Background/Aim Transforming growth factor-beta (TGF-β) has a dichotomous role, functioning as a tumor suppressor and tumor promoter. TGF-β signatures, explored in mouse hepatocytes, have been reported to predict the clinical outcomes of hepatocellular carcinoma (HCC) patients; HCCs exhibiting early TGF-β signatures showed a better prognosis than those with late TGF-β signatures. The expression status of early and late TGF-β signatures remains unclear in defined lesions of human B-viral multistep hepatocarcinogenesis.
Methods The expression of TGF-β signatures, early and late responsive signatures of TGF-β were investigated and analyzed for their correlation in cirrhosis, low-grade dysplastic nodules (DNs), high-grade DNs, early HCCs and progressed HCCs (pHCCs) by real-time PCR and immunohistochemistry.
Results The expression levels of TGF-β signaling genes (TGFB1, TGFBR1, TGFBR2 and SMAD4) gradually increased with the progression of hepatocarcinogenesis, peaking in pHCCs. The expression of early responsive genes of TGF-β (GADD45B, FBP1, CYP1A2 and CYP3A4) gradually decreased, and that of the late TGF-β signatures (TWIST and SNAI1) significantly increased according to the progression of multistep hepatocarcinogenesis. Furthermore, mRNA levels of TWIST and SNAI1 were well correlated with those of stemness markers, with upregulation of TGF-β signaling, whereas FBP1 expression was inversely correlated with that of stemness markers.
Conclusions The enrichment of the late responsive signatures of TGF-β with induction of stemness is considered to be involved in the progression of the late stage of multistep hepatocarcinogenesis, whereas the early responsive signatures of TGF-β are suggested to have tumor-suppressive roles in precancerous lesions of the early stage of multistep hepatocarcinogenesis.
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Structure, unique biological properties, and mechanisms of action of transforming growth factor β Nataliya Zelisko, Roman Lesyk, Rostyslav Stoika Bioorganic Chemistry.2024; 150: 107611. CrossRef
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A functional and biochemical features of TIS21(/BTG2/PC3) was explored in hepatocarcinogenesis. Growth of hepatocellular
carcinoma (HCC), developed by a single injection of diethylnitrosamine (DEN) was significantly higher in the TIS21 knockout
mice at 9 months. Expression of BTG2/TIS21 was significantly lower in both human and mouse hepatocellular carcinoma than in
the surrounding normal tissues. Over-expression of TIS21 inhibited cell proliferation and tumorigenic potential of Huh7
hepatoma cells. At the molecular mechanistic level, TIS21 inhibited FoxM1 phosphorylation, by reducing cyclin B1-cdk1
activity. Furthermore, TIS21 inhibited FoxM1 transcriptional activity. In conclusion, TIS21 negatively regulated hepatocarcinogenesis
in part by disruption of the FoxM1-cyclin B1 regulatory loop, thereby inhibiting proliferation of transformed cells
developed in mouse and human livers.
Hepatocellular carcinoma (HCC) surveillance programs have led to an increase in the adoption of radical therapies.
Nevertheless, HCCs often present at an advanced stage and the prognosis remains dismal even after resection due to the high rate
of recurrence. The study of tumor biology is important to predict clinical outcome enabling more appropriate therapeutic decisions
for HCC patients. Understanding molecular mechanisms of hepatocarcinogenesis may also lead to effective strategies in
chemoprevention. However, current staging systems based on clinicopathologic factors are limited in prognostic prediction.
Recently, there has been great interest in the study of gene expression profile in relation to prognosis of HCC. Global gene
expression profiling may be the most appropriate technology to unravel the pathogenesis of HCC and explore its heterogeneous
origin. The elucidation of tumor biology of HCC is of paramount clinical importance in the new era of molecular target therapy.