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Traditional Medicine Research  2018, Vol. 3 Issue (1): 10-21    DOI: 10.12032/TMR201809060
Modernization of Traditional Medicine     
TGF-β signaling in hepatocellular carcinoma suppression and progression
Jian Hao1, Dan Chen2,*()
1Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
2School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
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Highlights

This paper evaluates the suppressive and accelerant roles of TGF-β in hepatocellular carcinoma, discusses how a tumor-suppressor pathway can be so radically turned on its head and further provides some new molecular insights that may aid efforts towards targeted antitumor therapies.

Editor’s Summary

This review pays particular attention to the dual role of TGF-β in hepatocellular carcinoma. It also discusses the potential anti-tumor herbs through TGF-β signaling pathways.

Abstract

Derangements of several cell signaling pathways have been implicated in the initiation, progression, and development of hepatocellular carcinoma (HCC). One of such pathways is the activated TGF-β/Smad pathway. TGF-β inhibits proliferation and induces apoptosis in various cells types in the early tumor, and accumulation of loss-of-function mutations in the TGF-β receptor or Smad genes in tumor classify the pathway as a tumor suppressor. However, in chronic hepatitis, the cytostatic effect of TGF-β for hepatocytes attenuates as liver disease progresses from cirrhosis to HCC under persistent inflammatory microenvironments. In the later cancer period, TGF-β promotes tumor growth by modulating processes such as cell invasion, immune regulation, and microenvironment modification. Here we evaluate the suppressive and accelerant roles of TGF-β in HCC, discuss how a tumor-suppressor pathway can be so radically turned on its head and further provide some new molecular insights that may aid efforts towards targeted antitumor therapies. Moreover, we discussed the potential anti-tumor herbs through TGF-β signaling pathways.



Key wordsTGF-β      Hepatocellular Carcinoma      Suppression      Progression      Anti-tumor herbs     
Published: 05 January 2018
Corresponding Authors: Chen Dan     E-mail: ilvcd@163.com.
Cite this article:

Jian Hao, Dan Chen. TGF-β signaling in hepatocellular carcinoma suppression and progression. Traditional Medicine Research, 2018, 3(1): 10-21. doi: 10.12032/TMR201809060

URL:

https://www.tmrjournals.com/tmr/EN/10.12032/TMR201809060     OR     https://www.tmrjournals.com/tmr/EN/Y2018/V3/I1/10

Figure 1 Smad-dependent and Smad-independent TGF-β pathways

In the Smad-dependent pathway, the three TGF-β ligand isoforms, TGF-β1, TGF-β2, and TGF-β3, are activated and assisted by the membranous TGF-β type III receptor to bind to TGF-β type II receptor (TGF-βRII) with high affinity. TGF-βRII binding allows dimerization with TGF-β type I receptor (TGF-βRI) homodimers, activation of the TGF-βRI kinase domain and signal transduction via phosphorylation of the C-terminus of receptor-regulated SMADs (R-SMAD), SMAD2 and SMAD3. The TGF-βR dimer then forms a heterotrimeric complex with SMAD4 which translocates and accumulates in the nucleus. TGF-β dependent signaling can activate or repress hundreds of target genes through the interaction of SMADs with various transcription factors (TF). SMAD activities are regulated via expression of inhibitory SMAD6 and SMAD7. In the Smad-independent pathway, TGF-β signaling activates other pathways such as PI3K/AKT, MAPK pathways (ERK, JNK, and p38 MAPK) as well as NF-kB, Rho/Rac1, CDC42, FAK, Src, Abl. The TGF-β signaling pathway has pleiotropic functions regulating cell growth, differentiation, apoptosis, cell motility, extracellular matrix production, angiogenesis and cellular immune response.

Figure 2 TGF-β signaling in HCC progression and suppression

Tumor suppressive effects. Cell cycle arrest by increasing tumour suppressing genes and decreasing oncogenes; Induces autophagy, differentiation, senescence and apoptosis; Suppresses angiogenesis through inhibiting VEGF; Inhibits inflammatory cytokine production from lymphocytes and macrophages.

Tumor promoter effects. Growth and migration promotion of HCC cells via inducing the production of growth factors epithelial-mesenchymal transition induction, evasion of immune surveillance, Augments microenvironment-modifying proteases and cytokines; invasion and angiogenesis by inducing expression of genes such as MMP2, MMP9 and CTGF.

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