Liver cancer, also known as hepatocellular carcinoma (HCC), is the major malignancy of the liver and the third leading cause of cancer-related deaths globally. Prognosis remains bleak, with most patients dying within 6 to 20 months, and treatment, especially if surgery is not curative, has been largely ineffective. Associated with hepatitis viruses and other causes of cirrhosis, HCC develops through accumulation of genetic mutations, which are irreversible, and epigenetic changes, which are gene changes not involving mutation of DNA and thought to be potentially reversible, in a multi-step process. While the epidemiological risk factors for HCC are well known, the molecular mechanisms underlying development of liver cancer are not well characterized. It is especially important to understand the potentially reversible epigenetic mechanisms, since these changes are novel candidates for therapeutic targeting. Indeed, there is great general excitement in the cancer field of developing drugs which target epigenetic mechanisms, with some already utilized in the clinic.
One type of epigenetic change is RNA editing, defined as an alteration of RNA sequences. The classic view of flow of genetic information is from DNA, the chemical comprising our genes, to RNA, which transports the genetic code into proteins, which carry out functions in the body. RNA editing is a process in which the RNA sequence is “edited” so it is not identical to the DNA genetic code. This can be a normal process in normal cells, which make both the unedited and edited form of the RNA, coding for differences in proteins in the same cell. However, until now, RNA editing has not been described to be a process involved in cancer.
In our study, we performed genomic analysis of three paired samples, in each case a sample of liver cancer and adjacent non-tumor tissue from surgical specimens. We determined that there was a much higher level of a specific kind of RNA editing present in the cancer specimens. Furthermore, we were able to reveal that RNA editing of a specific gene known as antizyme inhibitor 1 (AZIN1), was much higher in the tumor samples, and that this editing event changed the product of this gene to a form which promoted the development of cancer. Studying a larger number of HCC patients revealed that RNA editing of the AZIN1 gene in tumors is significantly associated with the presence of liver cirrhosis, tumor recurrence, and poorer survival. Overall, our study has demonstrated for the first time a novel between excessive RNA editing activity and cancer development. Most importantly, by understanding the role of RNA editing of the AZIN1 gene, we have identified a novel target for HCC therapy.
Chen L, Li Y, Lin CH, Chan TH, Chow RK, Song Y, Liu M, Yuan YF, Fu L, Kong KL, Qi L, Li Y, Zhang N, Tong AH, Kwong DL, Man K, Lo CM, Lok S, Tenen DG*, Guan XY*. Recoding RNA editing of AZIN1 predisposes to hepatocellular carcinoma. Nat Med. 2013 Jan 6. *Corresponding authors.