Roles of transforming growth factor-β signaling in liver disease

Table 1 Potential targets of transforming growth factor-β signaling in liver disease

Potential targets	Members of the family	Disease	Research progress	Ref.
GDF	GDF-15	Hepatitis	GDF-15 directly inhibits fibrosis-related genes and osteopontin in hepatic stellate cells	[5]
		Hepatic fibrosis	GDF 15 attenuates chemically induced hepatic fibrosis and delays hepatic stellate cell activation	[5,19]
		Hepatic fibrosis	Through TGF-β1/SMAD3 signaling pathway, SMAD3 phosphorylation is blocked and liver fibrosis is inhibited	[20]
BMP	BMP8B	Hepatitis	BMP 8B signals through the SMAD 2/3 and SMAD1/5/9 branches of the TGFβ-BMP pathway in hepatic stellate cells to promote their pro-inflammatory phenotype	[6]
	BMP-2	Hepatic fibrosis	BMP-2 significantly inhibits the expression of TGF-β and its homologous type I and Type II receptor peptides, and induces Smad3 phosphorylation	[13]
	BMP-7	Liver cirrhosis	Adenovirus BMP-7 transduction induces a decrease in type I collagen deposition by increasing MMP-13 and decreasing TIMP-2 expression	[27]
	BMP-9	Liver cancer	Down-regulating the interstitial contact of cells surrounding the tumor induces epithelial–mesenchymal transformation of tumor cells, thereby promoting tumor metastasis and growth	[38]
TGF-β	TGF-β1	Hepatitis	TGF-β1 with its α-helix3 deleted is still effective against HCV, and TGF-β1 may inhibit HCV transmission in a manner independent of the TGF-β/SMAD signaling pathway	[7]
	TGF-β1	Liver cirrhosis	Few macrophages express TGF-β1 when cirrhosis is present; however, the protein is expressed in hepatocytes within several pseudolobules of the liver with advanced fibrosis and cirrhosis	[22-24]
	TGF-β	Liver cancer	TGF-β is a tumor suppressor in the early stages of liver cancer by inducing apoptosis and eliminating precursor lesions. During later stages, liver tumor cells often become resistant to apoptosis and produce large amounts of TGF-β	[31]
	TGF-β1/BMP-7	Liver cancer	Simultaneous knockdown of TGFBR2 and overexpressed ACVR1 induces complete activation of the BMP-7 pathway in HCC cells, significantly aggravating the invasiveness and stemness of HCC cells	[35-37]
Activin	Activin A	Hepatic fibrosis	Activin A can induce the expression of TGFβ1 and other fibrotic regulators and intermediates	[11-13]
	Activin βA	Liver cirrhosis	Activin βA induces hepatocyte apoptosis and inhibits liver regeneration in vivo, resulting in increased damage to liver regeneration during the later cirrhosis stages	[25,26]
	Activin βE	Liver cancer	Activin can negatively regulate the growth of hepatocellular carcinoma cells and inhibit the synthesis of raw DNA	[31-34]
miRNA	miR-199a	Hepatic fibrosis	miR-199a enhances the expression of fibrotic genes to promote liver fibrosis, such as genes encoding α1 procollagen, collagenase 3, and metalloproteinase inhibitor 1	[16,17]
	miR-200		miR-200 inhibits SMAD3 activity and attenuates TGF-β1-induced fibrosis	[18]

GDF: Growth and differentiation factor; TGF-β: Transforming growth factor-β; BMP: Bone morphogenetic protein; MMP: Matrix metalloproteinases; TIMP: Tissue inhibitor of matrix metalloproteinases; HCC: Hepatocellular carcinoma; HCV: Hepatitis C virus.