRNA transcription and energy turnover.

Notch-induced transcription factors are predictive of survival and 5-fluorouracil response in colorectal cancer patients.

Background: The purpose of this study was to evaluate the expression of Notch-induced transcription factors (NTFs) HEY1, HES1 and SOX9 in colorectal cancer (CRC) patients to determine their clinicopathologic and prognostic significance.

Methods: Levels of HEY1, HES1 and SOX9 protein were measured by immunohistochemistry in a nonmalignant and malignant tissue microarray of 441 CRC patients, and the findings correlated with pathologic, molecular and clinical variables.

Results: The NTFs HEY1, HES1 and SOX9 were overexpressed in tumours relative to colonic mucosa (OR=3.

RNA-induced silencing complex (RISC) Proteins PACT, TRBP, and Dicer are SRA binding nuclear receptor coregulators.

The cytoplasmic RNA-induced silencing complex (RISC) contains dsRNA binding proteins, including protein kinase RNA activator (PACT), transactivation response RNA binding protein (TRBP), and Dicer, that process pre-microRNAs into mature microRNAs (miRNAs) that target specific mRNA species for regulation. There is increasing evidence for important functional interactions between the miRNA and nuclear receptor (NR) signaling networks, with recent data showing that estrogen, acting through the estrogen receptor, can modulate initial aspects of nuclear miRNA processing. Here, we show that the cytoplasmic RISC proteins PACT, TRBP, and Dicer are steroid receptor RNA activator (SRA) binding NR coregulators that target steroid-responsive promoters and regulate NR activity and downstream gene expression.

Intratumoral TNFα improves immunotherapy.

Solid tumors are frequently resistant to immunotherapy. We demonstrated that low-dose tumor necrosis factorα (TNFα), when directly targeted to the tumor environment, exerts dual effects by improving vessel functionality and activating immune cells. This vascular remodeling in an inflammatory context enhances active immunotherapy and promotes tumor regression.

miRNA-7-5p inhibits melanoma cell migration and invasion.

Aberrant expression of microRNAs (miRNAs), a class of small non-coding regulatory RNAs, has been implicated in the development and progression of melanoma. However, the precise mechanistic role of many of these miRNAs remains unclear. We have investigated the functional role of miR-7-5p in melanoma, and demonstrate that miR-7-5p expression is reduced in metastatic melanoma-derived cell lines compared with primary melanoma cells, and that when ectopically expressed miR-7-5p significantly inhibits melanoma cell migration and invasion.

Regulation of epidermal growth factor receptor signaling and erlotinib sensitivity in head and neck cancer cells by miR-7.

Elevated expression and activity of the epidermal growth factor receptor (EGFR)/protein kinase B (Akt) signaling pathway is associated with development, progression and treatment resistance of head and neck cancer (HNC). Several studies have demonstrated that microRNA-7 (miR-7) regulates EGFR expression and Akt activity in a range of cancer cell types via its specific interaction with the EGFR mRNA 3'-untranslated region (3'-UTR). In the present study, we found that miR-7 regulated EGFR expression and Akt activity in HNC cell lines, and that this was associated with reduced growth in vitro and in vivo of cells (HN5) that were sensitive to the EGFR tyrosine kinase inhibitor (TKI) erlotinib (Tarceva).

Matrigel basement membrane matrix influences expression of microRNAs in cancer cell lines.

Matrigel is a medium rich in extracellular matrix (ECM) components used for three-dimensional cell culture and is known to alter cellular phenotypes and gene expression. microRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression and have roles in cancer. While miRNA profiles of numerous cell lines cultured on plastic have been reported, the influence of Matrigel-based culture on cancer cell miRNA expression is largely unknown.

Regulation of expression of deoxyhypusine hydroxylase (DOHH), the enzyme that catalyzes the activation of eIF5A, by miR-331-3p and miR-642-5p in prostate cancer cells.

The enzyme deoxyhypusine hydroxylase (DOHH) catalyzes the activation of eukaryotic translation initiation factor (eIF5A), a protein essential for cell growth. Using bioinformatic predictions and reporter gene assays, we have identified a 182-nt element within the DOHH 3'-untranslated region (3'-UTR) that contains a number of target sites for miR-331-3p and miR-642-5p. Quantitative RT-PCR studies demonstrated overexpression of DOHH mRNA and underexpression of miR-331-3p and miR-642-5p in several prostate cancer cell lines compared with normal prostate epithelial cells.

The RNA-binding protein HuR opposes the repression of ERBB-2 gene expression by microRNA miR-331-3p in prostate cancer cells.

ERBB-2 overexpression is associated with the development and progression of cancer and mediates its resistance to therapy. It has been suggested that post-transcriptional mechanisms control the overexpression of ERBB-2 in prostate cancer (PCa). We recently demonstrated that the 3'-untranslated region (3'-UTR) of ERBB-2 mRNA contains two specific target sites for binding of the microRNA miR-331-3p and that miR-331-3p represses ERBB-2 expression and signaling in PCa cells.

Steroid Receptor RNA Activator - A nuclear receptor coregulator with multiple partners: Insights and challenges.

Steroid Receptor RNA Activator (SRA) occupies a unique and enigmatic position within the nuclear receptor (NR) field and more broadly in transcriptional regulation. This is as a result of its transcripts having both coding and non-coding coactivator activities along with its protein product SRAP performing mixed coactivator/repressor functions. Recent publications have provided greater understanding of SRA gene product activities and how they affect not only NR function, but now more broadly, signalling pathways involved in differentiation and metabolism.

Regulation of ErbB receptor signalling in cancer cells by microRNA.

Recent years have seen a massive expansion in our understanding of the biology of microRNAs (miRNAs) in cancer, through the identification of miRNAs with aberrant expression in specific cancers and the functional validation of their critical target molecules and cellular effects. In parallel, targeted therapeutic agents to block signalling pathways critical to tumour growth and progression have been developed but have yielded disappointing clinical results. The discovery of miRNAs that regulate ErbB signalling in cancer cells brings new hope that in the future these oncogenic pathways can be more effectively inhibited to improve patient outcomes.

Targeted liposomal delivery of TLR9 ligands activates spontaneous antitumor immunity in an autochthonous cancer model.

Accessibility of tumors for highly effective local treatment represents a major challenge for anticancer therapy. Immunostimulatory oligodeoxynucleotides (ODN) with CpG motifs are ligands of TLR9, which prime spontaneous antitumor immunity, but are less effective when applied systemically. We therefore developed a liposome-based agent for selective delivery of CpG-ODN into the tumor environment.

Regulator of G protein signaling 5: a new player in vascular remodeling.

Regulators of G protein signaling (RGS) proteins are important modulators of G protein-coupled receptors and, therefore, critical for cardiovascular functions. One family member, RGS5, has recently been identified as a key regulator of vascular remodeling and pericyte maturation in tumors. Here, we discuss a potential role for RGS5 and its relatives, RGS2 and 4, within the cardiovascular system.

SRA and its binding partners: an expanding role for RNA-binding coregulators in nuclear receptor-mediated gene regulation.

The discovery that SRA RNA can function as a nuclear receptor (NR) coactivator resulted in a fundamental change in the perception of how NRs and their coregulators may regulate hormone signaling pathways. The subsequent identification of molecules capable of binding SRA, including SHARP, p68, and more recently SLIRP, which also function as coregulators, has further broadened our understanding of NR-dependent gene regulation. The integral role that NRs play in directing developmental, metabolic and pathological programs of transcription has defined them as paramount targets for treating a broad range of human diseases.

Modulation of g protein signaling normalizes tumor vessels.

G protein-coupled biological processes are important for an ever-increasing number of human diseases and require fine-tuning through accessory molecules such as the regulators of G protein signaling (RGS). RGS5, a marker for tumor-resident pericytes, was recently established as playing a pivotal role in vascular maturation and vessel remodeling during carcinogenesis. Remarkably, tumors arising in a RGS5-deficient background display vessels with normalized morphology and an overall improved blood flow.

Modulation of the "blood-tumor" barrier improves immunotherapy.

Blood vessels inside tumors are crucial for cancer survival and progression but equally contribute to the tumor's intrinsic resistance to therapy. Abnormal blood flow in the local tumor environment acts as a physiological barrier to the delivery of chemotherapeutic agents. Furthermore, tumor vasculature can also act as a barrier for immune cell migration into the tumor parenchyma.

Vascular targeting of anti-CD40 antibodies and IL-2 into autochthonous tumors enhances immunotherapy in mice.

Current anticancer therapy is a delicate balance between elimination of malignant cells and harmful side effects for the host. In this study, we used a tumor-homing peptide to engineer anti-CD40 agonist antibodies and recombinant IL-2 such that they were selectively delivered into spontaneously arising tumors in a transgenic mouse model of islet cell carcinogenesis. Intravenous injection of these agents, either separately or together, led to accumulation in the vicinity of tumor neovessels without toxic side effects.

SLIRP, a small SRA binding protein, is a nuclear receptor corepressor.

Steroid receptor RNA activator (SRA), the only known RNA coactivator, augments transactivation by nuclear receptors (NRs). We identified SLIRP (SRA stem-loop interacting RNA binding protein) binding to a functional substructure of SRA, STR7. SLIRP is expressed in normal and tumor tissues, contains an RNA recognition motif (RRM), represses NR transactivation in a SRA- and RRM-dependent manner, augments the effect of Tamoxifen, and modulates association of SRC-1 with SRA.

Hepatic oval cell response to the choline-deficient, ethionine supplemented model of murine liver injury is attenuated by the administration of a cyclo-oxygenase 2 inhibitor.

Oval cell proliferation precedes neoplasia in many rodent models of hepatocellular carcinoma and prevention of this proliferative response can reduce the risk of subsequent carcinoma. This study aimed to determine whether a selective cyclo-oxygenase-2 (COX-2) inhibitor, SC-236, affects (i) the oval cell response to liver injury in a mouse model of hepatocarcinogenesis and (ii) an oval cell line. Four-week-old mice were fed either normal chow or a choline deficient, ethionine supplemented (CDE) diet in the presence or absence of SC-236.

Shaking the tree: mapping complex disease genes with linkage disequilibrium.

Much effort and expense are being spent internationally to detect genetic polymorphisms contributing to susceptibility to complex human disease. Concomitantly, the technology for detecting and genotyping single nucleotide polymorphisms (SNPs) has undergone rapid development, yielding extensive catalogues of these polymorphisms across the genome. Population-based maps of the correlations amongst SNPs (linkage disequilibrium) are now being developed to accelerate the discovery of genes for complex human diseases.