Harnessing the RNA interference pathway to advance treatment and prevention of hepatocellular carcinoma

Abstract

Primary liver cancer is the fifth most common malignancy in the world and is a leading cause of cancer-related mortality. Available treatment for hepatocellular carcinoma (HCC), the commonest primary liver cancer, is rarely curative and there is a need to develop therapy that is more effective. Specific and powerful gene silencing that can be achieved by activating RNA interference (RNAi) has generated enthusiasm for exploiting this pathway for HCC therapy. Many studies have been carried out with the aim of silencing HCC-related cellular oncogenes or the hepatocarcinogenic hepatitis B virus (HBV) and hepatitis C virus (HCV). Proof of principle studies have demonstrated promising results, and an early clinical trial assessing RNAi-based HBV therapy is currently in progress. Although the data augur well, there are several significant hurdles that need to be overcome before the goal of RNAi-based therapy for HCC is realized. Particularly important are the efficient and safe delivery of RNAi effecters to target malignant tissue and the limitation of unintended harmful non-specific effects.

Figure 1

Schematic illustration of the RNAi pathway showing the essential steps, with nuclear or cytoplasmic location, involved in micro RNA processing. Exogenous activators of the pathway, which may be synthetic siRNA or expressed mimics of miR precursors, are shown.

Figure 2

RNAi targets that may be silenced to counter HCC. In addition to HBV and HCV genes, cellular sequences that are involved in hepatocyte transformation may be silenced to inhibit growth of malignant liver cells. Growth of HCC is also dependent on angiogenesis and inhibition of this process is expected to limit tumor growth.