Non-coding RNAs as therapeutic targets in hepatocellular cancer

Abstract

Hepatocellular carcinoma (HCC) is a common malignancy that affects a large number of patients worldwide, with an increasing incidence in the United States and Europe. The therapies that are currently available for patients with inoperable HCC have limited benefits. Although molecular targeted therapies against selected cell signaling pathways have shown some promising results, their impact has been minimal. There is a need to identify and explore other targets for the development of novel therapeutics. Several non-protein coding RNAs (ncRNA) have recently been implicated in hepatocarcinogenesis and tumor progression. These ncRNA genes represent promising targets for cancer. However, therapeutic targeting of ncRNA genes has not been employed for HCC. The use of antisense oligonucleotides and viral vector delivery approaches have been shown to be feasible approaches to modulate ncRNA expression. HCC is an optimal cancer to evaluate novel RNA based therapeutic approaches because of the potential of effective delivery and uptake of therapeutic agents to the liver. In this review, we discuss selected ncRNA that could function as potential targets in HCC treatment and outline approaches to target ncRNA expression. Future challenges include the need to achieve site-specific targeting with acceptable safety and efficacy.

Fig. (1)

Therapeutic approaches to target non coding RNAs. For ncRNA that are increased in expression in HCC, such as miR-221/222, miR-21, or TUC-338, therapeutic strategies to reduce their expression are considered. AntagomiRs are chemically modified, cholesterol conjugated, single strand RNA analogues complementary to selected miRNAs (or other ncRNAs). The stability and specificity of antisense miRNA could be increased by conjugation to locked nucleic acid (LNA). Several antisense oligonucleotides could potentially be combined in the so-called sponges. For ncRNA that are decreased in expression in HCC such as miR-26, potential replacement strategies using adenovirus-associated virus may be feasible.