A team of scientists from the Cancer Science Institute of Singapore (CSI) at the National University of Singapore (NUS) has identified a genetic process in which normal liver cells transform into cancerous ones. The finding provides new understanding into the pathogenesis of human cancers.
The team, which also includes researchers under the direction of Professor Guan Xin-Yuan at The University of Hong Kong, is the first to provide direct evidence that the "editing" of this protein-making sequence promotes the development of cancer.
Normally, deoxyribonucleic acid (DNA), which comprises the genetic code, serves as a template for production of ribonucleic acid (RNA) in precise fashion such that the DNA code and RNA code are identical. Editing is the process in which the RNA is changed after it is made from the DNA, resulting in production of an altered gene product.
This novel study, which was conducted from June 2010 to November 2012, was first published in the online version of Nature Medicine on 6 January 2013.
Focus on RNA
The development of liver cancer is believed to be a multi-step process, in which genetic and epigenetic alterations build up. However, it is much easier technically to detect genetic mutations through DNA sequencing. Epigenetic changes, which by definition do not involve changes in DNA sequence, have not been as well defined because it is much more difficult technically to identify them and demonstrate their role in cancer.
While recent use of next-generation sequencing of DNA and RNA have been suggestive, no apparent causal relationship between the levels of RNA editing, a process of altering RNA sequences, and cancer progression was thought to exist -- until now. As such, RNA editing is a novel epigenetic alteration in cancer.
Recognising the importance of molecular mechanisms that underlay the development of liver cancer, the research team studied the roles that RNA plays in the formation of proteins to carry out functions within the body. The researchers are the first to clearly link the RNA editing event of a protein to be significantly associated with the development of liver cancer.
Professor Daniel Tenen, Director of CSI and Principal Investigator for the study, said, "Up to now, scientists have focused on studying DNA, not RNA. Because RNA can be more easily modified than DNA, it suggests that therapeutic approaches are potentially available."
RNA Editing Process Changes Protein
In the study, the researchers performed genomic analysis of three pairs of tissue samples, each pair comprising a sample of liver cancer tissue and an adjacent non-tumour tissue, from surgical specimens of liver cancer patients.
They found that the RNA editing of a specific gene known as antizyme inhibitor 1 (AZIN1) was much higher in the tumour samples. They discovered that this editing process was catalysed by an enzyme called adenosine deaminase acting on RNA-1 (ADAR1), which changed the product of the AZIN1 protein to a form which promoted the development of cancer.
To verify their findings, the team repeated the tests on paired tissue samples of some 180 liver cancer patients.
The results obtained were consistent with the initial genomic analysis, indicating that the RNA editing of the AZIN1 gene in tumours is significantly associated with the presence of liver cirrhosis, tumor recurrence, and poorer survival rate.
Said Dr Polly Chen, Research Assistant Professor at CSI, and the lead author of the research team, "We believe that there is high possibility that the findings are applicable to other cancers, but further studies are required to ascertain this."
The Next Step
Moving forward, Prof Tenen and Dr Chen will investigate the characteristics of AZIN1 and ADAR1 to further understand their impact on tumour development. They also intend to look at these mechanisms in other cancers. They will also work on ways to correct the RNA editing process so as to block the cells' conversion from normal to malignant.
Both scientists hope that their findings will provide the medical community with a useful biomarker that can be used to detect early disorders leading to liver cancer, and even other forms of cancer, before clinical symptoms become apparent.
- Leilei Chen, Yan Li, Chi Ho Lin, Tim Hon Man Chan, Raymond Kwok Kei Chow, Yangyang Song, Ming Liu, Yun-Fei Yuan, Li Fu, Kar Lok Kong, Lihua Qi, Yan Li, Na Zhang, Amy Hin Yan Tong, Dora Lai-Wan Kwong, Kwan Man, Chung Mau Lo, Si Lok, Daniel G Tenen, Xin-Yuan Guan. Recoding RNA editing of AZIN1 predisposes to hepatocellular carcinoma. Nature Medicine, 2013; DOI: 10.1038/nm.3043
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