Targeting Wnt/β-catenin Pathway in Hepatocellular Carcinoma Treatment

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death worldwide. Liver cancer is generally related to hepatitis B or C infection and cirrhosis. Usually, patients with HCC are asymptomatic and are diagnosed at late stages when surgical treatment is no longer suitable. Limited treatment options for patients with advanced HCC are a major concern. Therefore, there is an urge for finding novel therapies to treat HCC. Liver cancer is highly heterogeneous and involved deregulation of several signaling pathways. Wnt/β-catenin pathway is frequently upregulated in HCC and it is implicated in maintenance of tumor initiating cells, drug resistance, tumor progression, and metastasis. A great effort in developing selective drugs to target components of the β-catenin pathway with anticancer activity is underway but only a few of them have reached phase I clinical trials. We aim to review the role of β-catenin pathway on hepatocarcinogenesis and liver cancer stem cell maintenance. We also evaluated the use of small molecules targeting the Wnt/β-catenin pathway with potential application for treatment of HCC

The T-cell-specific adapter protein family: TSAd, ALX, and SH2D4A/SH2D4B

Adapter proteins play key roles in intracellular signal transduction through complex formation with catalytically active signaling molecules. In T lymphocytes, the role of several different types of adapter proteins in T-cell antigen receptor signal transduction is well established. An exception to this is the family of T-cell-specific adapter (TSAd) proteins comprising of TSAd, adapter protein of unknown function (ALX), SH2D4A, and SH2D4B. Only recently has the function of these adapters in T-cell signal transduction been explored. Here, we discuss advances in our understanding of the role of this family of adapter proteins in T cells. Their function as regulators of signal transduction in other cell types is also discussed.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78649/1/j.1600-065X.2009.00829.x.pd

Riparian Corridors: A New Conceptual Framework for Assessing Nitrogen Buffering Across Biomes

Anthropogenic activities have more than doubled the amount of reactive nitrogen circulating on Earth, creating excess nutrients across the terrestrial-aquatic gradient. These excess nutrients have caused worldwide eutrophication, fundamentally altering the functioning of freshwater and marine ecosystems. Riparian zones have been recognized to buffer diffuse nitrate pollution, reducing delivery to aquatic ecosystems, but nutrient removal is not their only function in river systems. In this paper, we propose a new conceptual framework to test the capacity of riparian corridors to retain, remove, and transfer nitrogen along the continuum from land to sea under different climatic conditions. Because longitudinal, lateral, and vertical connectivity in riparian corridors influences their functional role in landscapes, we highlight differences in these parameters across biomes. More specifically, we explore how the structure of riparian corridors shapes stream morphology (the river's spine), their multiple functions at the interface between the stream and its catchment (the skin), and their biogeochemical capacity to retain and remove nitrogen (the kidneys). We use the nitrogen cycle as an example because nitrogen pollution is one of the most pressing global environmental issues, influencing directly and indirectly virtually all ecosystems on Earth. As an initial test of the applicability of our interbiome approach, we present synthesis results of gross ammonification and net nitrification from diverse ecosystems

Impaired T Cell Death and Lupus-like Autoimmunity in T Cell–specific Adapter Protein–deficient Mice

T cell–specific adaptor protein (TSAd) is a T lineage–restricted signaling adaptor molecule that is thought to participate in the assembly of intracellular signaling complexes in T cells. Previous studies of TSAd-deficient mice have revealed a role for TSAd in the induction of T cell interleukin 2 secretion and proliferation. We now show that TSAd-deficient mice are susceptible to lupus-like autoimmune disease. On the nonautoimmune-prone C57BL/6 genetic background, TSAd deficiency results in hypergammaglobulinemia that affects all immunoglobulin (Ig)G subclasses. Older C57BL/6 TSAd-deficient mice (1 yr of age) accumulate large numbers of activated T and B cells in spleen, produce autoantibodies against a variety of self-targets including single stranded (ss) and double stranded (ds) DNA, and, in addition, develop glomerulonephritis. We further show that immunization of younger C57BL/6 TSAd-deficient mice (at age 2 mo) with pristane, a recognized nonspecific inflammatory trigger of lupus, results in more severe glomerulonephritis compared with C57BL/6 controls and the production of high titer ss and ds DNA antibodies of the IgG subclass that are not normally produced by C57BL/6 mice in this model. The development of autoimmunity in TSAd-deficient mice is associated with defective T cell death in vivo. These findings illustrate the role of TSAd as a critical regulator of T cell death whose absence promotes systemic autoimmunity

Essential role of the T cell–specific adapter protein in the activation of LCK in peripheral T cells

T cell–specific adapter protein (TSAd) is a SRC-homology-2 (SH2) domain–containing intracellular signaling molecule that is required for T cell antigen receptor (TCR)–induced cytokine synthesis in T cells. How TSAd functions in TCR signal transduction is not clear. Previous work has suggested a nuclear role for this adapter. However, other evidence suggests that TSAd also functions in the cytoplasm. Using T cells from TSAd-deficient mice, we now show that the major role of TSAd in the cytoplasm is in activation of the LCK protein tyrosine kinase at the outset of TCR signal transduction. Consequently, TSAd regulates several downstream signaling events, including intracellular calcium mobilization and activation of the Ras–extracellular signal–regulated kinase signaling pathway. TSAd regulates LCK activity directly through physical interaction with LCK SH3 and SH2 domains. These studies reveal TSAd as a positive regulator of proximal TCR signal transduction and provide important new information on the mechanism of TCR-induced LCK activation

Prediction of enzyme function by combining sequence similarity and protein interactions

<p>Abstract</p> <p>Background</p> <p>A number of studies have used protein interaction data alone for protein function prediction. Here, we introduce a computational approach for annotation of enzymes, based on the observation that similar protein sequences are more likely to perform the same function if they share similar interacting partners.</p> <p>Results</p> <p>The method has been tested against the PSI-BLAST program using a set of 3,890 protein sequences from which interaction data was available. For protein sequences that align with at least 40% sequence identity to a known enzyme, the specificity of our method in predicting the first three EC digits increased from 80% to 90% at 80% coverage when compared to PSI-BLAST.</p> <p>Conclusion</p> <p>Our method can also be used in proteins for which homologous sequences with known interacting partners can be detected. Thus, our method could increase 10% the specificity of genome-wide enzyme predictions based on sequence matching by PSI-BLAST alone.</p

Quantification of metabolically active transient storage (MATS) in two reaches with contrasting transient storage and ecosystem respiration

Water transient storage zones are hotspots for metabolic activity in streams although the contribution of different types of transient storage zones to the whole-reach metabolic activity is difficult to quantify. In this study we present a method to measure the fraction of the transient storage that is metabolically active (MATS) in two consecutive reaches with contrasting hydrological and biological characteristics. We used combined additions of resazurin (Raz) and Cl in a reach scoured to bedrock and in a reach containing a deep alluvial deposit. The MATS zones measured 0.002 m² in the bedrock reach (37% of transient storage) and 0.291 m² in the alluvial reach (100% of transient storage). The effective rate coefficient of Raz transformation in the MATS of the bedrock reach was approximately 16 times that of the alluvial reach. However, when we take into account the contribution of the MATS zone to overall metabolic activity, Raz transformation in the MATS zone was 2.2 times slower in the bedrock reach than in the alluvial reach. The difference was similar to the difference in ecosystem respiration, which was 1.8 times lower in the bedrock reach than in the alluvial reach, suggesting that the MATS zones were important contributors to ecosystem respiration. Results indicate that the quantification of MATS can improve our understanding of the role that transient storage zones play on stream metabolic processes and demonstrate the utility of Raz as a “smart” tracer that provides new information on metabolic activity at a whole-reach and at smaller scale.This is the publisher’s final pdf. The published article is copyrighted by the American Geophysical Union and can be found at: http://www.agu.org/journals/jgr/

Autophagic Flux Modulation by Wnt/β-Catenin Pathway Inhibition in Hepatocellular Carcinoma

Autophagy targets cellular components for lysosomal-dependent degradation in which the products of degradation may be recycled for protein synthesis and utilized for energy production. Autophagy also plays a critical role in cell homeostasis and the regulation of many physiological and pathological processes and prompts this investigation of new agents to effect abnormal autophagy in hepatocellular carcinoma (HCC). 2,5-Dichloro-N-(2-methyl-4-nitrophenyl) benzenesulfonamide (FH535) is a synthetic inhibitor of the Wnt/β-catenin pathway that exhibits anti-proliferative and anti-angiogenic effects on different types of cancer cells. The combination of FH535 with sorafenib promotes a synergistic inhibition of HCC and liver cancer stem cell proliferation, mediated in part by the simultaneous disruption of mitochondrial respiration and glycolysis. We demonstrated that FH535 decreased HCC tumor progression in a mouse xenograft model. For the first time, we showed the inhibitory effect of an FH535 derivative, FH535-N, alone and in combination with sorafenib on HCC cell proliferation. Our study revealed the contributing effect of Wnt/β-catenin pathway inhibition by FH535 and its derivative (FH535-N) through disruption of the autophagic flux in HCC cells