**5.1 Transforming growth factor-**β**1 (TGF-**β**1)**

Transforming growth factor-β (TGF-β1) is a versatile growth factor associated with proliferation, cell differentiation, embryogenesis, vascular proliferation, invasion and immune activity. One study found that serum TGF-β1 levels increased in the HCC group compared to the group with non-malignant liver disease and the healthy group. With a cut-off of 800 pg./ml, the specificity of TGF-β1 HCC diagnostic serum is above 95%. Taking the same value as the serum AFP at the cut-off of 200 ng/ml, the sensitivity of TGF-β1 is 68%, which is superior to that of AFP (24%). Moreover, in patients with serum AFP within normal limits, increased TGF-β1 levels can be observed in 23% of cases [77]. It has been shown that TGF-β1 and TGF-β1 mRNA can be used as a marker to diagnose and predict HCC due to HBV with a sensitivity and specificity of 89.5% and 94.0% with a cutting level of TGF-β1 > 1.2 g/l [78]. TGF-β1 mediates various biological effects through signal paths and manifestations of TGF-β1 polymorphism may affect tumor susceptibility. The TGF-β1 signaling pathway can be considered as a target for HCC treatment. The subject is currently under study to confirm its role and promises to bring new cancer treatments.

#### **5.2 Vascular endothelial growth factor (VEGF)**

Vascular endothelial growth factor (VEGF) acts as an important factor in the process of tumor formation by forming new blood vessel systems that increase in size and promote invasion and metastasis. Studies have shown that angiogenesis is essential in tumor growth, including HCC, which is often characterized by the proliferation of blood vessels [79]. It has been demonstrated that VEGF expression in HCC tissues has a significantly higher incidence of portal vein thrombosis and

a lower average survival time than when VEGF expression is not present [80]. In the study of Xiang et al., VEGF was associated with lymph node metastatic characteristics in HCC. In addition, VEGF expression is closely related to relapse and prognosis. Notably, several manifestations of the VEGF receptor are related to some of the clinical characteristics and prognosis of HCC [81]. Inactivation of VEGF165 increases the expression of the *P53* gene that inhibits HCC development, invasion and metastasis.
