Published online Nov 14, 2015. doi: 10.3748/wjg.v21.i42.12171
Peer-review started: May 5, 2015
First decision: July 14, 2015
Revised: July 27, 2015
Accepted: September 30, 2015
Article in press: September 30, 2015
Published online: November 14, 2015
Hepatocellular carcinoma (HCC) is one of the most commonly diagnosed and deadly cancers worldwide; its incidence has been rising in the United States due to the increase in hepatitis C associated cirrhosis and the growing epidemic of obesity. There have been no effective therapeutic options in the advanced disease setting beyond sorafenib, a multi-targeted tyrosine kinase inhibitor that showed significant survival benefit. Because of this, there is an urgent need to search for novel pathways in sorafenib experienced patients. This review will focus on the role of hypoxia and hypoxia-inducible factor alpha (HIF-1α) in cancer development, specifically in HCC. We will discuss the biology of HIF-1α, the pathways with which it interacts, and the function of HIF-1α in HCC. Furthermore, we will review studies highlighting the relevance of HIF-1α in the clinical setting, as well as the pre-clinical data supporting its further investigation. Finally, we will conclude with a discussion of the potential role of a HIF-1α mRNA antagonist for the treatment of HCC, and hypothesize the ways in which such an inhibitor may be best utilized in the management of advanced HCC. Hypoxia plays a significant role in the development of HCC. HIF-1α is a key transcription factor involved in the hypoxic response of cancer cells. It activates transcription of genes responsible for angiogenesis, glucose metabolism, proliferation, invasion and metastasis in HCC. Its involvement in multiple, essential tumor pathways makes it an attractive potential therapeutic target in HCC.
Core tip: Beyond sorafenib, limited systemic treatment options exist for the treatment of advanced hepatocellular carcinoma (HCC). Hypoxia and hypoxia-inducible factor alpha (HIF-1α) have emerged as important factors in the development of HCC. This review focuses on the scientific background and pre-clinical data of HIF-1α and will conclude in a discussion of the clinical relevance of this transcription factor and its potential therapeutic role, particularly in combination with other therapies, in HCC. A phase IB clinical trial to investigate a HIF-1α mRNA antagonist in HCC patients who have failed first line systemic treatment is currently underway.