Abstract
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.
Highlights
Cirrhosis, the result of end-stage fibrosis, and steatohepatitis are common pre-neoplastic conditions associated with hepatocarcinogenesis [1]
The liver specific platelet-derived growth factor-C (PDGFC) Tg and phosphatase and tensin homolog (Pten) null mouse models reproduce the steps of hepatocellular carcinoma (HCC) development observed in humans progressing from steatohepatitis and fibrosis to hepatocyte dysplasia and tumorigenesis
The phenotypes of the tumors are different in these two models with characteristics of HCC in the PDGFC Tg model and with mixed cell characteristics of HCC and cholangiocarcinoma in the Pten null mice (Figure 1B)
Summary
The result of end-stage fibrosis, and steatohepatitis are common pre-neoplastic conditions associated with hepatocarcinogenesis [1]. Mice with liver-specific transgenic (Tg) expression of platelet-derived growth factor-C (PDGFC) represent a relevant model for such a study as members of the PDGF family play major roles in angiogenesis and fibrosis [2,3]. These mice develop liver fibrosis resembling human alcoholic and nonalcoholic fatty liver disease, which precedes development of HCC [4,5]. The presence of intermediate cells co-expressing both hepatocyte and biliary markers is associated with HCC occurrence [11] and acquisition of cholangiocarcinoma-like expression traits plays a critical role in the heterogeneous progression of HCC [12]. It is of particular relevance to compare liver proteome changes in both the PDGFC Tg and the Pten null models
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