scholarly journals Hepatocyte nuclear factor 4α and cancer-related cell signaling pathways: a promising insight into cancer treatment

2021 ◽  
Vol 53 (1) ◽  
pp. 8-18
Author(s):  
Duo-Duo Lv ◽  
Ling-Yun Zhou ◽  
Hong Tang
Keyword(s):  
Signaling Pathways ◽  
Transforming Growth Factor ◽  
Critical Factor ◽  
Transforming Growth Factor Β ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Cellular Processes ◽  
Hepatocyte Nuclear Factor 4Α ◽  
Transcription 3

AbstractHepatocyte nuclear factor 4α (HNF4α), a member of the nuclear receptor superfamily, is described as a protein that binds to the promoters of specific genes. It controls the expression of functional genes and is also involved in the regulation of numerous cellular processes. A large number of studies have demonstrated that HNF4α is involved in many human malignancies. Abnormal expression of HNF4α is emerging as a critical factor in cancer cell proliferation, apoptosis, invasion, dedifferentiation, and metastasis. In this review, we present emerging insights into the roles of HNF4α in the occurrence, progression, and treatment of cancer; reveal various mechanisms of HNF4α in cancer (e.g., the Wnt/β-catenin, nuclear factor-κB, signal transducer and activator of transcription 3, and transforming growth factor β signaling pathways); and highlight potential clinical uses of HNF4α as a biomarker and therapeutic target for cancer.

Co-activation of synovial fibroblasts by laminin-111 and transforming growth factor-β induces expression of matrix metalloproteinases 3 and 10 independently of nuclear factor-κB

2007 ◽  
Vol 67 (4) ◽  
pp. 559-562 ◽  
Author(s):  
K Warstat ◽  
T Pap ◽  
G Klein ◽  
S Gay ◽  
W K Aicher
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Synovial Fibroblasts ◽  
Transforming Growth Factor Β ◽  
Nuclear Factor Κb ◽  
Mrna Levels ◽  
Nuclear Factor ◽  
The Matrix ◽  
Specific Tissue ◽  
Significant Expression

We showed previously that the attachment of synovial fibroblasts to laminin (LM)-111 in the presence of transforming growth factor-β induces significant expression of the matrix metalloproteinase (MMP)-3. Here we go on to investigate the regulation of additional MMPs and their specific tissue inhibitors of matrix proteases (TIMPs). Changes in steady-state mRNA levels encoding TIMPs and MMPs were investigated by quantitative reverse transcription–polymerase chain reaction. Production of MMPs was monitored by a multiplexed immunoarray. Signal transduction pathways were studied by immunoblotting. Attachment of synovial fibroblasts to LM-111 in the presence of transforming growth factor-β induced significant increases in MMP-3 mRNA (12.35-fold, p<0.001) and protein (mean 62 ng/ml, sixfold, p<0.008) and in expression of MMP-10 mRNA (11.68-fold, p<0.05) and protein (54 ng/ml, 20-fold, p⩾0.02). All other TIMPs and MMPs investigated failed to show this LM-111-facilitated transforming growth factor-β response. No phosphorylation of nuclear factor-κB was observed. We conclude that co-stimulation of synovial fibroblasts by LM-111 together with transforming growth factor-β suffices to induce significant expression of MMP-3 and MMP-10 by synovial fibroblasts and that this induction is independent of nuclear factor-κB phosphorylation.

Hepatocyte nuclear factor 4α attenuates hepatic fibrosis in rats

Gut ◽  
2009 ◽  
Vol 59 (2) ◽  
pp. 236-246 ◽  
Author(s):  
H-Y Yue ◽  
C Yin ◽  
J-L Hou ◽  
X Zeng ◽  
Y-X Chen ◽  
...  
Keyword(s):  
Hepatic Fibrosis ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Fibrotic Liver ◽  
Mesenchymal Transition ◽  
Duct Ligation ◽  
Enhanced Expression ◽  
Hepatocyte Nuclear Factor 4Α

Background and aimsHepatocyte nuclear factor 4α (HNF4α) is a central transcriptional regulator of hepatocyte differentiation and function. The aim of this study was to evaluate the effect of HNF4α on attenuation of hepatic fibrosis.MethodsThe adenoviruses carrying HNF4α gene or containing siRNA targeting HNF4α were injected through tail vein on two distinct hepatic fibrosis models either induced by dimethylnitrosamine or by bile duct ligation in rats. Moreover, HNF4α, epithelial–mesenchymal transition (EMT)-related and fibrotic markers in hepatocytes, hepatic stellate cells (HSCs) and liver tissues were detected by real time PCR, immunofluorescence or immunohistochemistry.ResultsWe demonstrated that decreased expression of HNF4α and epithelial markers accompanied by enhanced expression of mesenchymal markers occurred in fibrotic liver. More importantly, forced expression of HNF4α remarkably alleviated hepatic fibrosis and improved liver function with suppression of EMT in both fibrosis models. In contrast, downregulation of HNF4α by siRNA aggravated hepatic fibrosis and decreased the expression of E-cadherin in association with the enhanced expression of vimentin and fibroblast-specific protein-1. In vitro study revealed that HNF4α could suppress the EMT process of hepatocytes induced by transforming growth factor-β1 and increase the expression of liver-specific genes. A similar phenomenon of the EMT process was observed during the activation of HSCs, which was abrogated by HNF4α. Additionally, HNF4α deactivated the myofibroblasts through inducing the mesenchymal-to-epithelial transition and inhibited their proliferation.ConclusionsOur study suggests that HNF4α is critical for hepatic fibrogenesis and upregulation of HNF4α might present as an ideal option for the treatment of hepatic fibrosis.

l-Theanine prevents carbon tetrachloride-induced liver fibrosis via inhibition of nuclear factor κB and down-regulation of transforming growth factor β and connective tissue growth factor

2015 ◽  
Vol 35 (2) ◽  
pp. 135-146 ◽  
Author(s):  
JE Pérez-Vargas ◽  
N Zarco ◽  
P Vergara ◽  
M Shibayama ◽  
J Segovia ◽  
...  
Keyword(s):  
Carbon Tetrachloride ◽  
Growth Factor ◽  
Connective Tissue ◽  
Connective Tissue Growth Factor ◽  
Hepatic Cirrhosis ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Nuclear Factor Κb ◽  
Tissue Growth ◽  
Nuclear Factor

Here we evaluated the ability of l-theanine in preventing experimental hepatic cirrhosis and investigated the roles of nuclear factor-κB (NF-κB) activation as well as transforming growth factor β (TGF-β) and connective tissue growth factor (CTGF) regulation. Experimental hepatic cirrhosis was established by the administration of carbon tetrachloride (CCl4) to rats (0.4 g/kg, intraperitoneally, three times per week, for 8 weeks), and at the same time, adding l-theanine (8.0 mg/kg) to the drinking water. Rats had ad libitum access to water and food throughout the treatment period. CCl4 treatment promoted NF-κB activation and increased the expression of both TGF-β and CTGF. CCl4 increased the serum activities of alanine aminotransferase and γ-glutamyl transpeptidase and the degree of lipid peroxidation, and it also induced a decrease in the glutathione and glutathione disulfide ratio. l-Theanine prevented increased expression of NF-κB and down-regulated the pro-inflammatory (interleukin (IL)-1β and IL-6) and profibrotic (TGF-β and CTGF) cytokines. Furthermore, the levels of messenger RNA encoding these proteins decreased in agreement with the expression levels. l-Theanine promoted the expression of the anti-inflammatory cytokine IL-10 and the fibrolytic enzyme metalloproteinase-13. Liver hydroxyproline contents and histopathological analysis demonstrated the anti-fibrotic effect of l-theanine. In conclusion, l-theanine prevents CCl4-induced experimental hepatic cirrhosis in rats by blocking the main pro-inflammatory and pro-fibrogenic signals.

scholarly journals Mechanism of a Transcriptional Cross Talk between Transforming Growth Factor-β–regulated Smad3 and Smad4 Proteins and Orphan Nuclear Receptor Hepatocyte Nuclear Factor-4

2003 ◽  
Vol 14 (3) ◽  
pp. 1279-1294 ◽  
Author(s):  
Wan-Chih Chou ◽  
Vassiliki Prokova ◽  
Keiko Shiraishi ◽  
Ulrich Valcourt ◽  
Aristidis Moustakas ◽  
...  
Keyword(s):  
Growth Factor ◽  
Nuclear Receptor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Nuclear Factor ◽  
Dna Binding Domain ◽  
Hepatocyte Nuclear Factor ◽  
Hepatocyte Nuclear Factor 4 ◽  
Target Promoters

We have shown previously that the transforming growth factor-β (TGFβ)-regulated Sma-Mad (Smad) protein 3 and Smad4 proteins transactivate the apolipoprotein C-III promoter in hepatic cells via a hormone response element that binds the nuclear receptor hepatocyte nuclear factor 4 (HNF-4). In the present study, we show that Smad3 and Smad4 but not Smad2 physically interact with HNF-4 via their Mad homology 1 domains both in vitro and in vivo.The synergistic transactivation of target promoters by Smads and HNF-4 was shown to depend on the specific promoter context and did not require an intact β-hairpin/DNA binding domain of the Smads. Using glutathione S-transferase interaction assays, we established that two regions of HNF-4, the N-terminal activation function 1 (AF-1) domain (aa 1–24) and the C-terminal F domain (aa 388–455) can mediate physical Smad3/HNF-4 interactions in vitro. In vivo, Smad3 and Smad4 proteins enhanced the transactivation function of various GAL4-HNF-4 fusion proteins via the AF-1 and the adjacent DNA binding domain, whereas a single tyrosine to alanine substitution in AF-1 abolished coactivation by Smads. The findings suggest that the transcriptional cross talk between the TGFβ-regulated Smads and HNF-4 is mediated by specific functional domains in the two types of transcription factors. Furthermore, the specificity of this interaction for certain target promoters may play an important role in various hepatocyte functions, which are regulated by TGFβ and the Smads.

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