Role of Hypoxia-Inducible Factor (HIF) in Liver Cancer

Abstract

Liver cancer is one of the major causes of cancer-related deaths in the United States, accounting for 4.5% of the total estimated cancer deaths in 2016 and standing as the second leading cause of cancer-related deaths in men worldwide in 2012. There are two major types of primary liver cancers, including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). The most common type of primary liver cancer is HCC, which begins in hepatocytes and accounts for approximately 75% of all liver cancers. Hypoxia, a condition of oxygen deprivation in the tissue, is a common feature of the cancer microenvironment due to increased cell proliferation and limited blood supply. Hypoxia-inducible factor-1 (HIF-1) was the first transcription factor discovered to regulate a wide range of target genes involved in many cellular processes in response to low oxygen levels. HIF-1 is a heterodimeric protein complex composed of two different subunits, α and β. During a condition of hypoxia, HIF-1 heterodimer activates target genes that contain a hypoxia response element (HRE) in the promoter region. The overexpression of HIF-1 is frequently observed in many human solid tumors, including liver cancer, and is associated with tumor development, poor prognosis, and resistance to chemotherapy, suggesting that HIF-1 is a new therapeutic target in liver cancer treatment. In this chapter, we define the molecular mechanism that controls HIF-1 and how it maintains a variation of biological processes in hypoxic environments.