Regulation of TGF-β1-induced proapoptotic signaling by growth factor receptors and extracellular matrix receptor integrins in the liver
Hepatocellular carcinoma (HCC) often arises from chronically diseased livers. Persistent liver inflammation causes the accumulation of excessive extracellular matrix (ECM) proteins and impairs the liver function, finally leading to the development of HCC. A pleiotropic cytokine, transforming growth...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2011-10-01
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| Series: | Frontiers in Physiology |
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| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fphys.2011.00078/full |
| _version_ | 1828303637383741440 |
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| author | Iwata eOzaki Iwata eOzaki Hiroshi eHamajima Sachiko eMatsuhashi Toshihiko eMizuta |
| author_facet | Iwata eOzaki Iwata eOzaki Hiroshi eHamajima Sachiko eMatsuhashi Toshihiko eMizuta |
| author_sort | Iwata eOzaki |
| collection | DOAJ |
| description | Hepatocellular carcinoma (HCC) often arises from chronically diseased livers. Persistent liver inflammation causes the accumulation of excessive extracellular matrix (ECM) proteins and impairs the liver function, finally leading to the development of HCC. A pleiotropic cytokine, transforming growth factor(TGF)-β, plays critical roles throughout the process of fibrogenesis and hepatocarcinogenesis. In the liver, TGF-β inhibits the proliferation of hepatocytes and stimulates the production of ECM from hepatic stellate cells (HSCs) to maintain tissue homeostasis. During disease progression, both growth factors/cytokines and the ECM alter the TGF-β signals by modifying the phosphorylation of Smad proteins at their C-terminal and linker regions. TGF-β stimulates the expression of integrin, a cellular receptor for ECM, along with an increase in ECM accumulation. The activation of integrin by the ECM modulates the response to TGF-β in hepatic cells, resulting in their resistance to TGF-β-induced growth suppression in hepatocytes and the sustained production of ECM proteins in activated HSCs/myofibroblasts. Both growth factor receptors and integrins modify the expression and/or functions of the downstream effectors of TGF-β, resulting in the escape of hepatocytes from TGF-β-induced apoptosis. Recent studies have revealed that the alterations of Smad phosphorylation that occur as the results of the crosstalk between TGF-β, growth factors and integrins could change the nature of TGF-β1 signals from tumor suppression to promotion. Therefore, the modification of Smad phosphorylation could be an attractive target for the prevention and/or treatment of HCC. |
| first_indexed | 2024-04-13T13:57:06Z |
| format | Article |
| id | doaj.art-ebf749b92c124c85a5cf81125744d047 |
| institution | Directory Open Access Journal |
| issn | 1664-042X |
| language | English |
| last_indexed | 2024-04-13T13:57:06Z |
| publishDate | 2011-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Physiology |
| spelling | doaj.art-ebf749b92c124c85a5cf81125744d0472022-12-22T02:44:11ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2011-10-01210.3389/fphys.2011.0007814442Regulation of TGF-β1-induced proapoptotic signaling by growth factor receptors and extracellular matrix receptor integrins in the liverIwata eOzaki0Iwata eOzaki1Hiroshi eHamajima2Sachiko eMatsuhashi3Toshihiko eMizuta4Saga Medical SchoolSaga Medical SchoolSaga Medical SchoolSaga Medical SchoolSaga Medical SchoolHepatocellular carcinoma (HCC) often arises from chronically diseased livers. Persistent liver inflammation causes the accumulation of excessive extracellular matrix (ECM) proteins and impairs the liver function, finally leading to the development of HCC. A pleiotropic cytokine, transforming growth factor(TGF)-β, plays critical roles throughout the process of fibrogenesis and hepatocarcinogenesis. In the liver, TGF-β inhibits the proliferation of hepatocytes and stimulates the production of ECM from hepatic stellate cells (HSCs) to maintain tissue homeostasis. During disease progression, both growth factors/cytokines and the ECM alter the TGF-β signals by modifying the phosphorylation of Smad proteins at their C-terminal and linker regions. TGF-β stimulates the expression of integrin, a cellular receptor for ECM, along with an increase in ECM accumulation. The activation of integrin by the ECM modulates the response to TGF-β in hepatic cells, resulting in their resistance to TGF-β-induced growth suppression in hepatocytes and the sustained production of ECM proteins in activated HSCs/myofibroblasts. Both growth factor receptors and integrins modify the expression and/or functions of the downstream effectors of TGF-β, resulting in the escape of hepatocytes from TGF-β-induced apoptosis. Recent studies have revealed that the alterations of Smad phosphorylation that occur as the results of the crosstalk between TGF-β, growth factors and integrins could change the nature of TGF-β1 signals from tumor suppression to promotion. Therefore, the modification of Smad phosphorylation could be an attractive target for the prevention and/or treatment of HCC.http://journal.frontiersin.org/Journal/10.3389/fphys.2011.00078/fullintegrinHepatocellular Carcinomaliver fibrosisSmadTGF-β |
| spellingShingle | Iwata eOzaki Iwata eOzaki Hiroshi eHamajima Sachiko eMatsuhashi Toshihiko eMizuta Regulation of TGF-β1-induced proapoptotic signaling by growth factor receptors and extracellular matrix receptor integrins in the liver Frontiers in Physiology integrin Hepatocellular Carcinoma liver fibrosis Smad TGF-β |
| title | Regulation of TGF-β1-induced proapoptotic signaling by growth factor receptors and extracellular matrix receptor integrins in the liver |
| title_full | Regulation of TGF-β1-induced proapoptotic signaling by growth factor receptors and extracellular matrix receptor integrins in the liver |
| title_fullStr | Regulation of TGF-β1-induced proapoptotic signaling by growth factor receptors and extracellular matrix receptor integrins in the liver |
| title_full_unstemmed | Regulation of TGF-β1-induced proapoptotic signaling by growth factor receptors and extracellular matrix receptor integrins in the liver |
| title_short | Regulation of TGF-β1-induced proapoptotic signaling by growth factor receptors and extracellular matrix receptor integrins in the liver |
| title_sort | regulation of tgf β1 induced proapoptotic signaling by growth factor receptors and extracellular matrix receptor integrins in the liver |
| topic | integrin Hepatocellular Carcinoma liver fibrosis Smad TGF-β |
| url | http://journal.frontiersin.org/Journal/10.3389/fphys.2011.00078/full |
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