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1.
Hepatology ; 65(4): 1369-1383, 2017 04.
Article in English | MEDLINE | ID: mdl-27981605

ABSTRACT

Autotaxin (ATX) is a secreted lysophospholipase D that catalyzes the production of lysophosphatidic acid (LPA), a pleiotropic growth-factor-like lysophospholipid. Increased ATX expression has been detected in various chronic inflammatory disorders and different types of cancer; however, little is known about its role and mode of action in liver fibrosis and cancer. Here, increased ATX expression was detected in chronic liver disease (CLD) patients of different etiologies, associated with shorter overall survival. In mice, different hepatotoxic stimuli linked with the development of different forms of CLDs were shown to stimulate hepatocyte ATX expression, leading to increased LPA levels, activation of hepatic stellate cells (HSCs), and amplification of profibrotic signals. Hepatocyte-specific, conditional genetic deletion and/or transgenic overexpression of ATX established a liver profibrotic role for ATX/LPA, whereas pharmacological ATX inhibition studies suggested ATX as a possible therapeutic target in CLDs. In addition, hepatocyte ATX ablation and the consequent deregulation of lipid homeostasis was also shown to attenuate hepatocellular carcinoma (HCC) development, thus implicating ATX/LPA in the causative link of cirrhosis and HCC. CONCLUSION: ATX is a novel player in the pathogenesis of liver fibrosis and cancer and a promising therapeutic target. (Hepatology 2017;65:1369-1383).


Subject(s)
Benzoxazoles/pharmacology , Carcinoma, Hepatocellular/pathology , Liver Cirrhosis/pathology , Liver Neoplasms/pathology , Phosphoric Diester Hydrolases/genetics , Piperazines/pharmacology , Animals , Biopsy, Needle , Carcinoma, Hepatocellular/genetics , Case-Control Studies , Cells, Cultured , Chronic Disease , Disease Models, Animal , Disease Progression , Gene Deletion , Hepatocytes/cytology , Hepatocytes/metabolism , Humans , Immunohistochemistry , Liver Cirrhosis/genetics , Liver Neoplasms/genetics , Mice , Mice, Inbred C57BL , Molecular Targeted Therapy , Phosphoric Diester Hydrolases/drug effects
2.
Oncoimmunology ; 4(9): e1002721, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26405589

ABSTRACT

IL-15 regulates the development, survival, and proliferation of multiple innate and adaptive immune cells and plays a dual role, inducing both tumor cell growth and antitumor immunity. However, the role of IL-15 in inflammation-induced cancer remains unclear. To explore this, we have compared the colon carcinoma burden of Il15-/- and Il15rα -/- mice with wild type (WT) mice after induction of colitis-associated colon carcinogenesis utilizing the AOM/DSS model. Compared to WT mice, Il15-/- but not Il15rα -/- mice showed reduced survival, along with higher tumor incidence, colon weight, and tumor size. This suggests that low affinity IL-15 signaling via the shared IL-2Rß/γc decreases the risk for developing colitis-associated cancer. CD11c-Il15 mice, in which IL-15 expression is reconstituted in Il15-/- mice under the control of the CD11c-promoter, showed that selective reconstitution of IL-15 in antigen-presenting cells restored the CD8+ T and NK cell compartments, serum levels of IFNγ, G-CSF, IL-10, and CXCL1 and reduced tumor burden. After demonstrating IL-15 expression in human colorectal cancer (CRC) cells in situ, we investigated the role of this cytokine in the modulation of key colonic oncogenic pathways in the tumor. While these pathways were found to be unaltered in the absence of IL-15, tumor transcriptome analysis showed that the loss of IL-15 upregulates key inflammatory mediators associated with colon cancer progression, such as IL-1ß, IL-22, IL-23, Cxcl5, and Spp1. These findings provide evidence that IL-15 suppresses colitis-associated colon carcinogenesis through regulation of antitumor cytotoxicity, and modulation of the inflammatory tumor micromilieu.

3.
J Clin Exp Dent ; 7(1): e180-2, 2015 Feb.
Article in English | MEDLINE | ID: mdl-25810835

ABSTRACT

Oral non-Hodgkin's lymphomas (O-NHLs) are a rare group of diverse lymphoid tissue malignancies and represent less than 5% of the oral cavity malignancies and 2% of all extra-nodal NHLs. Oral-NHLs affect the Waldeyer's-ring, the salivary glands, the bone of the jaws and the oral mucosa, their clinical appearance is very heterogeneous. Among the risk factors for NHLs are immunosuppression (primary or secondary), autoimmunity and inflammation. O-NHLs share the same risk factors. This case report describes a patient with O-NHL which was possibly linked to the combination of methotrexate and etanercept for the treatment of her rheumatoid arthritis. To our knowledge this is probably among the first cases of O-NHL with possible relation to the use of a Tumor Necrosis Factor (TNF) antagonist biological agent (etanercept). This case could contribute to the sensitization of the dentists for the signs and symptoms of this rare malignancy. It also underlines the need for thorough medical history and medication recording for all the dental patients. Key words:Lymphoma (oral) methotrexate, etanercept.

4.
Nat Cell Biol ; 15(8): 967-77, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23851489

ABSTRACT

The DNA damage response (DDR) pathway and ARF function as barriers to cancer development. Although commonly regarded as operating independently of each other, some studies proposed that ARF is positively regulated by the DDR. Contrary to either scenario, we found that in human oncogene-transformed and cancer cells, ATM suppressed ARF protein levels and activity in a transcription-independent manner. Mechanistically, ATM activated protein phosphatase 1, which antagonized Nek2-dependent phosphorylation of nucleophosmin (NPM), thereby liberating ARF from NPM and rendering it susceptible to degradation by the ULF E3-ubiquitin ligase. In human clinical samples, loss of ATM expression correlated with increased ARF levels and in xenograft and tissue culture models, inhibition of ATM stimulated the tumour-suppressive effects of ARF. These results provide insights into the functional interplay between the DDR and ARF anti-cancer barriers, with implications for tumorigenesis and treatment of advanced tumours.


Subject(s)
ADP-Ribosylation Factor 1/metabolism , Cell Cycle Proteins/metabolism , DNA-Binding Proteins/metabolism , Neoplasms/physiopathology , Protein Serine-Threonine Kinases/metabolism , Tumor Suppressor Protein p14ARF/metabolism , ADP-Ribosylation Factor 1/genetics , Animals , Ataxia Telangiectasia Mutated Proteins , Carrier Proteins/metabolism , Cell Cycle/physiology , Cell Cycle Proteins/genetics , Cell Line , Cell Line, Tumor , DNA-Binding Proteins/genetics , Gene Expression Regulation, Neoplastic , HeLa Cells , Humans , Male , Mice , NIMA-Related Kinases , Neoplasms/enzymology , Neoplasms/pathology , Phosphorylation , Protein Serine-Threonine Kinases/genetics , Protein Stability , Ribosomes/metabolism , Signal Transduction , Transplantation, Heterologous , Tumor Suppressor Protein p14ARF/genetics , Ubiquitin-Protein Ligases/metabolism
5.
Exp Dermatol ; 20(9): 725-31, 2011 Sep.
Article in English | MEDLINE | ID: mdl-21672030

ABSTRACT

TNF is critically involved in the pathogenesis of psoriasis. TL1A is a TNF-like cytokine, which, after binding to death domain receptor DR3, provides costimulatory signals to lymphocytes, amplifies Th1- and Th17-mediated immune responses and induces apoptotic cell death. These functions are inhibited when TL1A associates to decoy receptor DcR3. In the present study, we investigated the expression profiles for TL1A, DR3 and DcR3 in the normal skin and in psoriatic skin lesions. By use of immunohistochemistry, we were able to demonstrate constitutive cutaneous expression of DR3 and DcR3 but not of TL1A in healthy skin. On the other hand, in patients with active psoriasis, we observed abundant immunostaining for TL1A and significant upregulation of its receptors (P < 0.05 in comparison to healthy skin). TL1A, DR3 and DcR3 proteins, as well as mRNA transcripts reflecting in situ production of TL1A and DcR3, were also specifically increased in lesional as compared to non-lesional skin from patients with psoriasis (P < 0.05). These proteins were upregulated in cell populations that are critically involved in the pathogenesis of chronic skin inflammation, such as keratinocytes, macrophages in deep dermis and cells at the perivascular/endothelial area. Finally, we provide evidence for the existence of nuclear localization of TL1A in inflammatory cells from psoriatic lesions. This was also observed in inflamed synovia from patients with rheumatoid arthritis, but not in neoplastic TL1A-expressing cell lines. We conclude that interactions between TL1A and its two receptors may be involved in the pathogenesis of chronic skin inflammation that takes place in psoriasis.


Subject(s)
Psoriasis/genetics , Psoriasis/metabolism , Receptors, Tumor Necrosis Factor, Member 25/genetics , Receptors, Tumor Necrosis Factor, Member 25/metabolism , Receptors, Tumor Necrosis Factor, Member 6b/genetics , Receptors, Tumor Necrosis Factor, Member 6b/metabolism , Tumor Necrosis Factor Ligand Superfamily Member 15/genetics , Tumor Necrosis Factor Ligand Superfamily Member 15/metabolism , Adult , Aged , Cell Nucleus/metabolism , Female , Gene Expression Profiling , Humans , Immunohistochemistry , Male , Middle Aged , Psoriasis/pathology , RNA, Messenger/genetics , RNA, Messenger/metabolism , Skin/metabolism , Skin/pathology , Up-Regulation
6.
Ultrastruct Pathol ; 35(2): 60-5, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21299345

ABSTRACT

Ischemia-reperfusion injury can be detrimental to the solitary kidney, especially when it is accompanied by ablation. To the authors' knowledge, the effects of partial nephrectomy with prolonged application of ischemia have never been described at the ultrastructural level. Therefore, the authors used an animal model and focused on putative structural effects in the glomerular basement membrane and the podocytes. They demonstrate the advantageous role of cold ischemia, even in up to 120 min. In contrast, more than 60 min of warm ischemia leads to catastrophic lesions in all the cellular structures, as is reflected by mortality due to acute renal failure.


Subject(s)
Acute Kidney Injury/pathology , Cold Ischemia , Kidney/ultrastructure , Nephrectomy , Reperfusion Injury/pathology , Warm Ischemia , Acute Kidney Injury/etiology , Acute Kidney Injury/prevention & control , Animals , Glomerular Basement Membrane/ultrastructure , Kidney/surgery , Microscopy, Electron, Transmission , Nephrectomy/adverse effects , Podocytes/ultrastructure , Rabbits , Reperfusion Injury/etiology , Reperfusion Injury/prevention & control , Time Factors , Warm Ischemia/adverse effects
8.
Int J Cancer ; 119(11): 2546-56, 2006 Dec 01.
Article in English | MEDLINE | ID: mdl-16988944

ABSTRACT

Knowing the status of molecules involved in cell cycle control in cancer is vital for therapeutic approaches aiming at their restoration. The p27(KIP1) and p57(KIP2) cyclin-dependent kinase inhibitors are nodal factors controlling normal cell cycle. Their expression in normal lung raises the question whether they have a mutual exclusive or redundant role in nonsmall cell lung cancer (NSCLC). A comparative comprehensive analysis was performed in a series of 70 NSCLCs. The majority of cases showed significantly reduced expression of both members compared to normal counterparts. Low KIP protein levels correlated with increased proliferation, which seems to be histological subtype preponderant. At mechanistic level, degradation by SKP2 was demonstrated, in vivo and in vitro, by siRNA-methodology, to be the most important downregulating mechanism of both KIPs in NSCLC. Decreased p57(KIP) (2)-transcription complements the above procedure in lowering p57(KIP2)-protein levels. Methylation was the main cause of decreased p57(KIP) (2)-mRNA levels. Allelic loss and imprinting from LIT1 mRNA contribute also to decreased p57(KIP2) transcription. In vitro recapitulation of the in vivo findings, in A549 lung cells (INK4A-B((-/-))), suggested that inhibition of the SKP2-degradation mechanism restores p27(KIP1) and p57(KIP2) expression. Double siRNA treatments demonstrated that each KIP is independently capable of restraining cell growth. An additional demethylation step is required for complete reconstitution of p57(KIP2) expression in NSCLC.


Subject(s)
Carcinoma, Non-Small-Cell Lung/genetics , Cyclin-Dependent Kinase Inhibitor p27/genetics , Cyclin-Dependent Kinase Inhibitor p57/genetics , DNA Methylation , Down-Regulation , Lung Neoplasms/genetics , S-Phase Kinase-Associated Proteins/physiology , Base Sequence , DNA Primers , Humans , Loss of Heterozygosity , Reverse Transcriptase Polymerase Chain Reaction
9.
Hum Pathol ; 33(8): 812-8, 2002 Aug.
Article in English | MEDLINE | ID: mdl-12203214

ABSTRACT

Induction of angiogenesis is essential for carcinogenesis and facilitates the processes of tumor development and metastasis. Vascular endothelial growth factor (VEGF) is an important angiogenic regulator under physiologic and pathologic conditions. To elucidate the role of angiogenesis in malignant growth, we evaluated angiogenesis and VEGF expression in a panel of 68 non-small-cell lung carcinomas (NSCLCs) and examined their relation with the kinetic parameters, ploidy, and p53 protein status, which have been analyzed previously. Angiogenesis was estimated as microvascular density (MVD) of the tumor area by CD31 immunodetection. Expression of VEGF was also immunohistochemically evaluated. All possible associations were assessed through a series of statistical methods. The mean MVD value was 39 microvessels/mm(2), and high VEGF immunoreactivity was observed in all specimens, with a mean percentage of positive cells of 73%. The relation between MVD and VEGF expression was not statistically significant (P = 0.065). No association was observed between MVD or VEGF levels with the proliferation index, apoptotic index, tumor ploidy status, p53 expression, and overall survival. We conclude that in a subset of NSCLCs, angiogenesis may be associated with VEGF, but other factors also participate in this process. Angiogenesis and growth (proliferation and apoptosis) are independent and probably differentially operated procedures, with only growth partially controlled by p53 protein expression.


Subject(s)
Carcinoma, Non-Small-Cell Lung/blood supply , Carcinoma, Non-Small-Cell Lung/pathology , Cell Division , Lung Neoplasms/blood supply , Lung Neoplasms/pathology , Microcirculation/pathology , Carcinoma, Non-Small-Cell Lung/mortality , Endothelial Growth Factors/analysis , Humans , Lung Neoplasms/mortality , Lymphokines/analysis , Neovascularization, Pathologic , Platelet Endothelial Cell Adhesion Molecule-1/analysis , Ploidies , Survival Rate , Tumor Suppressor Protein p53/analysis , Vascular Endothelial Growth Factor A , Vascular Endothelial Growth Factors
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