Mechanism of Hypoxia-Inducible Factor-1alpha Over- Expression and Molecular-Target Therapy for Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is one of the most common and rapidly fatal malignancies worldwide and has been ranked the second highest cancer killer in China since the 1990s, particularly in the eastern and southern areas, including the inshore area of the Yangtze River (1). Multiple risk factors are associated with HCC disease etiology, with the highest incidence in patients with chronic hepatitis B virus (HBV) and hepatitis C virus (HCV), although other factors such as genetic makeup and environmental exposure are involved (2~4). As a common malignant, solid tumor, HCC is characterized by fast infiltrating growth, early metastasis, high-grade malignancy, and poor therapeutic efficacy. It is a highly vascular tumor dependent on neovascularization and one of the most common and rapidly developing malignancies (5, 6). HCC treatment options are severely limited by the frequent presence of metastases (7~10, Fig.1). Multistep malignance of HCC progression with multigene alterations mostly accompany with chronic hepatitis and liver cirrhosis (11, 12). Hypoxia inducible factor-1 (HIF-1) is a basic-Helix–Loop–Helix Per-Arnt-Sim protein (bHLH-PAS) consisting of ┙ and ┚ subunits and a key transcription factor regulating cellular responses to hypoxia (13, 14), and can regulate neovascularization, activate expressions of many hypoxia-response genes, leading to closely associate with HCC ecosystem for tumor growth, infiltration, metastasis and prognosis (15~17). HIF-1┙ is an oxygen-dependent protein, which is degraded by poly ubiquitination and proteasomal degradation via the Von-Hippel-Lindau tumor suppressor protein under normoxic conditions (4, 18, 19). Here we briefly review the expression of rat hepatic HIF-1┙ and its gene during the malignant transformation of hepatocytes, the hepatic expression and circulating level of HIF-1┙ in patients with liver diseases for prospectively elucidating the relationship between HIF-1┙ level and the pathological features as well as the diagnosis and metastasis of HCC, and the effect of miRNA silencing HIF-1┙ gene on inhibition of HepG2 cell proliferation.