Extracellular Matrix Dynamics in Hepatocarcinogenesis: a Comparative Proteomics Study of Transgenic and Null Mouse Models
We are reporting qualitative and quantitative changes of the extracellular matrix (ECM) and associated receptor proteomes, occurring during the transition from liver fibrosis and steatohepatitis to hepatocellular carcinoma (HCC). We compared two mouse models relevant to human HCC: PDGFC transgenic (Tg) and Pten null mice, models of disease progression from fibrosis and steatohepatitis to HCC. Using mass spectrometry, we identified in the liver of both models proteins for 26 collagen-encoding genes, providing the first evidence of expression at the protein level for 16 collagens. We also identified post-transcriptional protein variants for six collagens and lysine hydroxylation modifications for 14 collagens. Tumor-associated collagen proteomes were similar in both models with increased expression of collagens type IV, VI, VII, X, XIV, XV, XVI, and XVIII. Splice variants for Col4a2, Col6a2, Col6a3 were co-upregulated while only the short form of Col18a1 increased in the tumors. We also identified tumor specific increases of nidogen 1, decorin, perlecan, and of six laminin subunits. The changes in these non-collagenous ECM proteins were similar in both models with the exception of laminin β3, detected specifically in the Pten null tumors. Pdgfa and Pdgfc mRNA expression was increased in the Pten null liver, a possible mechanism for the similarity in ECM composition observed in the tumors of both models. In contrast and besides the strong up-regulation of integrin α5 protein observed in the liver tumors of both models, the expression of the six other integrins identified was specific to each model, with integrins α2b, α3, α6, and β1 up-regulated in Pten null tumors and integrins α8 and β5 up-regulated in the PDGFC Tg tumors. In conclusion, HCC–associated ECM proteins and ECM–integrin networks, common or specific to HCC subtypes, were identified, providing a unique foundation to using ECM composition for HCC classification, diagnosis, prevention, or treatment.
Vyšlo v časopise:
Extracellular Matrix Dynamics in Hepatocarcinogenesis: a Comparative Proteomics Study of Transgenic and Null Mouse Models. PLoS Genet 7(6): e32767. doi:10.1371/journal.pgen.1002147
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1002147
Souhrn
We are reporting qualitative and quantitative changes of the extracellular matrix (ECM) and associated receptor proteomes, occurring during the transition from liver fibrosis and steatohepatitis to hepatocellular carcinoma (HCC). We compared two mouse models relevant to human HCC: PDGFC transgenic (Tg) and Pten null mice, models of disease progression from fibrosis and steatohepatitis to HCC. Using mass spectrometry, we identified in the liver of both models proteins for 26 collagen-encoding genes, providing the first evidence of expression at the protein level for 16 collagens. We also identified post-transcriptional protein variants for six collagens and lysine hydroxylation modifications for 14 collagens. Tumor-associated collagen proteomes were similar in both models with increased expression of collagens type IV, VI, VII, X, XIV, XV, XVI, and XVIII. Splice variants for Col4a2, Col6a2, Col6a3 were co-upregulated while only the short form of Col18a1 increased in the tumors. We also identified tumor specific increases of nidogen 1, decorin, perlecan, and of six laminin subunits. The changes in these non-collagenous ECM proteins were similar in both models with the exception of laminin β3, detected specifically in the Pten null tumors. Pdgfa and Pdgfc mRNA expression was increased in the Pten null liver, a possible mechanism for the similarity in ECM composition observed in the tumors of both models. In contrast and besides the strong up-regulation of integrin α5 protein observed in the liver tumors of both models, the expression of the six other integrins identified was specific to each model, with integrins α2b, α3, α6, and β1 up-regulated in Pten null tumors and integrins α8 and β5 up-regulated in the PDGFC Tg tumors. In conclusion, HCC–associated ECM proteins and ECM–integrin networks, common or specific to HCC subtypes, were identified, providing a unique foundation to using ECM composition for HCC classification, diagnosis, prevention, or treatment.
Zdroje
1. El-SeragHBRudolphKL 2007 Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 132 2557 2576
2. ReigstadLJVarhaugJELillehaugJR 2005 Structural and functional specificities of PDGF-C and PDGF-D, the novel members of the platelet-derived growth factors family. FEBS J 272 5723 5741
3. BatallerRBrennerDA 2005 Liver fibrosis. J Clin Invest 115 209 218
4. CampbellJSHughesSDGilbertsonDGPalmerTEHoldrenMS 2005 Platelet-derived growth factor C induces liver fibrosis, steatosis, and hepatocellular carcinoma. Proc Natl Acad Sci U S A 102 3389 3394
5. FaustoNCampbellJS 2010 Mouse models of hepatocellular carcinoma. Semin Liver Dis 30 87 98
6. HorieYSuzukiAKataokaESasakiTHamadaK 2004 Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas. J Clin Invest 113 1774 1783
7. StilesBWangYStahlABassilianSLeeWP 2004 Liver-specific deletion of negative regulator Pten results in fatty liver and insulin hypersensitivity [corrected]. Proc Natl Acad Sci U S A 101 2082 2087
8. XuXKobayashiSQiaoWLiCXiaoC 2006 Induction of intrahepatic cholangiocellular carcinoma by liver-specific disruption of Smad4 and Pten in mice. J Clin Invest 116 1843 1852
9. RountreeCBSenadheeraSMatoJMCrooksGMLuSC 2008 Expansion of liver cancer stem cells during aging in methionine adenosyltransferase 1A-deficient mice. Hepatology 47 1288 1297
10. RoskamsT 2006 Liver stem cells and their implication in hepatocellular and cholangiocarcinoma. Oncogene 25 3818 3822
11. ZiolMNaultJCAoutMBargetNTepperM 2010 Intermediate hepatobiliary cells predict an increased risk of hepatocarcinogenesis in patients with hepatitis C virus-related cirrhosis. Gastroenterology 139 335 343 e332
12. WooHGLeeJHYoonJHKimCYLeeHS 2010 Identification of a cholangiocarcinoma-like gene expression trait in hepatocellular carcinoma. Cancer Res 70 3034 3041
13. LaiKKKolippakkamDBerettaL 2008 Comprehensive and quantitative proteome profiling of the mouse liver and plasma. Hepatology 47 1043 1051
14. HynesRO 2009 The extracellular matrix: not just pretty fibrils. Science 326 1216 1219
15. SchuppanDRuehlMSomasundaramRHahnEG 2001 Matrix as a modulator of hepatic fibrogenesis. Semin Liver Dis 21 351 372
16. Van HulNKAbarca-QuinonesJSempouxCHorsmansYLeclercqIA 2009 Relation between liver progenitor cell expansion and extracellular matrix deposition in a CDE-induced murine model of chronic liver injury. Hepatology 49 1625 1635
17. GaliciaVAHeLDangHKanelGVendryesC 2010 Expansion of hepatic tumor progenitor cells in Pten-null mice requires liver injury and is reversed by loss of AKT2. Gastroenterology
18. ThornerPSZhengKKalluriRJacobsRHudsonBG 1996 Coordinate gene expression of the alpha3, alpha4, and alpha5 chains of collagen type IV. Evidence from a canine model of X-linked nephritis with a COL4A5 gene mutation. J Biol Chem 271 13821 13828
19. Le BailBFaouziSBoussarieLBalabaudCBioulac-SageP 1997 Extracellular matrix composition and integrin expression in early hepatocarcinogenesis in human cirrhotic liver. J Pathol 181 330 337
20. QuelardDLavergneEHendaouiIElamaaHTiirolaU 2008 A cryptic frizzled module in cell surface collagen 18 inhibits Wnt/beta-catenin signaling. PLoS ONE 3 e1878 doi:10.1371/journal.pone.0001878
21. MussoOTheretNHeljasvaaraRRehnMTurlinB 2001 Tumor hepatocytes and basement membrane-producing cells specifically express two different forms of the endostatin precursor, collagen XVIII, in human liver cancers. Hepatology 33 868 876
22. Ortiz-UrdaSGarciaJGreenCLChenLLinQ 2005 Type VII collagen is required for Ras-driven human epidermal tumorigenesis. Science 307 1773 1776
23. AumailleyMBruckner-TudermanLCarterWGDeutzmannREdgarD 2005 A simplified laminin nomenclature. Matrix Biol 24 326 332
24. KikkawaYSudoRKonJMizuguchiTNomizuM 2008 Laminin alpha 5 mediates ectopic adhesion of hepatocellular carcinoma through integrins and/or Lutheran/basal cell adhesion molecule. Exp Cell Res 314 2579 2590
25. SrisomsapCSawangareetrakulPSubhasitanontPChokchaichamnankitDChiablaemK 2010 Proteomic studies of cholangiocarcinoma and hepatocellular carcinoma cell secretomes. J Biomed Biotechnol 2010 437143
26. OkamuraNYoshidaMShibuyaASugiuraHOkayasuI 2005 Cellular and stromal characteristics in the scirrhous hepatocellular carcinoma: comparison with hepatocellular carcinomas and intrahepatic cholangiocarcinomas. Pathol Int 55 724 731
27. WellsRG 2008 Cellular sources of extracellular matrix in hepatic fibrosis. Clin Liver Dis 12 759 768, viii
28. FriedmanSL 2008 Mechanisms of hepatic fibrogenesis. Gastroenterology 134 1655 1669
29. HeinoJKapylaJ 2009 Cellular receptors of extracellular matrix molecules. Curr Pharm Des 15 1309 1317
30. HynesRO 2002 Integrins: bidirectional, allosteric signaling machines. Cell 110 673 687
31. EvseenkoDSchenke-LaylandKDravidGZhuYHaoQL 2009 Identification of the critical extracellular matrix proteins that promote human embryonic stem cell assembly. Stem Cells Dev 18 919 928
32. RodinSDomogatskayaAStromSHanssonEMChienKR 2010 Long-term self-renewal of human pluripotent stem cells on human recombinant laminin-511. Nat Biotechnol 28 611 615
33. HoppoTFujiiHHiroseTYasuchikaKAzumaH 2004 Thy1-positive mesenchymal cells promote the maturation of CD49f-positive hepatic progenitor cells in the mouse fetal liver. Hepatology 39 1362 1370
34. BergaminiCSgarraCTrerotoliPLupoLAzzaritiA 2007 Laminin-5 stimulates hepatocellular carcinoma growth through a different function of alpha6beta4 and alpha3beta1 integrins. Hepatology 46 1801 1809
35. CraigRBeavisRC 2004 TANDEM: matching proteins with tandem mass spectra. Bioinformatics 20 1466 1467
36. NesvizhskiiAIKellerAKolkerEAebersoldR 2003 A statistical model for identifying proteins by tandem mass spectrometry. Anal Chem 75 4646 4658
37. KellerANesvizhskiiAIKolkerEAebersoldR 2002 Empirical statistical model to estimate the accuracy of peptide identifications made by MS/MS and database search. Anal Chem 74 5383 5392
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2011 Číslo 6
- Gynekologové a odborníci na reprodukční medicínu se sejdou na prvním virtuálním summitu
- Je „freeze-all“ pro všechny? Odborníci na fertilitu diskutovali na virtuálním summitu
Najčítanejšie v tomto čísle
- Statistical Inference on the Mechanisms of Genome Evolution
- Recurrent Chromosome 16p13.1 Duplications Are a Risk Factor for Aortic Dissections
- Chromosomal Macrodomains and Associated Proteins: Implications for DNA Organization and Replication in Gram Negative Bacteria
- Maps of Open Chromatin Guide the Functional Follow-Up of Genome-Wide Association Signals: Application to Hematological Traits