Table 2.
Regulation of Smad Proteins in Liver Cancer.
| Regulators | Functions | Alternation of the Regulators | References |
|---|---|---|---|
| FHL1 | Exerts a tumor-suppressive role in liver cancer by triggering CK1δ-mediated and TGF-β receptor-independent phosphorylation of R-Smads. | Decreased in HCC tissues | [152] |
| NEK6 | Exerts a tumor-promoting effect by interacting with Smad4 and attenuating the anti-proliferative effect of TGF-β. | Undetermined | [153] |
| IL-37 | Inhibits Smad3-mediated oncogenic effects by inducing a conversion from the pSmad3L/c-Myc signaling to the pSmad3C/p21 signaling. | Decreased in human HCC tissues and cell lines | [157] |
| ELF | Acts as an adaptor protein for Smad3 and Smad4, therefore promoting the cytostatic effects of TGF-β in liver cancer. ELF+/- mice spontaneously developed HCC. | Reduced in liver cancer tissues | [147,148,149] |
| PRAJA | Alleviates the tumor-inhibitory effect of TGF-β by associating with both ELF and Smad3 upon ligand stimulation. | Elevated in liver cancer tissues | [150] |
| GRK2 | Interferes with Smad-mediated cytostatic effects by inhibiting TGF-β-induced C-terminal phosphorylation of Smad2/3. | Undetermined | [151] |
| TNF-α/ IL-1β |
Promotes hepatocyte proliferation by inducing JNK-mediated linker phosphorylation of Smad3 and enhancing c-Myc expression. | Undetermined | [154] |
| MUC1 | Converts the pSmad2/3C/p21 signaling to the pSmad2/3L/c-Myc oncogenic signaling by inducing JNK-mediated linker phosphorylation of Smad2/3. | Overexpressed in HCC cell lines | [83,84,156] |
| TRIM52 | Promotes liver cancer progression by inducing PPM1A degradation and enhancing the pSmad2/3C levels. | Highly expressed in HCC tissues | [158,159] |
| TIF1γ | Antagonizes TGF-β-mediated cytostatic effects in the early stage and inhibiting EMT in the late stage by mono-ubiquitynating Smad4 and inhibiting its oligomerization with R-Smads. | Reduced in advanced HCCs | [160] |
| NCX1/ TRPC6 |
Be required for TGF-β-induced R-Smad activation and contribute to TGF-β-mediated EMT, invasion and intrahepatic metastasis. | Elevated in human HCC cells | [161] |
| CXXC5 | Removes the histone deacetylase HDAC1 from activated Smad2/3 to potentiate TGF-β-mediated growth inhibition of HCC cells. | Decreased in HCC tissues | [169,170] |
| KLF17 | Interacts with and enhances the transcriptional activity of Smad3, thereby facilitating TGF-β-mediated cytostatic effects in HCC. | Decreased in advanced HCCs | [171] |
| SRF | Attenuates the cytostatic functions of TGF-β by inhibiting Smad-DNA binding in HCC cells. | Undetermined | [168] |
| EVI | Acts as a transcriptional repressor for Smad3 to blunt TGF-β-mediated growth inhibition of HCC cells. | Elevated in a subset of primary HCCs | [172] |
| FoxO3 | Interact with TGF-β-activated Smad2/3 and mediates TGF-β-induced apoptosis of liver cancer cells. | Undetermined | [163,164] |
| cPLA2α | Counteracts TGF-β-induced cytostasis by activating PPARγ and inhibiting R-Smad activity, and promotes HCC cell proliferation, EMT, migration and invasion by activating PI3K/Akt signaling. | Highly expressed in metastatic HCC cell lines and at the invasive edge in HCC tissues | [173,174] |
| p53 | Cooperates with Smads to enhance the expression levels of cell cycle- and apoptosis-related genes like p21, p15, Bim and DAPK, and meanwhile to inhibit those of AFP and Snail. | Reduced or mutated in liver cancer | [127,165,166,167] |