Molecular signature and pathway analysis of human primary squamous and adenocarcinoma lung cancers.

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, with a poor response to chemotherapy and low survival rate. This unfavorable treatment response is likely to derive from both late diagnosis and from complex, incompletely understood biology, and heterogeneity among NSCLC subtypes. To define the relative contributions of major cellular pathways to the biogenesis of NSCLC and highlight major differences between NSCLC subtypes, we studied the molecular signatures of lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC), based on analysis of gene expression and comparison of tumor samples with normal lung tissue. Our results suggest the existence of specific molecular networks and subtype-specific differences between lung ADC and SCC subtypes, mostly found in cell cycle, DNA repair, and metabolic pathways. However, we also observed similarities across major gene interaction networks and pathways in ADC and SCC. These data provide a new insight into the biology of ADC and SCC and can be used to explore novel therapeutic interventions in lung cancer chemoprevention and treatment.

Loss of function genetic screens reveal MTGR1 as an intracellular repressor of beta1 integrin-dependent neurite outgrowth.

Integrins are transmembrane receptors that promote neurite growth and guidance. To identify regulators of integrin-dependent neurite outgrowth, here we used two loss of function genetic screens in SH-SY5Y neuroblastoma cells. First, we screened a genome-wide retroviral library of genetic suppressor elements (GSEs). Among the many genes identified in the GSE screen, we isolated the hematopoetic transcriptional factor MTGR1 (myeloid translocation gene-related protein-1). Treatment of SH-SY5Y cells with MTGR1 siRNA enhanced neurite outgrowth and concurrently increased expression of GAP-43, a protein linked to neurite outgrowth. Second, we transduced SH-SY5Y with a genome-wide GFP-labeled lentiviral siRNA library, which expressed 40,000 independent siRNAs targeting 8500 human genes. From this screen we isolated GFI1 (growth factor independence-1), which, like MTGR1, is a member of the myeloid translocation gene on 8q22 (MTG8)/ETO protein complex of nuclear repressor proteins. These results reveal novel contributions of MTGR1 and GFI1 to the regulation of neurite outgrowth and identify novel repressors of integrin-dependent neurite outgrowth.

Protease-activated receptors: contribution to physiology and disease.

Proteases acting at the surface of cells generate and destroy receptor agonists and activate and inactivate receptors, thereby making a vitally important contribution to signal transduction. Certain serine proteases that derive from the circulation (e.g., coagulation factors), inflammatory cells (e.g., mast cell and neutrophil proteases), and from multiple other sources (e.g., epithelial cells, neurons, bacteria, fungi) can cleave protease-activated receptors (PARs), a family of four G protein-coupled receptors. Cleavage within the extracellular amino terminus exposes a tethered ligand domain, which binds to and activates the receptors to initiate multiple signaling cascades. Despite this irreversible mechanism of activation, signaling by PARs is efficiently terminated by receptor desensitization (receptor phosphorylation and uncoupling from G proteins) and downregulation (receptor degradation by cell-surface and lysosomal proteases). Protease signaling in tissues depends on the generation and release of proteases, availability of cofactors, presence of protease inhibitors, and activation and inactivation of PARs. Many proteases that activate PARs are produced during tissue damage, and PARs make important contributions to tissue responses to injury, including hemostasis, repair, cell survival, inflammation, and pain. Drugs that mimic or interfere with these processes are attractive therapies: selective agonists of PARs may facilitate healing, repair, and protection, whereas protease inhibitors and PAR antagonists can impede exacerbated inflammation and pain. Major future challenges will be to understand the role of proteases and PARs in physiological control mechanisms and human diseases and to develop selective agonists and antagonists that can be used to probe function and treat disease.