Clinico-Pathological Importance of TGF-β/Phospho-Smad Signaling during Human Hepatic Fibrocarcinogenesis
<p>Differential phospho-Smad signals between tumor suppression and fibrocarcinogenesis. (<b>A</b>) Activated transforming growth factor (TGF)-β type I receptor (TβRI) phosphorylates COOH-tail serine residues of Smad2 and Smad3. Both COOH-terminally phosphorylated Smad2/3 (pSmad2C and pSmad3C) translocate with Smad4 to the nuclei of quiescent hepatocytes after regeneration. Smad2/3/4, complex binds the p21<sup>waf1</sup> promoter and suppresses cell growth; (<b>B</b>) Pro-inflammatory cytokines (CK) such as tumor necrosis factor-α activate c-Jun N-terminal kinase (JNK), which phosphorylates the linker regions of Smad2 and Smad3. Linker phosphorylated Smad3 (PSmad3L) translocates with Smad4 to the nucleus and binds plasminogen activator inhibitor type 1 (PAI-1) promoter. Linker phosphorylated Smad2 (PSmad2L) is localized in the cytoplasm, and Smad2 translocates to the nucleus only after COOH-tail phosphorylation by TβRI. PSmad2L/C in cooperation with pSmad3L and Smad4 stimulate PAI-1 transcription and extracellular matrix (ECM) deposition. PSmad3L up-regulates c-Myc and stimulates cell growth, while suppressing the pSmad3C-mediated tumor suppressive pathway.</p> "> Figure 2
<p>Phenotypic alternations of hepatocytes and HSC during the fibrocarcinogenic process in human chronic liver diseases. Quiescent hepatic stellate cells (HSC) are characterized by retinoid droplets in the cytoplasm and maintain liver homeostasis. HSC undergo constitutive activation to become myofibroblasts (MFB)-like cells after liver injury. MFB persistently produce an extracellular matrix (ECM) and induce liver fibrosis. The contraction of MFB contributes to increased portal resistance during liver fibrosis that presumably is reversible until the thickened septae, intrahepatic shunts, and lobular distortion that are characteristic of cirrhosis development, leading to fixed increases in portal pressure. Chronic liver damage promotes recurrent cycles of cellular proliferation, inflammation, fibrosis, and carcinogenesis. In pre-neoplastic hepatocytes, several growth factors and cytokines activate proliferation and invasion. As human hepatitis virus-related chronic liver diseases progress, chronic inflammation and hepatitis virus additively accelerate liver fibrosis and increase the risk of hepatocellular carcinoma (HCC). Genetic and epigenetic changes in the liver result in carcinogenesis. Effective antiviral therapy can reverse the pre-neoplastic properties of hepatocytes to a tumor-suppressive mode before the occurrence of genetic mutations that have been implicated for HCC occurrence.</p> ">
Abstract
:1. Introduction
2. Multiple Smad Phospho-Isoforms Signaling Exist
3. PSmad3C Displays Cytostatic Activity
4. PSmad3L (Ser-213) Enhances Mitogenic Pathways
5. PSmad2L/C and pSmad3L/C Promote Pro-Tumorigenic/Fibrogenic Pathways
6. A Shift of Hepatocytic Phospho-Smad Signaling from the Tumor-Suppressive pSmad3C Pathway to Carcinogenic pSmad3L and Fibrogenic pSmad2L/C Pathways Observed during Hepatic Fibrocarcinogenesis
7. Effective Antiviral Treatment Can Reverse Phospho-Smad Signaling in Early Stages of Chronic Liver Disease
8. Implications for HCC Prevention and Therapy
9. EMT in Liver Fibrosis and HCC Progression
10. Conclusions
Conflicts of Interest
References
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Yoshida, K.; Matsuzaki, K.; Murata, M.; Yamaguchi, T.; Suwa, K.; Okazaki, K. Clinico-Pathological Importance of TGF-β/Phospho-Smad Signaling during Human Hepatic Fibrocarcinogenesis. Cancers 2018, 10, 183. https://doi.org/10.3390/cancers10060183
Yoshida K, Matsuzaki K, Murata M, Yamaguchi T, Suwa K, Okazaki K. Clinico-Pathological Importance of TGF-β/Phospho-Smad Signaling during Human Hepatic Fibrocarcinogenesis. Cancers. 2018; 10(6):183. https://doi.org/10.3390/cancers10060183
Chicago/Turabian StyleYoshida, Katsunori, Koichi Matsuzaki, Miki Murata, Takashi Yamaguchi, Kanehiko Suwa, and Kazuichi Okazaki. 2018. "Clinico-Pathological Importance of TGF-β/Phospho-Smad Signaling during Human Hepatic Fibrocarcinogenesis" Cancers 10, no. 6: 183. https://doi.org/10.3390/cancers10060183