79 results on '"Musso O"'
Search Results
2. Blocking Wnt signaling by SFRP-like molecules inhibits in vivo cell proliferation and tumor growth in cells carrying active β-catenin
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Lavergne, E, Hendaoui, I, Coulouarn, C, Ribault, C, Leseur, J, Eliat, P-A, Mebarki, S, Corlu, A, Clément, B, and Musso, O
- Published
- 2011
- Full Text
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3. Addenda und Corrigenda zu Bd. 62 (1986) S. 45
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Musso, O.
- Published
- 1986
4. Evoluzione tecnica dei sistemi d’impianto nella peschicoltura degli ambienti a clima tipicamente mediterraneo
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Caruso T., DeJong T., Di Miceli C., Guarino F., Musso O., Reginato G. H., DI VAIO, CLAUDIO, Di Vaio C., Damiano C., Fideghelli C., Caruso, T., Dejong, T., Di Miceli, C., DI VAIO, Claudio, Guarino, F., Musso, O., and Reginato, G. H.
- Subjects
Sistemi d'impianto ,Pesco - Published
- 2009
5. Evoluzione tecnica dei sistemi d'impianto nella peschicoltura degli ambienti a clima tipicamente mediterraneo
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CARUSO, Tiziano, DI MICELI, Claudia, MARRA, Francesco Paolo, DeJong, T, Di Vaio, C, Guarino, F, Musso, O, Reginato, GH, Caruso, T, DeJong, T, Di Miceli, C, Di Vaio, C, Guarino, F, Marra, FP, Musso, O, and Reginato, GH
- Subjects
Settore AGR/03 - Arboricoltura Generale E Coltivazioni Arboree ,pesco, sistemi d'impianto, forma di allevamento, controllo della crescita vegetativa, gestione della chioma, efficienza del lavoro manuale - Abstract
In peach industry, due to the increasing cost of the land, energy and salaries, in the last thirty years have been developed horticultural strategies to increase the productivity of the orchards and to reduce the employment of hand workers. In areas in which large part of the days are brilliant, clean sky, with high levels of light intensity, and relative humidity is low, as those with a Mediterranean climate, to reach the above mentioned goal have been developed planting systems based on high tree densities and new tree shapes. In Southern Italy, technicians have been particularly active in performing new tree canopy architectures and growers showed to be very sensitive to these innovations as evidenced from the replacement of the traditional open vase with “inclined double walls” systems Y, V and Tatura trellis. These new planting systems, respect to those based on the “open vase“ allowed to obtain higher yield together with a larger amount of top quality fruits and this as consequence of the increased amount of light intercepted and more uniformly distributed within the tree. In this last decade, the increasing costs of the trellis components (iron wires and poles) to build up the trellis and the costs of the trees, due to the royalties protecting the new released cultivars, became the major limits of this super-intensive planting systems. For this reasons, despite the high efficiency of the workers in practicing the manual techniques (fruit thinning, harvest and pruning) the “inclined double walls” started to be abandoned and technicians and growers start to move to the catalan vase. This new system has been develop recently in Spain, being a new tree shape, a dwarfed vase named catalano, that complies relative high density with low cost for orchard planting and management. This training system, to control vegetative excessive growth , is based on several treatments of topping, some of them, particularly during the summer season, are performed mechanically. Preliminary observations carried out in Sibari, seem to confirm that the vasetto catalano - even managed without treatments with paclobutrazol, a growth retardant, as used in Spain, - could represent a valid planting system to produce both fruit for the fresh and for the processed (fresh cut, sliced fruits) fruits market. In greenhouse production, where precocious and high yield are the required conditions to have early return, planting systems have to be based on tree shapes that fit with high densities, as Y and V, currently the only one able to provide fruit of optimal quality for out-of-season peaches market. In California, although a certain agronomic success has been obtained by the KAC V, the “inclined double wall “systems were unsuccessful. Other shapes as “Quad V” and “Hex-V” , that are a sort of compromise between the perpendicular “V” system and the traditional open vase, have been developed in order to address some of the vigor issue inherent in the two scaffold perpendicular system as well as to reduce planting densities and orchard establishment cost. Scientist and field technicians are still searching for the molecule for fruit thinning and to build up the right machine for harvesting trees trained to open vase. Unfortunately, so far, only summer pruning mechanization has been developed. In Chile most of the information necessary to develop the important advances of fruit industry occurred in the last 25 years have been introduced or adapted from abroad. Peach orchards have been steadily intensified, predominantly using denser orchards with refined form of the open vase system, with the perpendicular V or three arm trees currently being the most common system. Generally, tree size reduction has been one of the main objective of breeders by searching for compact and brachitic vegetative habitus and for dwarfing rootstocks but no satisfactory genotypes has been selected yet and this last still remain a potential tool for high density planting systems. The researches on the use of chemical agents able to control vegetative growth were abandoned in many Countries because the environmentalist movements hardly contrasted such kind of solution. However, rational irrigation, mineral nutrition and soil management (controlled water stress, fertirrigation according to phenologic tree phase and real absorption, cover crops) could contribute to improve planting systems, controlling the vigor trees in orchard.
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- 2009
6. THE GYPSUM: FROM ECONOMIC RESOURCE TO CULTURAL AND GEOLOGICAL HERITAGE OF THE MONFERRATO
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Bonetto, SABRINA MARIA RITA, DELA PIERRE, Francesco, Lozar, Francesca, Marengo, A., Masciocco, Luciano, Musso, O., Natalicchio, Marcello, and Ponzi, M.
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- 2014
7. Evoluzione tecnica dei modelli d’impianto nella peschicoltura degli ambienti mediterranei
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Caruso T., DeJong T., Di Miceli C., Guarino F., Marra F. P., Musso O., Reginato G. H., DI VAIO, CLAUDIO, Caruso, T., Dejong, T., Di Miceli, C., DI VAIO, Claudio, Guarino, F., Marra, F. P., Musso, O., and Reginato, G. H.
- Published
- 2008
8. Evoluzione tecnica dei modelli di impianto nella peschicoltura degli ambienti mediterranei
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CARUSO, Tiziano, DI MICELI, Claudia, MARRA, Francesco Paolo, DEJONG T, DI VAIO C, GUARINO F, MUSSO O, REGINATO GH, CARUSO T, DEJONG T, DI MICELI C, DI VAIO C, GUARINO F, MARRA FP, MUSSO O, and REGINATO GH
- Abstract
Una costante attenzione verso l’ottimizzazione dei fattori della produzione ha determinato una rapida adozione delle innovazioni proposte dalla ricerca nel campo dei sistemi d’impianto, per la grande importanza che essi rivestono nella qualità delle produzioni e nella redditività della coltura. Riduzione dei costi di produzione e massima efficienza della manodopera gli obiettivi prioritari, talora ottenuti attraverso l''“estensivizzazione” colturale, con bassi costi d’investimento. Un confronto fra l’Italia meridionale, California e Cile.
- Published
- 2008
9. The “Fibrous Nest”: A Biotope including WNT Signals, Extracellular Matrix Remodeling and Stemness in Hepatocellular Carcinoma
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Désert, R., primary, Mebarki, S., additional, Desille, M., additional, Sicard, M., additional, Lavergne, E., additional, Renaud, S., additional, Bergeat, D., additional, Sulpice, L., additional, Perret, C., additional, Turlin, B., additional, Clément, B., additional, and Musso, O., additional
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- 2016
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10. FRI-084 - The “Fibrous Nest”: A Biotope including WNT Signals, Extracellular Matrix Remodeling and Stemness in Hepatocellular Carcinoma
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Désert, R., Mebarki, S., Desille, M., Sicard, M., Lavergne, E., Renaud, S., Bergeat, D., Sulpice, L., Perret, C., Turlin, B., Clément, B., and Musso, O.
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- 2016
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11. La coltura protetta del pesco
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DE SALVADOR, F. R., SCARASCIA MUGNOZZA, Giacomo, and Musso, O.
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- 1998
12. Blocking Wnt signaling by SFRP-like molecules inhibits in vivo cell proliferation and tumor growth in cells carrying active β-catenin
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Lavergne, E, primary, Hendaoui, I, additional, Coulouarn, C, additional, Ribault, C, additional, Leseur, J, additional, Eliat, P-A, additional, Mebarki, S, additional, Corlu, A, additional, Clément, B, additional, and Musso, O, additional
- Published
- 2010
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13. [75] SFRP1 AND SFRP5, TWO NEWLY IDENTIFIED TUMOR SUPPRESSORS IN HUMAN HEPATOCELLULAR CARCINOMA?
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Lavergne, E., primary, Quelard, D., additional, Hendaoui, I., additional, Clement, B., additional, and Musso, O., additional
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- 2007
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14. [288] THE LIVER-SPECIFIC PROMOTER OF COLLAGEN XVIII IS A FUNCTIONAL TARGET OF THE C/EBPB TRANSCRIPTION FACTOR IN HUMAN LIVER
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Armelin-Correa, L., primary, Fautrel, A., additional, Lavergne, E., additional, Quelard, D., additional, Bonnier, D., additional, Theret, N., additional, Turlin, B., additional, Passos Bueno, M.R., additional, Clement, B., additional, and Musso, O., additional
- Published
- 2007
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15. CA 6-Le module frizzled du COL18A1 induit la mort de cellules tumorales via l’inhibition de la voie de signalisation WNT-B-caténine
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Quélard, D., primary, Lavergne, E., additional, Hendaoui, I., additional, Elamaa, H., additional, Robert, E., additional, Turlin, B., additional, Boudjema, K., additional, Campion, J.P., additional, Pihlajaniemi, T., additional, Clément, B., additional, and Musso, O., additional
- Published
- 2006
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16. CA 7-Induction du gène suppresseur de tumeur ménine dans le carcinome hépatocellulaire et son rôle dans la fibrogenèse
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Zindy, P.J., primary, Helgoualc’h, A.L., additional, Bonnier, D., additional, Le Béchec, A., additional, Bourd-Boitin, K., additional, Zhang, C.X., additional, Musso, O., additional, Glaise, D., additional, Troadec, M.B., additional, Loréal, O., additional, Turlin, B., additional, léger, J., additional, Clément, B., additional, and Théret, N., additional
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- 2006
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17. CA4 - La surexpression de sFRPs diminue la stabilisation de la ɛ-caténine dans la lignée de cellules d’hépatome humain HEPG2
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Quélard, D., primary, Robert, E., additional, Clément, B., additional, and Musso, O., additional
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- 2005
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18. Tumor hepatocytes and basement membrane–Producing cells specifically express two different forms of the endostatin precursor, collagen XVIII, in human liver cancers
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Musso, O, primary
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- 2001
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19. COMPARATIVE EVALUATION OF PEACH AND NECTARINE CULTIVARS TRAINED TO PERMANENT CANOPY IN PROTECTED CULTURE IN SICILY
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Bellini, E., primary, Falqui, D., additional, and Musso, O., additional
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- 1998
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20. COMPARISON BETWEEN TWO TRAINING SYSTEMS IN PEACH PROTECTED CULTURE IN SICILY
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Bellini, E., primary, Falqui, D., additional, and Musso, O., additional
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- 1998
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21. PROTECTED PEACH CULTURE IN SICILY. SIX YEARS OF RESEARCH ON TRAINING SYSTEMS AND PRUNING METHODS.
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Bellini, E., primary, Falqui, D., additional, and Musso, O., additional
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- 1992
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22. Poetae novi Antonius Traglia
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Musso, O.
- Published
- 1965
23. The Satyricon Petronius William Arrowsmith
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Musso, O.
- Published
- 1965
24. In situ detection of human cytomegalovirus DNA in gastrointestinal biopsies from AIDS patients by means of various PCR-derived methods
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Musso, O., Sommer, P., Drouet, E., Cotte, L., Neyra, M., Grimaud, J.-A., and Chevallier, M.
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- 1996
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25. In situ detection of matrix metalloproteinase-2 (MMP2) and the metalloproteinase inhibitor TIMP2 transcripts in human primary hepatocellular carcinoma and in liver metastasis
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Musso, O., Theret, N., Campion, J. P., Turlin, B., Milani, S., Grappone, C., and Clement, B.
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- 1997
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26. Tumor progression is associated with a significant decrease in the expression of the endostatin precursor collagen XVIII in human hepatocellular carcinomas
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Musso, O., Rehn, M., nathalie theret, Turlin, B., Bioulac-Sage, P., Lotrian, D., Campion, Jp, Pihlajaniemi, T., and Clement, B.
- Subjects
Male ,Alternative Splicing ,Carcinoma, Hepatocellular ,Neovascularization, Pathologic ,Liver Neoplasms ,Disease Progression ,Humans ,Female ,Collagen ,RNA, Messenger ,Peptide Fragments ,Collagen Type XVIII ,Endostatins - Abstract
Endostatin inhibits angiogenesis and tumor growth in mice. The role of its endogenous precursor collagen XVIII in human cancer is unknown. In normal tissues, two variants of collagen XVIII, namely, the short and long forms regulate tissue specificity, the long form being almost exclusively expressed by hepatocytes in the liver. We analyzed RNA arrays from 57 hepatocellular carcinomas (HCCs) with common and variant-specific probes and investigated the relationships between collagen XVIII expression and angiogenesis by measuring the CD34-positive microvessel density. Low collagen XVIII expression by tumor hepatocytes was associated with large tumor size (r, -0.63; P0.001) and replacement of trabeculae with pseudoglandular-solid architecture (chi2, 28; P0.001), which indicate tumor progression. Tumors expressing the highest collagen XVIII levels were smaller and had lower microvessel density (P = 0.01) than those expressing moderate levels; and HCCs with the lowest collagen XVIII levels approached a plateau of microvessel density, which indicated that a decrease in collagen XVIII expression is associated with angiogenesis in primary liver cancer. HCCs recurring within 2 years of resection showed 2.2-fold lower collagen XVIII mRNA than nonrecurring ones (P = 0.02). The findings relied on the hepatocyte-specific long form. Thus, the endogenous expression of the endostatin precursor decreases along with tumor progression in HCCs.
27. Sp1-mediated transactivation of LamC1 promoter and coordinated expression of laminim-γ1 and Sp1 in human hepatocellular carcinomas
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Liétard, J., Musso, O., Théret, N., L Helgoualc H, A., Campion, J. -P, Yamada, Y., and Clément, B.
28. EFFECT OF PACLOBUTRAZOL ON PRODUCTIVE BEHAVIOUR OF PEACH UNDER PROTECTED CULTIVATION
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Loreti, F., primary, Scalabrelli, G., additional, and Musso, O., additional
- Published
- 1989
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29. Reply: Intratumor fibrotic HCC, a subtype matching the Hoshida S1 subclass?
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Désert R, Foucher F, Guillout M, Nieto N, and Musso O
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- Humans, Mutation, Carcinoma, Hepatocellular pathology, Liver Neoplasms pathology
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- 2024
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30. SARS-CoV-2 receptor ACE2 is upregulated by fatty acids in human MASH.
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Cano L, Desquilles L, Ghukasyan G, Angenard G, Landreau C, Corlu A, Clément B, Turlin B, Le Ferrec E, Aninat C, Massart J, and Musso O
- Abstract
Background & Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) results in steatosis, inflammation (steatohepatitis), and fibrosis. Patients with MASLD more likely develop liver injury in coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). As viral RNA has been identified in liver tissues, we studied expression levels and cellular sources of the viral receptor angiotensin-converting enzyme 2 (ACE2) and coreceptors in MASLD and fibroinflammatory liver diseases., Methods: We built a transcriptomic MASLD meta-dataset (N = 243) to study SARS-CoV-2 receptor expression and verified results in 161 additional cases of fibroinflammatory liver diseases. We assessed the fibroinflammatory microenvironment by deconvoluting immune cell populations. We studied the cellular sources of ACE2 by multiplex immunohistochemistry followed by high-resolution confocal microscopy (N = 9 fatty livers; N = 7 controls), meta-analysis of two single-cell RNA sequencing datasets (N = 5 cirrhotic livers; N = 14 normal livers), and bulk transcriptomics from 745 primary cell samples. In vitro, we tested ACE2 mRNA expression in primary human hepatocytes treated with inflammatory cytokines, bacterial lipopolysaccharides, or long-chain fatty acids., Results: We detected ACE2 at the apical and basal poles of hepatocyte chords, in CLEC4M
+ liver sinusoidal endothelial cells, the lumen of ABCC2+ bile canaliculi, HepPar-1+ -TMPRSS2+ hepatocytes, cholangiocytes, and CD34+ capillary vessels. ACE2 steeply increased between 30 and 50 years of age; was related to liver fat area, inflammation, high immune reactivity, and fibrogenesis; and was upregulated in steatohepatitis. Although ACE2 mRNA was unmodified in alcoholic or viral hepatitis, it was upregulated in fibroinflammatory livers from overweight patients. In vitro, treatment of primary human hepatocytes with inflammatory cytokines alone downregulated but long chain fatty acids upregulated ACE2 mRNA expression., Conclusions: Lipid overload in fatty liver disease leads to an increased availability of ACE2 receptors., Impact and Implications: COVID-19 can be a deadly disease in vulnerable individuals. Patients with fatty liver disease are at a higher risk of experiencing severe COVID-19 and liver injury. Recent studies have indicated that one of the reasons for this vulnerability is the presence of a key cell surface protein called ACE2, which serves as the main SARS-CoV-2 virus receptor. We describe the cellular sources of ACE2 in the liver. In patients with fatty liver disease, ACE2 levels increase with age, liver fat content, fibroinflammatory changes, enhanced positive immune checkpoint levels, and innate immune reactivity. Moreover, we show that long chain fatty acids can induce ACE2 expression in primary human hepatocytes. Understanding the cellular sources of ACE2 in the liver and the factors that influence its availability is crucial. This knowledge will guide further research and help protect potentially vulnerable patients through timely vaccination boosters, dietary adjustments, and improved hygiene practices., Competing Interests: The authors of this study declare that they do not have any conflict of interest. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2023 The Author(s).)- Published
- 2023
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31. Hepatocellular carcinomas, exhibiting intratumor fibrosis, express cancer-specific extracellular matrix remodeling and WNT/TGFB signatures, associated with poor outcome.
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Desert R, Chen W, Ge X, Viel R, Han H, Athavale D, Das S, Song Z, Lantvit D, Cano L, Naba A, Musso O, and Nieto N
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- Humans, Mice, Animals, Fibrosis, Extracellular Matrix metabolism, Extracellular Matrix Proteins metabolism, Carcinoma, Hepatocellular pathology, Liver Neoplasms pathology
- Abstract
Background and Aims: HCC, the third leading cause of cancer-related death, arises in the context of liver fibrosis. Although HCC is generally poorly fibrogenic, some tumors harbor focal intratumor extracellular matrix (ECM) deposits called "fibrous nests." To date, the molecular composition and clinical relevance of these ECM deposits have not been fully defined., Approach and Results: We performed quantitative matrisome analysis by tandem mass tags mass spectrometry in 20 human cancer specific matrisome (HCCs) with high or low-grade intratumor fibrosis and matched nontumor tissues, as well as in 12 livers from mice treated with vehicle, carbon tetrachloride, or diethylnitrosamine. We found 94 ECM proteins differentially abundant between high and low-grade fibrous nests, including interstitial and basement membrane components, such as several collagens, glycoproteins, proteoglycans, enzymes involved in ECM stabilization and degradation, and growth factors. Pathway analysis revealed a metabolic switch in high-grade fibrosis, with enhanced glycolysis and decreased oxidative phosphorylation. Integrating the quantitative proteomics with transcriptomics from HCCs and nontumor livers (n = 2,285 samples), we identified a subgroup of fibrous nest HCCs, characterized by cancer-specific ECM remodeling, expression of the WNT/TGFB (S1) subclass signature, and poor patient outcome. Fibrous nest HCCs abundantly expressed an 11-fibrous-nest - protein signature, associated with poor patient outcome, by multivariate Cox analysis, and validated by multiplex immunohistochemistry., Conclusions: Matrisome analysis highlighted cancer-specific ECM deposits, typical of the WNT/TGFB HCC subclass, associated with poor patient outcomes. Hence, histologic reporting of intratumor fibrosis in HCC is of clinical relevance., (Copyright © 2023 American Association for the Study of Liver Diseases.)
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- 2023
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32. Modeling liver hereditary hemorrhagic telangiectasia with right heart overload to the core of liver sinusoidal endothelial cells.
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Musso O
- Subjects
- Humans, Endothelial Cells, Liver, Hepatocytes, Telangiectasia, Hereditary Hemorrhagic complications, Arteriovenous Malformations
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- 2023
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33. Metabolic Networks: Weighted Gene Correlation Network Analysis.
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Desquilles L and Musso O
- Subjects
- Metabolic Networks and Pathways genetics, Gene Expression Profiling methods, Gene Regulatory Networks, Software
- Abstract
Weighted Gene Correlation Network Analysis (WGCNA) is used to build weighted gene networks representing direct interconnections among genes. This method is useful to identify gene modules associated with biological functions, revealing core functional differences between samples. Here, we describe a step-by-step methodology to build a WGCNA network associated with a phenotype of interest. The results can be visualized using Cytoscape and other available software or used as a basis for further functional enrichment analyses., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)
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- 2023
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34. Role of Hepatocyte-Derived Osteopontin in Liver Carcinogenesis.
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Desert R, Ge X, Song Z, Han H, Lantvit D, Chen W, Das S, Athavale D, Abraham-Enachescu I, Blajszczak C, Chen Y, Musso O, Guzman G, Hoshida Y, and Nieto N
- Subjects
- Animals, Carcinogenesis genetics, Hepatocytes metabolism, Humans, Mice, Osteopontin genetics, Carcinoma, Hepatocellular genetics, Liver Neoplasms genetics
- Abstract
Osteopontin (OPN) expression correlates with tumor progression in many cancers, including hepatocellular carcinoma (HCC); however, its role in the onset of HCC remains unclear. We hypothesized that increased hepatocyte-derived OPN is a driver of hepatocarcinogenesis. Analysis of a tissue microarray of 366 human samples revealed a continuous increase in OPN expression during hepatocarcinogenesis. In patients with cirrhosis, a transcriptome-based OPN correlation network was associated with HCC incidence along 10 years of follow-up, together with messenger RNA (mRNA) signatures of carcinogenesis. After diethylnitrosamine (DEN) injection, mice with conditional overexpression of Opn in hepatocytes (Opn
Hep transgenic [Tg]) showed increased tumor burden. Surprisingly, mice with conditional ablation of Opn in hepatocytes (OpnΔHep ) expressed a similar phenotype. The acute response to DEN was reduced in OpnΔHep , which also showed more cancer stem/progenitor cells (CSCs, CD44+ AFP+ ) at 5 months. CSCs from OpnHep Tg mice expressed several mRNA signatures known to promote carcinogenesis, and mRNA signatures from OpnHep Tg mice were associated with poor outcome in human HCC patients. Treatment with rOPN had little effect on CSCs, and their progression to HCC was similar in Opn-/- compared with wild-type mice. Finally, ablation of Cd44, an OPN receptor, did not reduce tumor burden in Cd44-/- OpnHep Tg mice. Conclusions: Hepatocyte-derived OPN acts as a tumor suppressor at physiological levels by controlling the acute response to DEN and the presence of CSCs, while induction of OPN is pro-tumorigenic. This is primarily due to intracellular events rather that by the secretion of the protein and receptor activation., (© 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)- Published
- 2022
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35. Well-differentiated liver cancers reveal the potential link between ACE2 dysfunction and metabolic breakdown.
- Author
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Desquilles L, Cano L, Ghukasyan G, Mouchet N, Landreau C, Corlu A, Clément B, Turlin B, Désert R, and Musso O
- Subjects
- Angiotensin-Converting Enzyme 2 genetics, DNA Methylation, Gene Expression, Humans, Inflammation, Mutation, Oxidative Stress genetics, RNA, Messenger genetics, RNA, Messenger metabolism, Receptors, Virus genetics, Serine Endopeptidases genetics, Serine Endopeptidases metabolism, beta Catenin genetics, beta Catenin metabolism, Angiotensin-Converting Enzyme 2 metabolism, COVID-19, Carcinoma, Hepatocellular metabolism, Hepatocytes metabolism, Liver Neoplasms metabolism, Receptors, Virus metabolism, SARS-CoV-2
- Abstract
Angiotensin-converting enzyme 2 (ACE2) is the receptor of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causing Coronavirus disease 2019 (COVID-19). Transmembrane serine protease 2 (TMPRSS2) is a coreceptor. Abnormal hepatic function in COVID-19 suggests specific or bystander liver disease. Because liver cancer cells express the ACE2 viral receptor, they are widely used as models of SARS-CoV-2 infection in vitro. Therefore, the purpose of this study was to analyze ACE2 and TMPRSS2 expression and localization in human liver cancers and in non-tumor livers. We studied ACE2 and TMPRSS2 in transcriptomic datasets totaling 1503 liver cancers, followed by high-resolution confocal multiplex immunohistochemistry and quantitative image analysis of a 41-HCC tissue microarray. In cancers, we detected ACE2 and TMPRSS2 at the biliary pole of tumor hepatocytes. In whole mount sections of five normal liver samples, we identified ACE2 in hepatocyte's bile canaliculi, biliary epithelium, sinusoidal and capillary endothelial cells. Tumors carrying mutated β-catenin showed ACE2 DNA hypomethylation and higher mRNA and protein expression, consistently with predicted β-catenin response sites in the ACE2 promoter. Finally, ACE2 and TMPRSS2 co-expression networks highlighted hepatocyte-specific functions, oxidative stress and inflammation, suggesting a link between inflammation, ACE2 dysfunction and metabolic breakdown., (© 2022. The Author(s).)
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- 2022
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36. Comment on: "Wnt Binding Affinity Prediction for Putative Frizzled-Type Cysteine-Rich Domains".
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Musso O
- Subjects
- Cysteine, Protein Domains, Signal Transduction, Frizzled Receptors, Wnt Proteins
- Abstract
Dear Editor, [...].
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- 2019
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37. Hepatocellular carcinomas: evolution to sorafenib resistance through hepatic leukaemia factor.
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Musso O and Beraza N
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- Humans, Niacinamide, Phenylurea Compounds, Sorafenib, Carcinoma, Hepatocellular, Leukemia, Liver Neoplasms
- Abstract
Competing Interests: Competing interests: None declared.
- Published
- 2019
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38. Retrodifferentiation of Human Tumor Hepatocytes to Stem Cells Leads to Metabolic Reprogramming and Chemoresistance.
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Fekir K, Dubois-Pot-Schneider H, Désert R, Daniel Y, Glaise D, Rauch C, Morel F, Fromenty B, Musso O, Cabillic F, and Corlu A
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- Apoptosis, Carcinoma, Hepatocellular metabolism, Cell Differentiation, Cell Proliferation, Cellular Reprogramming, Hepatocytes metabolism, Humans, Liver Neoplasms metabolism, Neoplasm Recurrence, Local metabolism, Neoplastic Stem Cells metabolism, Prognosis, Survival Rate, Tumor Cells, Cultured, Biomarkers, Tumor metabolism, Carcinoma, Hepatocellular pathology, Drug Resistance, Neoplasm, Hepatocytes pathology, Liver Neoplasms pathology, Neoplasm Recurrence, Local pathology, Neoplastic Stem Cells pathology
- Abstract
Human hepatocellular carcinoma (HCC) heterogeneity promotes recurrence and therapeutic resistance. We recently demonstrated that inflammation favors hepatocyte retrodifferentiation into progenitor cells. Here, we identify the molecular effectors that induce metabolic reprogramming, chemoresistance, and invasiveness of retrodifferentiated HCC stem cells. Spheroid cultures of human HepaRG progenitors (HepaRG-Spheres), HBG-BC2, HepG2, and HuH7 cells and isolation of side population (SP) from HepaRG cells (HepaRG-SP) were analyzed by transcriptomics, signaling pathway analysis, and evaluation of chemotherapies. Gene expression profiling of HepaRG-SP and HepaRG-Spheres revealed enriched signatures related to cancer stem cells, metastasis, and recurrence and showed that HepaRG progenitors could retrodifferentiate into an immature state. The transcriptome from these stem cells matched that of proliferative bad outcome HCCs in a cohort of 457 patients. These HCC stem cells expressed high levels of cytokines triggering retrodifferentiation and displayed high migration and invasion potential. They also showed changes in mitochondrial activity with reduced membrane potential, low ATP production, and high lactate production. These changes were, in part, related to angiopoietin-like 4 (ANGPTL4)-induced upregulation of pyruvate dehydrogenase kinase 4 (PDK4), an inhibitor of mitochondrial pyruvate dehydrogenase. Upregulation of ANGPTL4 and PDK4 paralleled that of stem cells markers in human HCC specimens. Moreover, the PDK4 inhibitor dichloroacetate reversed chemoresistance to sorafenib or cisplatin in HCC stem cells derived from four HCC cell lines. In conclusion, retrodifferentiated cancer cells develop enhanced invasion and therapeutic resistance through ANGPTL4 and PDK4. Therefore, restoration of mitochondrial activity in combination with chemotherapy represents an attractive therapeutic approach in HCC. SIGNIFICANCE: Restoring mitochondrial function in human hepatocellular carcinomas overcomes cancer resistance., (©2019 American Association for Cancer Research.)
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- 2019
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39. Dimensions of hepatocellular carcinoma phenotypic diversity.
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Désert R, Nieto N, and Musso O
- Subjects
- Carcinoma, Hepatocellular immunology, Carcinoma, Hepatocellular pathology, Cell Differentiation, Cell Proliferation, Hepatocytes pathology, Humans, Liver cytology, Liver pathology, Liver Neoplasms immunology, Liver Neoplasms pathology, Phenotype, Tumor Microenvironment immunology, Biomarkers, Tumor metabolism, Carcinoma, Hepatocellular classification, Liver metabolism, Liver Neoplasms classification
- Abstract
Hepatocellular carcinoma (HCC) is the 3
rd leading cause of cancer-related death worldwide. More than 80% of HCCs arise within chronic liver disease resulting from viral hepatitis, alcohol, hemochromatosis, obesity and metabolic syndrome or genotoxins. Projections based on Western lifestyle and its metabolic consequences anticipate a further increase in incidence, despite recent breakthroughs in the management of viral hepatitis. HCCs display high heterogeneity of molecular phenotypes, which challenges clinical management. However, emerging molecular classifications of HCCs have not yet formed a unified corpus translatable to the clinical practice. Thus, patient management is currently based upon tumor number, size, vascular invasion, performance status and functional liver reserve. Nonetheless, an impressive body of molecular evidence emerged within the last 20 years and is becoming increasingly available to medical practitioners and researchers in the form of repositories. Therefore, the aim this work is to review molecular data underlying HCC classifications and to organize this corpus into the major dimensions explaining HCC phenotypic diversity. Major efforts have been recently made worldwide toward a unifying "clinically-friendly" molecular landscape. As a result, a consensus emerges on three major dimensions explaining the HCC heterogeneity. In the first dimension, tumor cell proliferation and differentiation enabled allocation of HCCs to two major classes presenting profoundly different clinical aggressiveness. In the second dimension, HCC microenvironment and tumor immunity underlie recent therapeutic breakthroughs prolonging patients' survival. In the third dimension, metabolic reprogramming, with the recent emergence of subclass-specific metabolic profiles, may lead to adaptive and combined therapeutic approaches. Therefore, here we review recent molecular evidence, their impact on tumor histopathological features and clinical behavior and highlight the remaining challenges to translate our cognitive corpus into patient diagnosis and allocation to therapeutic options., Competing Interests: Conflict-of-interest statement: The authors have no conflict of interest to declare.- Published
- 2018
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40. Human hepatocellular carcinomas with a periportal phenotype have the lowest potential for early recurrence after curative resection.
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Désert R, Rohart F, Canal F, Sicard M, Desille M, Renaud S, Turlin B, Bellaud P, Perret C, Clément B, Lê Cao KA, and Musso O
- Subjects
- Carcinoma, Hepatocellular genetics, Carcinoma, Hepatocellular mortality, Carcinoma, Hepatocellular surgery, France epidemiology, Hepatocyte Nuclear Factor 4 metabolism, Humans, Liver Neoplasms genetics, Liver Neoplasms mortality, Liver Neoplasms surgery, Mutation, Neoplasm Recurrence, Local genetics, Phenotype, Transcriptome, Carcinoma, Hepatocellular pathology, Liver pathology, Liver Neoplasms pathology, Neoplasm Recurrence, Local pathology, beta Catenin genetics
- Abstract
Hepatocellular carcinomas (HCCs) exhibit a diversity of molecular phenotypes, raising major challenges in clinical management. HCCs detected by surveillance programs at an early stage are candidates for potentially curative therapies (local ablation, resection, or transplantation). In the long term, transplantation provides the lowest recurrence rates. Treatment allocation is based on tumor number, size, vascular invasion, performance status, functional liver reserve, and the prediction of early (<2 years) recurrence, which reflects the intrinsic aggressiveness of the tumor. Well-differentiated, potentially low-aggressiveness tumors form the heterogeneous molecular class of nonproliferative HCCs, characterized by an approximate 50% β-catenin mutation rate. To define the clinical, pathological, and molecular features and the outcome of nonproliferative HCCs, we constructed a 1,133-HCC transcriptomic metadata set and validated findings in a publically available 210-HCC RNA sequencing set. We show that nonproliferative HCCs preserve the zonation program that distributes metabolic functions along the portocentral axis in normal liver. More precisely, we identified two well-differentiated, nonproliferation subclasses, namely periportal-type (wild-type β-catenin) and perivenous-type (mutant β-catenin), which expressed negatively correlated gene networks. The new periportal-type subclass represented 29% of all HCCs; expressed a hepatocyte nuclear factor 4A-driven gene network, which was down-regulated in mouse hepatocyte nuclear factor 4A knockout mice; were early-stage tumors by Barcelona Clinic Liver Cancer, Cancer of the Liver Italian Program, and tumor-node-metastasis staging systems; had no macrovascular invasion; and showed the lowest metastasis-specific gene expression levels and TP53 mutation rates. Also, we identified an eight-gene periportal-type HCC signature, which was independently associated with the highest 2-year recurrence-free survival by multivariate analyses in two independent cohorts of 247 and 210 patients., Conclusion: Well-differentiated HCCs display mutually exclusive periportal or perivenous zonation programs. Among all HCCs, periportal-type tumors have the lowest intrinsic potential for early recurrence after curative resection. (Hepatology 2017;66:1502-1518)., (© 2017 by the American Association for the Study of Liver Diseases.)
- Published
- 2017
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41. The rs3957357C>T SNP in GSTA1 Is Associated with a Higher Risk of Occurrence of Hepatocellular Carcinoma in European Individuals.
- Author
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Akhdar H, El Shamieh S, Musso O, Désert R, Joumaa W, Guyader D, Aninat C, Corlu A, and Morel F
- Subjects
- Carcinoma, Hepatocellular ethnology, Europe, Gene Expression Profiling methods, Gene Expression Profiling statistics & numerical data, Gene Expression Regulation, Neoplastic, Gene Frequency, Gene Ontology, Genetic Predisposition to Disease ethnology, Genotype, Hepatocytes metabolism, Humans, Kaplan-Meier Estimate, Linkage Disequilibrium, Liver metabolism, Liver Neoplasms ethnology, Polymerase Chain Reaction, Polymorphism, Restriction Fragment Length, Proportional Hazards Models, Reverse Transcriptase Polymerase Chain Reaction, Risk Factors, White People genetics, Carcinoma, Hepatocellular genetics, Genetic Predisposition to Disease genetics, Glutathione Transferase genetics, Liver Neoplasms genetics, Polymorphism, Single Nucleotide
- Abstract
Glutathione S-transferases (GSTs) detoxify toxic molecules by conjugation with reduced glutathione and regulate cell signaling. Single nucleotide polymorphisms (SNPs) of GST genes have been suggested to affect GST functions and thus to increase the risk of human hepatocellular carcinoma (HCC). As GSTA1 is expressed in hepatocytes and the rs3957357C>T (TT) SNP is known to downregulate GSTA1 mRNA expression, the aims of this study were: (i) to explore the relationship between the TT SNP in GSTA1 and the occurrence of HCC; (ii) to measure GSTA1 mRNA expression in HCCs. For that purpose, we genotyped non-tumor-tissue-derived DNA from 48 HCC patients and white-blood-cell-derived DNA from 37 healthy individuals by restriction fragment length polymorphism (RFLP). In addition, expression of GSTA1 mRNA was assessed by real-time PCR in 18 matching pairs of HCCs and non-tumor livers. Survival analysis was performed on an annotated microarray dataset containing 247 HCC patients (GSE14520). The GSTA1 TT genotype was more frequent in HCC than in non-HCC patients (27% versus 5%, respectively), suggesting that individuals carrying this genotype could be associated with 2-fold higher risk of developing HCCs (odds ratio = 2.1; p = 0.02). Also, we found that GSTA1 mRNA expression was lower in HCCs than in non-tumor livers. HCCs expressing the highest GSTA1 mRNA levels were the smallest in size (R = -0.67; p = 0.007), expressed the highest levels of liver-enriched genes such as ALB (albumin, R = -0.67; p = 0.007) and COL18A1 (procollagen type XVIII, R = -0.50; p = 0.03) and showed the most favorable disease-free (OR = 0.54; p<0.001) and overall (OR = 0.56; p = 0.006) outcomes. Moreover, GSTA1 was found within a 263-gene network involved in well-differentiated hepatocyte functions. In conclusion, HCCs are characterized by two GSTA1 features: the TT SNP and reduced GSTA1 gene expression in a context of hepatocyte de-differentiation., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2016
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42. "Fibrous nests" in human hepatocellular carcinoma express a Wnt-induced gene signature associated with poor clinical outcome.
- Author
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Désert R, Mebarki S, Desille M, Sicard M, Lavergne E, Renaud S, Bergeat D, Sulpice L, Perret C, Turlin B, Clément B, and Musso O
- Subjects
- Actins metabolism, Basement Membrane metabolism, Biomarkers, Tumor metabolism, Carcinoma, Hepatocellular complications, Carcinoma, Hepatocellular diagnosis, Cell Differentiation, Humans, Laminin metabolism, Liver Cirrhosis complications, Liver Neoplasms complications, Liver Neoplasms diagnosis, Mesoderm pathology, Myofibroblasts pathology, Neoplasm Invasiveness, Neoplastic Stem Cells pathology, Prognosis, Recurrence, Tumor Microenvironment, Wnt Signaling Pathway genetics, Carcinoma, Hepatocellular genetics, Carcinoma, Hepatocellular pathology, Gene Expression Regulation, Neoplastic, Liver Neoplasms genetics, Liver Neoplasms pathology, Wnt Proteins metabolism
- Abstract
Hepatocellular carcinoma (HCC) is the 3rd cause of cancer-related death worldwide. Most cases arise in a background of chronic inflammation, extracellular matrix (ECM) remodeling, severe fibrosis and stem/progenitor cell amplification. Although HCCs are soft cellular tumors, they may contain fibrous nests within the tumor mass. Thus, the aim of this study was to explore cancer cell phenotypes in fibrous nests. Combined anatomic pathology, tissue microarray and real-time PCR analyses revealed that HCCs (n=82) containing fibrous nests were poorly differentiated, expressed Wnt pathway components and target genes, as well as markers of stem/progenitor cells, such as CD44, LGR5 and SOX9. Consistently, in severe liver fibroses (n=66) and in HCCs containing fibrous nests, weighted correlation analysis revealed a gene network including the myofibroblast marker ACTA2, the basement membrane components COL4A1 and LAMC1, the Wnt pathway members FZD1; FZD7; WNT2; LEF1; DKK1 and the Secreted Frizzled Related Proteins (SFRPs) 1; 2 and 5. Moreover, unbiased random survival forest analysis of a transcriptomic dataset of 247 HCC patients revealed high DKK1, COL4A1, SFRP1 and LAMC1 to be associated with advanced tumor staging as well as with bad overall and disease-free survival. In vitro, these genes were upregulated in liver cancer stem/progenitor cells upon Wnt-induced mesenchymal commitment and myofibroblast differentiation. In conclusion, fibrous nests express Wnt target genes, as well as markers of cancer stem cells and mesenchymal commitment. Fibrous nests embody the specific microenvironment of the cancer stem cell niche and can be detected by routine anatomic pathology analyses., (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Published
- 2016
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43. De novo HAPLN1 expression hallmarks Wnt-induced stem cell and fibrogenic networks leading to aggressive human hepatocellular carcinomas.
- Author
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Mebarki S, Désert R, Sulpice L, Sicard M, Desille M, Canal F, Dubois-Pot Schneider H, Bergeat D, Turlin B, Bellaud P, Lavergne E, Le Guével R, Corlu A, Perret C, Coulouarn C, Clément B, and Musso O
- Subjects
- Aged, Cell Differentiation, Cell Line, Cell Line, Tumor, Cluster Analysis, Extracellular Matrix Proteins genetics, Female, Fibroblasts metabolism, Follow-Up Studies, Gene Expression Profiling, Humans, Immunohistochemistry, Ligands, Liver metabolism, Liver pathology, Male, Middle Aged, Neoplasm Invasiveness, Proteoglycans genetics, Signal Transduction, Stem Cells cytology, Tissue Array Analysis, Carcinoma, Hepatocellular metabolism, Extracellular Matrix Proteins metabolism, Gene Expression Regulation, Neoplastic, Liver Neoplasms metabolism, Mesoderm metabolism, Proteoglycans metabolism, Stem Cells metabolism, Wnt Proteins metabolism
- Abstract
About 20% hepatocellular carcinomas (HCCs) display wild-type β-catenin, enhanced Wnt signaling, hepatocyte dedifferentiation and bad outcome, suggesting a specific impact of Wnt signals on HCC stem/progenitor cells. To study Wnt-specific molecular pathways, cell fates and clinical outcome, we fine-tuned Wnt/β-catenin signaling in liver progenitor cells, using the prototypical Wnt ligand Wnt3a. Cell biology assays and transcriptomic profiling were performed in HepaRG hepatic progenitors exposed to Wnt3a after β-catenin knockdown or Wnt inhibition with FZD8_CRD. Gene expression network, molecular pathology and survival analyses were performed on HCCs and matching non-tumor livers from 70 patients by real-time PCR and tissue micro-array-based immunohistochemistry. Wnt3a reprogrammed liver progenitors to replicating fibrogenic myofibroblast-like cells displaying stem and invasive features. Invasion was inhibited by 30 nM FZD7 and FZD8 CRDs. Translation of these data to human HCCs revealed two tight gene networks associating cell surface Wnt signaling, stem/progenitor markers and mesenchymal commitment. Both networks were linked by Hyaluronan And Proteoglycan Link Protein 1 (HAPLN1), that appeared de novo in aggressive HCCs expressing cytoplasmic β-catenin and stem cell markers. HAPLN1 was independently associated with bad overall and disease-free outcome. In vitro, HAPLN1 was expressed de novo in EPCAM¯/NCAM+ mesoderm-committed progenitors, upon spontaneous epithelial-mesenchymal transition and de-differentiation of hepatocyte-like cells to liver progenitors. In these cells, HAPLN1 knockdown downregulated key markers of mesenchymal cells, such as Snail, LGR5, collagen IV and α-SMA. In conclusion, HAPLN1 reflects a signaling network leading to stemness, mesenchymal commitment and HCC progression., Competing Interests: The authors declare no conflicts of interest.
- Published
- 2016
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44. Growth and survival of lung cancer cells: regulation by kallikrein-related peptidase 6 via activation of proteinase-activated receptor 2 and the epidermal growth factor receptor.
- Author
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Michel N, Heuzé-Vourc'h N, Lavergne E, Parent C, Jourdan ML, Vallet A, Iochmann S, Musso O, Reverdiau P, and Courty Y
- Subjects
- Cadherins metabolism, Cell Line, Tumor, Cell Nucleus metabolism, Cell Proliferation, Cell Survival, Extracellular Signal-Regulated MAP Kinases metabolism, Gene Silencing, Humans, Ligands, Mutant Proteins metabolism, Phosphorylation, Protein Transport, Proto-Oncogene Proteins c-akt metabolism, beta Catenin metabolism, ErbB Receptors metabolism, Kallikreins metabolism, Lung Neoplasms metabolism, Lung Neoplasms pathology, Receptor, PAR-2 metabolism
- Abstract
The dysregulated expression of kallikrein-related peptidase 6 (KLK6) is involved in non-small cancer (NSCLC) cell growth. However, the mechanism that sustains KLK6 signaling remains unknown. We used an isogenic non-small cell lung cancer (NSCLC) cell model system to demonstrate that KLK6 promotes the proliferation of lung tumoral cells and restrains their apoptosis in vitro via ligand-dependent EGFR transactivation. KLK6 activated the ERK and Akt pathways and triggered the nuclear translocation of β-catenin. The stimulating effects of KLK6 required its proteolytic activity and were dependent on the protease-activated receptor 2 (PAR2). These observations support the concept of a role for KLK6 in the oncogenesis of NSCLC.
- Published
- 2014
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45. Inhibition of Wnt/β-catenin signaling by a soluble collagen-derived frizzled domain interacting with Wnt3a and the receptors frizzled 1 and 8.
- Author
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Hendaoui I, Lavergne E, Lee HS, Hong SH, Kim HZ, Parent C, Heuzé-Vourc'h N, Clément B, and Musso O
- Subjects
- Animals, Cell Proliferation drug effects, DNA biosynthesis, Extracellular Space drug effects, Extracellular Space metabolism, HEK293 Cells, Humans, Mice, Models, Biological, Protein Binding drug effects, Protein Multimerization drug effects, Protein Structure, Tertiary, Solubility drug effects, Collagen Type XVIII chemistry, Collagen Type XVIII metabolism, Collagen Type XVIII pharmacology, Frizzled Receptors metabolism, Wnt Signaling Pathway drug effects, Wnt3 Protein metabolism
- Abstract
The Wnt/β-catenin pathway controls cell proliferation, death and differentiation. Several families of extracellular proteins can antagonize Wnt/β-catenin signaling, including the decoy receptors known as secreted frizzled related proteins (SFRPs), which have a cysteine-rich domain (CRD) structurally similar to the extracellular Wnt-binding domain of the frizzled receptors. SFRPs inhibit Wnt signaling by sequestering Wnts through the CRD or by forming inactive complexes with the frizzled receptors. Other endogenous molecules carrying frizzled CRDs inhibit Wnt signaling, such as V3Nter, which is proteolytically derived from the cell surface component collagen XVIII and contains a biologically active frizzled domain (FZC18) inhibiting in vivo cell proliferation and tumor growth in mice. We recently showed that FZC18 expressing cells deliver short-range signals to neighboring cells, decreasing their proliferation in vitro and in vivo through the Wnt/β-catenin signaling pathway. Here, using low concentrations of soluble FZC18 and Wnt3a, we show that they physically interact in a cell-free system. In addition, soluble FZC18 binds the frizzled 1 and 8 receptors' CRDs, reducing cell sensitivity to Wnt3a. Conversely, inhibition of Wnt/β-catenin signaling was partially rescued by the expression of full-length frizzled 1 and 8 receptors, but enhanced by the expression of a chimeric cell-membrane-tethered frizzled 8 CRD. Moreover, soluble, partially purified recombinant FZC18_CRD inhibited Wnt3a-induced β-catenin activation. Taken together, the data indicate that collagen XVIII-derived frizzled CRD shifts Wnt sensitivity of normal cells to a lower pitch and controls their growth.
- Published
- 2012
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46. A cryptic frizzled module in cell surface collagen 18 inhibits Wnt/beta-catenin signaling.
- Author
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Quélard D, Lavergne E, Hendaoui I, Elamaa H, Tiirola U, Heljasvaara R, Pihlajaniemi T, Clément B, and Musso O
- Subjects
- Cell Line, Tumor, Cell Lineage, Cell Membrane metabolism, Collagen chemistry, Extracellular Matrix metabolism, Gene Expression Regulation, Neoplastic, Humans, Liver Neoplasms metabolism, Models, Biological, Protein Processing, Post-Translational, Protein Structure, Tertiary, Collagen physiology, Frizzled Receptors metabolism, Signal Transduction, Wnt Proteins metabolism, beta Catenin metabolism
- Abstract
Collagens contain cryptic polypeptide modules that regulate major cell functions, such as cell proliferation or death. Collagen XVIII (C18) exists as three amino terminal end variants with specific amino terminal polypeptide modules. We investigated the function of the variant 3 of C18 (V3C18) containing a frizzled module (FZC18), which carries structural identity with the extracellular cysteine-rich domain of the frizzled receptors. We show that V3C18 is a cell surface heparan sulfate proteoglycan, its topology being mediated by the FZC18 module. V3C18 mRNA was expressed at low levels in 21 normal adult human tissues. Its expression was up-regulated in fibrogenesis and in small well-differentiated liver tumors, but decreased in advanced human liver cancers. Low FZC18 immunostaining in liver cancer nodules correlated with markers of high Wnt/beta-catenin activity. V3C18 (M(r) = 170 kD) was proteolytically processed into a cell surface FZC18-containing 50 kD glycoprotein precursor that bound Wnt3a in vitro through FZC18 and suppressed Wnt3a-induced stabilization of beta-catenin. Ectopic expression of either FZC18 (35 kD) or its 50 kD precursor inhibited Wnt/beta-catenin signaling in colorectal and liver cancer cell lines, thus downregulating major cell cycle checkpoint gatekeepers cyclin D1 and c-myc and reducing tumor cell growth. By contrast, full-length V3C18 was unable to inhibit Wnt signaling. In summary, we identified a cell-surface signaling pathway whereby FZC18 inhibits Wnt/beta-catenin signaling. The signal, encrypted within cell-surface C18, is released by enzymatic processing as an active frizzled cysteine-rich domain (CRD) that reduces cancer cell growth. Thus, extracellular matrix controls Wnt signaling through a collagen-embedded CRD behaving as a cell-surface sensor of proteolysis, conveying feedback cues to control cancer cell fate.
- Published
- 2008
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47. Prokineticin 2/Bv8 is expressed in Kupffer cells in liver and is down regulated in human hepatocellular carcinoma.
- Author
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Monnier J, Piquet-Pellorce C, Feige JJ, Musso O, Clement B, Turlin B, Theret N, and Samson M
- Subjects
- Aged, Down-Regulation, Female, Humans, Liver pathology, Male, Middle Aged, Models, Biological, Neovascularization, Pathologic, Reverse Transcriptase Polymerase Chain Reaction, Transcriptional Activation, Carcinoma, Hepatocellular metabolism, Gastrointestinal Hormones biosynthesis, Gene Expression Regulation, Neoplastic, Kupffer Cells metabolism, Liver metabolism, Liver Neoplasms metabolism, Neuropeptides biosynthesis
- Abstract
Aim: To study the implication of prokineticin 1 (PK1/EG-VEGF) and prokineticin 2 (PK2/Bv8) in hepatocellular carcinoma angiogenesis., Methods: The gene induction of PK1/EG-VEGF and PK2/Bv8 was investigated in 10 normal, 28 fibrotic and 28 tumoral livers by using real time PCR. Their expression was compared to the expression of VEGF (an angiogenesis marker), vWF (an endothelial cell marker) and to CD68 (a monocyte/macrophage marker). Furthermore, the mRNA levels of PK1/EG-VEGF, PK2/Bv8, prokineticin receptor 1 and 2 were evaluated by real time PCR in isolated liver cell populations. Finally, PK2/Bv8 protein was detected in normal liver paraffin sections and in isolated liver cells by immunohistochemistry and immunocytochemistry., Results: PK2/Bv8 mRNA but not PK1/EG-VEGF was expressed in all types of normal liver samples examined. In the context of liver tumor development, we reported that PK2/Bv8 correlates only with CD68 and showed a significant decrease in expression as the pathology evolves towards cancer. Whereas, VEGF and vWF mRNA were significantly upregulated in both fibrosis and HCC, as expected. In addition, out of all isolated liver cells examined, only Kupffer cells (liver resident macrophages) express significant levels of PK2/Bv8 and its receptors, prokineticin receptor 1 and 2., Conclusion: In normal liver PK2/Bv8 and its receptors were specifically expressed by Kupffer cells. PK2/Bv8 expression decreased as the liver evolves towards cancer and did not correlate with HCC angiogenesis.
- Published
- 2008
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48. Upregulation of the tumor suppressor gene menin in hepatocellular carcinomas and its significance in fibrogenesis.
- Author
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Zindy PJ, L'Helgoualc'h A, Bonnier D, Le Béchec A, Bourd-Boitin K, Zhang CX, Musso O, Glaise D, Troadec MB, Loréal O, Turlin B, Léger J, Clément B, and Théret N
- Subjects
- Carcinoma, Hepatocellular etiology, Carcinoma, Hepatocellular metabolism, Gene Library, Genes, Tumor Suppressor, Humans, Liver Cirrhosis complications, Oligonucleotide Array Sequence Analysis, Proto-Oncogene Proteins biosynthesis, RNA, Messenger biosynthesis, Transfection, Transforming Growth Factor beta metabolism, Up-Regulation, Carcinoma, Hepatocellular genetics, Collagen Type I metabolism, Hepatocytes physiology, Liver Cirrhosis metabolism, Proto-Oncogene Proteins genetics
- Abstract
The molecular mechanisms underlying the progression of cirrhosis toward hepatocellular carcinoma were investigated by a combination of DNA microarray analysis and literature data mining. By using a microarray screening of suppression subtractive hybridization cDNA libraries, we first analyzed genes differentially expressed in tumor and nontumor livers with cirrhosis from 15 patients with hepatocellular carcinomas. Seventy-four genes were similarly recovered in tumor (57.8% of differentially expressed genes) and adjacent nontumor tissues (64% of differentially expressed genes) compared with histologically normal livers. Gene ontology analyses revealed that downregulated genes (n = 35) were mostly associated with hepatic functions. Upregulated genes (n = 39) included both known genes associated with extracellular matrix remodeling, cell communication, metabolism, and post-transcriptional regulation gene (e.g., ZFP36L1), as well as the tumor suppressor gene menin (multiple endocrine neoplasia type 1; MEN1). MEN1 was further identified as an important node of a regulatory network graph that integrated array data with array-independent literature mining. Upregulation of MEN1 in tumor was confirmed in an independent set of samples and associated with tumor size (P = .016). In the underlying liver with cirrhosis, increased steady-state MEN1 mRNA levels were correlated with those of collagen alpha2(I) mRNA (P < .01). In addition, MEN1 expression was associated with hepatic stellate cell activation during fibrogenesis and involved in transforming growth factor beta (TGF-beta)-dependent collagen alpha2(I) regulation. In conclusion, menin is a key regulator of gene networks that are activated in fibrogenesis associated with hepatocellular carcinoma through the modulation of TGF-beta response.
- Published
- 2006
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49. Overexpression of the two nucleotide excision repair genes ERCC1 and XPC in human hepatocellular carcinoma.
- Author
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Fautrel A, Andrieux L, Musso O, Boudjema K, Guillouzo A, and Langouët S
- Subjects
- Aged, Carcinoma, Hepatocellular metabolism, Carcinoma, Hepatocellular pathology, DNA-Binding Proteins biosynthesis, Disease Progression, Endonucleases biosynthesis, Female, Genetic Markers, Humans, Immunoblotting, Liver Neoplasms metabolism, Liver Neoplasms pathology, Male, RNA, Neoplasm biosynthesis, Reverse Transcriptase Polymerase Chain Reaction, Carcinoma, Hepatocellular genetics, DNA Repair genetics, DNA-Binding Proteins genetics, Endonucleases genetics, Gene Expression Regulation, Neoplastic, Liver Neoplasms genetics, RNA, Neoplasm genetics
- Abstract
Background/aims: Little is known about the nucleotide excision repair (NER) pathway in the resistance of human hepatocellular carcinoma (HCC) to chemotherapeutics. We investigated expression of several NER genes in human HCC and matching non-tumor tissue (NT) and in normal liver., Methods: Expression of CSA, CSB, XPC, hHR23B, XPA, XPB, ERCC1 and p53 genes was analyzed by quantitative RT-PCR and immunoblotting in 26 HCC and 9 normal livers., Results: The seven NER genes and p53 were frequently overexpressed in HCC compared to matched NT. XPA, XPC, hHR23B and ERCC1 mRNA levels were significantly increased (p<0.05) in HCC arising in cirrhotic livers compared to non fibrotic tissue. Moreover, expression of ERCC1, XPA and XPC mRNA was significantly augmented in HCC, even more in tumors arising in cirrhotic liver. ERCC1, XPC ad XPA mRNA levels were highly correlated in NT and HCC. XPC and ERCC1 protein levels were also increased in HCC., Conclusions: Our findings strongly suggest that overexpression of two key genes involved in the early steps of the NER process, ERCC1 and XPC, is associated with liver fibrogenesis and cancer and could be related to the well recognized resistance of HCC to chemotherapeutics.
- Published
- 2005
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- View/download PDF
50. Upregulation of DNA repair genes in active cirrhosis associated with hepatocellular carcinoma.
- Author
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Zindy P, Andrieux L, Bonnier D, Musso O, Langouët S, Campion JP, Turlin B, Clément B, and Théret N
- Subjects
- Adult, Aged, Carcinoma, Hepatocellular genetics, Carcinoma, Hepatocellular metabolism, DNA-Binding Proteins analysis, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Endonucleases analysis, Endonucleases genetics, Endonucleases metabolism, Endothelial Cells immunology, Endothelial Cells pathology, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Liver immunology, Liver pathology, Liver Cirrhosis etiology, Liver Cirrhosis metabolism, Liver Neoplasms genetics, Liver Neoplasms metabolism, Male, Middle Aged, Oligonucleotide Array Sequence Analysis, Xeroderma Pigmentosum Group A Protein, Carcinoma, Hepatocellular etiology, DNA Repair genetics, Liver Cirrhosis complications, Liver Cirrhosis genetics, Liver Neoplasms etiology, Up-Regulation
- Abstract
Phenotypic changes in injured livers involve complex network of genes whose interplays may lead to fibrosis and cirrhosis, a major risk of hepatocellular carcinoma. Gene expression profiles in fibrotic livers were analyzed by using cDNA microarray, hierarchical clustering and gene ontology. Analyses of a major cluster of upregulated genes in cirrhosis identified a new set of genes involved in DNA repair and damage. The upregulation of DNA repair genes was confirmed by real-time quantitative polymerase chain reaction and associated with necroinflammatory activity (P<0.001). Increased DNA repair activity in cirrhosis with inflammatory activity may reflect increased DNA damages as a consequence of chronic liver injury.
- Published
- 2005
- Full Text
- View/download PDF
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