Effect of BRMS1 on Tumorigenicity and Metastasis of Human Rectal Cancer

Breast cancer metastasis suppressor gene-1 (BRMS1) is newly discovered tumor metastasis gene, which has been reported to play an important role in the progression of human tumor. However, its role in rectal cancer has never been investigated. In this present study, we evaluated the associated of BRMS1 with colorectal cancer, its value in prognosis, and its role in metastasis of rectal cancer. BRMS1 expression examined in 80 patients and the role of BRMS1 in metastasis was studied using mice model. Our results showed that BRMS1 expression was significantly associated with clinicopathological parameters in rectal cancer patients and overexpression of BRMS1 in rectal cancer xenograft led to decreased growth, invasiveness and metastasis. Our findings indicate that high expression of BRSM1 in rectal cancer plays an essential role in tumor progression.     

The important anti-apoptotic role and its regulation mechanism of PTTG1 in UV-induced apoptosis

Pituitary tumor transforming gene (PTTG1) is widely detected in many tumors. Increasing evidence reveals that PTTG1 is associated with cell proliferation, cellular transformation and apoptosis. However, the functions of PTTG1, especially its role in DNA damage-induced apoptosis, remain largely unclear. In this report, we used UV irradiation to induce apoptosis in HeLa cells to examine the role of PTTG1 in UV-induced apoptosis by RNAi-mediated knockdown and overexpression of PTTG1. RNAi-mediated knockdown of PTTG1 expression increased and overexpression of PTTG1 decreased the UV-induced apoptosis. Furthermore, UV irradiation decreased PTTG1 mRNA and protein expression. These effects were found to be mediated by JNK pathway. Therefore, PTTG1 had an important anti-apoptotic role in UV-induced apoptosis and this role was mediated by JNK pathway. These results may provide important information for understanding the exact role and the regulation mechanism of PTTG1 in UV-induced apoptosis.     

Caveolin-1 Regulates Endothelial Adhesion of Lung Cancer Cells via Reactive Oxygen Species-Dependent Mechanism

The knowledge regarding the role of caveolin-1 (Cav-1) protein on endothelium adhesion of cancer cells is unclear. The present study revealed that Cav-1 plays a negative regulatory role on cancer-endothelium interaction. Endogenous Cav-1 was shown to down-regulate during cell detachment and the level of such a protein was conversely associated with tumor-endothelial adhesion. Furthermore, the ectopic overexpression of Cav-1 attenuated the ability of the cancer cells to adhere to endothelium while shRNA-mediated Cav-1 knock-down exhibited the opposite effect. We found that cell detachment increased cellular hydrogen peroxide and hydroxyl radical generation and such reactive oxygen species (ROS) were responsible for the increasing interaction between cancer cells and endothelial cells through vascular endothelial cell adhesion molecule-1 (VCAM-1). Importantly, Cav-1 was shown to suppress hydrogen peroxide and hydroxyl radical formation by sustaining the level of activated Akt which was critical for the role of Cav-1 in attenuating the cell adhesion. Together, the present study revealed the novel role of Cav-1 and underlying mechanism on tumor adhesion which explain and highlight an important role of Cav-1 on lung cancer cell metastasis.     

The ALK-1/Smad1 pathway in cardiovascular physiopathology. A new target for therapy?

Activin receptor-like kinase-1 or ALK-1 is a type I cell surface receptor for the transforming growth factor-β (TGF-β) family of proteins. The role of ALK-1 in endothelial cells biology and in angiogenesis has been thoroughly studied by many authors. However, it has been recently suggested a possible role of ALK-1 in cardiovascular homeostasis.ALK-1 is not only expressed in endothelial cells but also in smooth muscle cells, myofibroblast, hepatic stellate cells, chondrocytes, monocytes, myoblasts, macrophages or fibroblasts, but its role in these cells have not been deeply analyzed. Due to the function of ALK-1 in these cells, this receptor plays a role in several cardiovascular diseases. Animals with ALK-1 haploinsufficiency and patients with mutations in Acvrl1 (the gene that codifies for ALK-1) develop type-2 Hereditary Hemorrhagic Telangiectasia. Moreover, ALK-1 heterozygous mice develop pulmonary hypertension. Higher levels of ALK-1 have been observed in atherosclerotic plaques, suggesting a possible protector role of this receptor. ALK-1 deficiency is also related to the development of arteriovenous malformations (AVMs). Besides, due to the ability of ALK-1 to regulate cell proliferation and migration, and to modulate extracellular matrix (ECM) protein expression in several cell types, ALK-1 has been now demonstrated to play an important role in cardiovascular remodeling.In this review, we would like to offer a complete vision of the role of ALK-1 in many process related to cardiovascular homeostasis, and the involvement of this protein in the development of cardiovascular diseases, suggesting the possibility of using the ALK-1/smad-1 pathway as a powerful therapeutic target.     

Hydrogen peroxide inhibits non-small cell lung cancer cell anoikis through the inhibition of caveolin-1 degradation

Anoikis or detachment-induced apoptosis plays an essential role in the regulation of cancer cell metastasis. Caveolin-1 (Cav-1) is a key protein involved in tumor metastasis, but its role in anoikis and its regulation during cell detachment are unclear. We report here that Cav-1 plays a key role as a negative regulator of anoikis through a reactive oxygen species (ROS)-dependent mechanism in human lung carcinoma H460 cells. During cell detachment, Cav-1 is downregulated, whereas ROS generation is upregulated. Hydrogen peroxide and hydroxyl radical are two key ROS produced by cells during detachment. Treatment of the cells with hydrogen peroxide scavengers, catalase and N-acetylcysteine, promoted Cav-1 downregulation and anoikis during cell detachment, indicating that produced hydrogen peroxide plays a primary role in preventing anoikis by stabilizing Cav-1 protein. Catalase and N-acetylcysteine promoted ubiquitination and proteasomal degradation of Cav-1, which is a major pathway of its downregulation during cell anoikis. Furthermore, addition of hydrogen peroxide exogenously to the cells inhibited Cav-1 downregulation by preventing the formation of Cav-1-ubiquitin complex, supporting the inhibitory role of endogenous hydrogen peroxide in Cav-1 degradation during cell detachment. Together, these results indicate a novel role of hydrogen peroxide as an endogenous suppressor of cell anoikis through its stabilizing effect on Cav-1.     

Physiological and pathological functions of sphingolipids in pregnancy

Signaling by the bioactive sphingolipid, sphingosine 1–phosphate (S1P), and its precursors are emerging areas in pregnancy research. S1P and ceramide levels increase towards end of gestation, suggesting a physiological role in parturition. However, high levels of circulating S1P and ceramide are correlated with pregnancy disorders such as preeclampsia, gestational diabetes mellitus and intrauterine growth restriction. Expression of placental and decidual enzymes that metabolize S1P and S1P receptors are also dysregulated during pregnancy complications. In this review, we provide an in-depth examination of the signaling mechanism of S1P and ceramide in various reproductive tissues during gestation. These factors determine implantation and early pregnancy success by modulating corpus luteum function from progesterone production to luteolysis through to apoptosis. We also highlight the role of S1P through receptor signaling in inducing decidualization and angiogenesis in the decidua, as well as regulating extravillous trophoblast migration to anchor the placenta into the uterine wall. Recent advances on the role of the S1P:ceramide rheostat in controlling the fate of villous trophoblasts and the role of S1P as a negative regulator of trophoblast syncytialization to a multinucleated placental barrier are discussed. This review also explores the role of S1P in anti-inflammatory and pro-inflammatory signaling, its role as a vasoconstrictor, and the effects of S1P metabolizing enzymes and receptors in pregnancy.     

Regulation of AHI1 expression in adult rat brain: Implication in hypothalamic feeding control

Recent studies revealed that Abelson helper integration site 1 (AHI1) plays a role in brain development. However, little is known about the role of AHI1 in adult brain. To directly assess the role of AHI1 in the adult brain, we cloned full-length cDNA of rat AHI1 and observed prominent expression of AHI1 in the hypothalamus, which contributes mainly to the control of energy homeostasis. Furthermore, we demonstrated that food deprivation caused induction of AHI1 in the hypothalamus and subsequent re-feeding down-regulated AHI1 expression, suggesting the involvement of AHI1 in feeding control. Moreover, the expression of AHI1 was increased in serum-depleted Neuro2A cells and restored by subsequent insulin treatment. Furthermore, treatment in food-deprived rat with intraperitoneal glucose also reduced the increased AHI1 expression. These results demonstrate that AHI1 expression can be regulated through diet and suggest the novel role of AHI1 in feeding behavior.     

An important role for syndecan-1 in herpes simplex virus type-1 induced cell-to-cell fusion and virus spread

Herpes simplex virus type-1 (HSV-1) is a common human pathogen that relies heavily on cell-to-cell spread for establishing a lifelong latent infection. Molecular aspects of HSV-1 entry into host cells have been well studied; however, the molecular details of the spread of the virus from cell-to-cell remain poorly understood. In the past, the role of heparan sulfate proteoglycans (HSPG) during HSV-1 infection has focused solely on the role of HS chains as an attachment receptor for the virus, while the core protein has been assumed to perform a passive role of only carrying the HS chains. Likewise, very little is known about the involvement of any specific HSPGs in HSV-1 lifecycle. Here we demonstrate that a HSPG, syndecan-1, plays an important role in HSV-1 induced membrane fusion and cell-to-cell spread. Interestingly, the functions of syndecan-1 in fusion and spread are independent of the presence of HS on the core protein. Using a mutant CHO-K1 cell line that lacks all glycosaminoglycans (GAGs) on its surface (CHO-745) we demonstrate that the core protein of syndecan-1 possesses the ability to modulate membrane fusion and viral spread. Altogether, we identify a new role for syndecan-1 in HSV-1 pathogenesis and demonstrate HS-independent functions of its core protein in viral spread.     

NAD(P)H:quinone oxidoreductase 1 protects lungs from oxidant-induced emphysema in mice

Emphysema is currently a leading cause of mortality with no known effective therapy to attenuate progressive loss of lung function. Previous work supports that activation of nuclear factor erythroid 2-related factor 2 (Nrf2) is protective to the lung through induction of hundreds of antioxidant genes. In models of lung injury, the expression of NAD(P)H:quinone oxidoreductase 1 (NQO1) is upregulated in a manner dependent on Nrf2 and human emphysema is associated with reduced levels of NQO1. However, the functional role of NQO1 in emphysema remains unknown. In this study, we demonstrate the protective role of NQO1 in the development of emphysema using mouse models. NQO1-deficient animals demonstrated premature age-related emphysema and were more susceptible to both elastase and inhaled lipopolysaccharide models of emphysema. The absence of NQO1 was associated with enhanced markers of oxidant stress. Treatment of NQO1-deficient animals with the antioxidant N-acetylcysteine reversed the NQO1-dependent emphysematous changes. In vitro studies utilizing either inhibition or induction of NQO1 demonstrated a potent antioxidant role of NQO1 in macrophages, suggesting a role for macrophage-derived oxidants in the pathogenesis of emphysema. These novel findings support a functional role for NQO1 in protecting the lung from development of emphysema.     

Protein Tyrosine Phosphatase 1B in Hematopoiesis

Protein tyrosine phosphatase 1B (PTP-1B) is a ubiquitously expressed cytosolicphosphatase best known for its role in insulin signaling. Despite the fact that it is highlyexpressed in hematopoietic tissues and has been shown to downregulate cytokinereceptor signaling, no physiological role for PTP-1B in immune regulation had beenreported. Our recent results show that the absence of PTP-1B affects murinemyelopoiesis through increased phosphorylation of the CSF-1 receptor tyrosine kinase.Here we further discuss the role of PTP-1B in monocyte/macrophage differentiation aswell as the implications of our findings in the context of PTP-1B inhibitors.     

Significant role of IL-1 signaling, but limited role of inflammasome activation, in oviduct pathology during Chlamydia muridarum genital infection

IL-1β has been implicated in the development of oviduct pathology during Chlamydia muridarum genital infection in the mouse model. The goal of this study was to characterize the role of IL-1 signaling and the inflammasome-activation pathways during genital chlamydial infection. Compared with control mice, IL-1R-deficient mice displayed delayed clearance and increased chlamydial colonization. Consistent with the role for IL-1 signaling in infection clearance, mice deficient for the IL-1R antagonist cleared infection at a faster rate. Despite increased infection, IL-1R-deficient mice had significantly reduced oviduct pathology, which was associated with decreased numbers of neutrophils, but more macrophages, in the genital tract. IL-1β secretion is dependent on caspase-1 and apoptosis-associated speck-like protein containing caspase recruitment domain (ASC) inflammasome during in vitro infection of primed macrophages with C. muridarum. To investigate the role of inflammasome components during in vivo genital infection, mice lacking NLRP3, NLRC4, and ASC were tested and found to display no reduction in oviduct pathology compared with control mice. Mice deficient for ASC displayed a prolonged course of infection, which was associated with reduced T cell recruitment and proliferation. Further, ASC-deficient mice displayed normal levels of IL-1β in genital secretions. However, a significant decrease in caspase-1-dependent IL-18 was observed in both ASC- and NLRP3-deficient mice. These data demonstrate a major role for IL-1 signaling, but a limited role for the inflammasome pathway, in IL-1β secretion and development of oviduct pathology during genital chlamydial infection. The data also suggest an IL-1-independent role for ASC in adaptive immunity during genital chlamydial infection.     

Role of α-Factor and the Mfα1 α-Factor Precursor in Mating in Yeast

The peptide pheromones secreted by a and α cells (called a-factor and α-factor, respectively) are each encoded by two structural genes. For strains of either mating type, addition of exogenous pheromone does not alleviate the mating defect of mutants with disruptions of both structural genes. In addition, a particular insertion mutation in the major α-factor structural gene (MFα1) that should result in an altered product inhibits α mating. These results suggested that the pheromone precursors (the MFα1 pro region in particular) might play a second role in mating separate from the role of pheromone production. To analyze the role of α-factor and the MFα1 precursor in α mating, we have constructed two classes of mutants. The mating defects of mutants that should produce the MFα1 pro region peptide but no α-factor could not be alleviated by addition of exogenous α-factor in crosses to a wild-type a strain, indicating that the previous results were not due to an inability of the disruption mutants to produce the pro region peptide. Mutants able to produce α-factor, but with a variety of alterations in MFα1 precursor structure, mated at levels proportional to the levels of α-factor produced, suggesting that the only role of the α-factor precursor in mating is to produce α-factor. Both of these results argue against a role for the MFα1 pro region separate from its role in α-factor production. We also describe results that show that in vivo production of α-factor'' (the form of α-factor encoded by one of the two α-factor repeats of MFα2) is equivalent to the major form of α-factor for induction of all responses necessary for mating. We discuss the implications of these results on the role of the pheromones in mating.     

ALK1 heterozygosity increases extracellular matrix protein expression,proliferation and migration in fibroblasts

Fibrosis is a pathological situation in which excessive amounts of extracellular matrix (ECM) are deposited in the tissue. Myofibroblasts play a crucial role in the development and progress of fibrosis as they actively synthesize ECM components such as collagen I, fibronectin and connective tissue growth factor (CTGF) and cause organ fibrosis. Transforming growth factor beta 1 (TGF-β1) plays a major role in tissue fibrosis. Activin receptor-like kinase 1 (ALK1) is a type I receptor of TGF-β1 with an important role in angiogenesis whose function in cellular biology and TGF-β signaling is well known in endothelial cells, but its role in fibroblast biology and its contribution to fibrosis is poorly studied. We have recently demonstrated that ALK1 regulates ECM protein expression in a mouse model of obstructive nephropathy. Our aim was to evaluate the role of ALK1 in several processes involved in fibrosis such as ECM protein expression, proliferation and migration in ALK1^+/+ and ALK1^+/− mouse embryonic fibroblasts (MEFs) after TGF-β1 stimulations and inhibitors. ALK1 heterozygous MEFs show increased expression of ECM proteins (collagen I, fibronectin and CTGF/CCN2), cell proliferation and migration due to an alteration of TGF-β/Smad signaling. ALK1 heterozygous disruption shows an increase of Smad2 and Smad3 phosphorylation that explains the increases in CTGF/CCN2, fibronectin and collagen I, proliferation and cell motility observed in these cells. Therefore, we suggest that ALK1 plays an important role in the regulation of ECM protein expression, proliferation and migration.     

Sirtuin 1 alleviates neuroinflammation-induced apoptosis after traumatic brain injury

Sirtuin 1 (SIRT1) plays a very important role in a wide range of biological responses, such as metabolism, inflammation and cell apoptosis. Changes in the levels of SIRT1 have been detected in the brain after traumatic brain injury (TBI). Further, SIRT1 has shown a neuroprotective effect in some models of neuronal death; however, its role and working mechanisms are not well understood in the model of TBI. This study aimed to address this issue. SIRT1-specific inhibitor (sirtinol) and activator (A3) were introduced to explore the role of SIRT1 in cell apoptosis. Results of the study suggest that SIRT1 plays an important role in neuronal apoptosis after TBI by inhibiting NF-κB, IL-6 and TNF-α deacetylation and the apoptotic pathway sequentially, possibly by alleviating neuroinflammation.     

Utilization of antisense oligonucleotides to study the role of 5-cytosine DNA methyltransferase in cellular transformation and oncogenesis

A large body of data point toward 5-cytosine DNA methyltransferase 1 (DNMT1) as a critical component of oncogenic programs. The study of the role of DNMT1 in cancer has been hindered by the lack of specific inhibitors. A different approach to study the role of DNMT1 in cancer is to use sequence-specific antisense oligonucleotides against DNMT1 mRNA. This paper discusses methods used to identify sequence-specific antisense oligonucleotides and to assess their DNA methylation inhibitory properties. Antisense oligonucleotides are applied to determine whether DNMT1 plays a causal role in specific cancer models ex vivo as well as in vivo.     

p73: a Positive or Negative Regulator of Angiogenesis,or Both?

The role of p73, the homologue of the tumor suppressor p53, in regulating angiogenesis has recently been extensively investigated, resulting in the publication of five articles. Of these, two studies suggested a suppressive role, while the others implied a stimulatory role for the p73 isoforms in regulating angiogenesis. A negative role for TAp73, the full-length form that is often associated with tumor suppression, in blood vessel formation, is consistent with its general attributes and was proposed to be effected indirectly through the degradation of hypoxia-inducible factor 1α (HIF1-α), the master angiogenic regulator. In contrast, a positive role for TAp73 coincides with its recently understood role in supporting cellular survival and thus tumorigenesis, consistent with TAp73 being not-mutated but rather often overexpressed in clinical contexts. In the latter case, TAp73 expression was induced by hypoxia via HIF1-α, and it appears to directly promote angiogenic target gene activation and blood vessel formation independent of HIF1-α. This mini review will provide an overview of these seemingly opposite recent findings as well as earlier data, which collectively establish the definite possibility that TAp73 is indeed capable of both promoting and inhibiting angiogenesis, depending on the cellular context.     

RhoH plays distinct roles in T-cell migrations induced by different doses of SDF1α

Hematopoietic-specific RhoGTPase RhoH displays an important role in regulating T-cell development, a process that is accompanied by ordered and directed migration of progenitors through thymus. While RhoGTPases are key regulators of cytokinesis, the precise role of RhoH in T-cell migration is unknown. Here, by using Jurkat cell migration as a model, we found that RhoH is required for cell migration in response to the high concentration of SDF1α but displays inhibitory roles in regulating migration in the absence of SDF1α or in the range of low concentrations. We further found that RhoH-mediated migration requires PAK1 but not ITK. Indeed, both the low and high concentrations of SDF1α activate PAK1 but only the high concentration-induced activation of PAK1 requires RhoH. Further study of the RhoH–PAK interaction revealed that RhoH is able to bind and activate PAK1, indicating that RhoH plays a positive role in response to the high concentration of SDF1α. In contrast, at rest, RhoH indirectly inhibits Slp76/ITK activity through its modulation on TCR signaling, supporting a negative regulatory role for RhoH when SDF1α is insufficient to activate the RhoH–PAK1 pathway. Together, our study uncovered a dual role for RhoH in SDF1α signaling in T-cell responses.