Abstract
Epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) are observed during both physiological liver wound healing and the pathological fibrotic/carcinogenic (fibro-carcinogenetic) process. TGF-β and pro-inflammatory cytokine are considered to be the major factors accelerating liver fibrosis and promoting liver carcinogenesis. Smads, consisting of intermediate linker regions connecting Mad homology domains, act as the intracellular mediators of the TGF-β signal transduction pathway. As the TGF-β receptors, c-Jun N-terminal kinase and cyclin-dependent kinase, differentially phosphorylate Smad2/3, we have generated numerous antibodies against linker (L) and C-terminal (C) phosphorylation sites in Smad2/3 and identified four types of phosphorylated forms: cytostatic COOH-terminally-phosphorylated Smad3 (pSmad3C), mitogenic pSmad3L (Ser-213) signaling, fibrogenic pSmad2L (Ser-245/250/255)/C signaling and migratory pSmad2/3L (Thr-220/179)/C signaling. After acute liver injury, TGF-β upregulates pSmad3C signaling and terminates pSmad3L (Ser-213)-mediated hepatocyte proliferation. TGF-β and pro-inflammatory cytokines cooperatively enhance collagen synthesis by upregulating pSmad2L (Thr-220)/C and pSmad3L (Thr-179)/C pathways in activated hepatic stellate cells. During chronic liver injuries, hepatocytes persistently affected by TGF-β and pro-inflammatory cytokines eventually become pre-neoplastic hepatocytes. Both myofibroblasts and pre-neoplastic hepatocyte exhibit the same carcinogenic (mitogenic) pSmad3L (Ser-213) and fibrogenic pSmad2L (Ser-245/250/255)/C signaling, with acquisition of fibro-carcinogenic properties and increasing risk of hepatocellular carcinoma (HCC). Firstly, we review phospho-Smad-isoform signalings in epithelial and mesenchymal cells in physiological and pathological conditions and then consider Smad linker phosphorylation as a potential target for pathological EMT during human fibro-carcinogenesis, because human Smad phospho-isoform signals can reverse from fibro-carcinogenesis to tumor-suppression in a process of MET after therapy.
Highlights
An epithelial-mesenchymal transition (EMT), firstly reported by Elizabeth Hay in 1982, is a biologic process that allows a polarized epithelial cell, which normally undergoes multiple biochemical changes, to be able to assume a mesenchymal cell phenotype [1]
Undergoing an EMT refers to the loss of apicobasal polarity in epithelial cells; intercellular adhesion complexes undergo dramatic phenotypic change, causing them to become nonpolar and, allowing these cells to move through the extracellular matrix (ECM) like mesenchymal cells [2]
These results suggest that transforming growth factor (TGF)-β is the most established mediator and regulator molecule in liver EMT and fibrosis
Summary
An epithelial-mesenchymal transition (EMT), firstly reported by Elizabeth Hay in 1982, is a biologic process that allows a polarized epithelial cell, which normally undergoes multiple biochemical changes, to be able to assume a mesenchymal cell phenotype [1]. Current evidence suggests that regulation of ECM accumulation by fibrogenic TGF-β signals involves different mechanisms in acute and chronic liver injuries, plasma TGF-β is elevated and thought to control liver regeneration and fibrosis in both situations [10,11]. Several conditions in chronically-damaged livers favor human hepatocarcinogenesis, mostly resulting from recurrent cycles of cellular proliferation, inflammation and fibrosis. Within this anomalous environment, certain clones of hepatocytes acquire proliferative and survival advantages, eventually forming dysplastic nodules, the histological substrate of HCC [17]. We consider the TGF-β signal as a potential target for pathological EMT during human fibro-carcinogenesis, because the human TGF-β signal can reverse from fibro-carcinogenesis to tumor-suppression in a process of mesenchymal-to-epithelial transition (MET) after therapy
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