Hypoxia-inducible factor-1α: A critical target for inhibiting the metastasis of hepatocellular carcinoma

Abstract

Metastasis is one of the major reasons for patient mortality in hepatocellular carcinoma (HCC), and the progression of HCC to a metastatic state depends on the local microenvironment. Hypoxia is a key condition affecting the microenvironment of HCC. Currently, various studies have shown that the expression of hypoxia-ainducible factor-1α (HIF-1α) is associated with the invasion and metastasis of HCC. High expression of HIF-1α often leads to poor prognosis in patients with HCC. In this review, the molecular structure of HIF-1α is described, and the expression pattern of HIF-1α in HCC under hypoxia, which is associated with metastasis and poor prognosis in HCC, is explained. The molecular mechanisms of HIF-1α function and the metastasis of HCC are further discussed. The modulation of HIF-1α can reduce sorafenib resistance and improve the prognosis of patients after TACE. Therefore, HIF-1α may be a critical target for inhibiting HCC metastasis in the future.

Keywords: HIF-1α; hepatocellular carcinoma; hypoxia; hypoxia-inducible factor-1α; tumor metastasis.

Figure 1.

Structure and synthetic pathway of HIF-1α. (A) Structure of HIF-1α. (B) (a) High expression of HDAC5 in hepatocellular carcinoma leads to silencing of HIPK2, which in turn induces the upregulation of HIF-1α. (b) M2-phenotype TAMs release IL-1β in the presence of persistent hypoxia and inflammation, which promotes HIF-1α synthesis. (c) DAAM can induce HIF-1α by reducing the expression of VHL in hepatoma cells. (d) Activated HSCs promote the upregulation of TGM2 in HCC cells through inflammatory signals, which can cause VHL depletion and lead to HIF-1α accumulation. TAMs, tumor-associated macrophages; IL-1β, interleukin-1β; HDAC5, histone deacetylase5; HIF-1α, hypoxia-inducible factor-1α; HIPK2, recombinant homeodomain interacting protein kinase 2; HSCs, hepatic stellate cells; VHL, Von Hippel-Lindau; TGM2, transglutaminase 2; DAAM, Dishevelled-associated activator of morphogenesis.