HKU finds ribonucleic acid (RNA) editing a new cancer cause Reversible nature of RNA editing brings hope for liver cancer treatment
 
Jan 29, 2013
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The Cancer Genetic Laboratory of the Department of Clinical Oncology, The University of Hong Kong (HKU) Li Ka Shing Faculty of Medicine, discovered for the first time a ribonucleic acid (RNA) editing event which predisposes to liver cancer by transfrorming normal liver cells into tumour cells. Genetic mutation has long been identified as one of the cancer causes, yet specific genetic mutations only account for a small proportion of cancer cases. In contrast, the phenomenon of RNA editing deregulation frequently occurs in a wide range of patients. Compared with those irreversible genetic mutations, RNA editing is a potentially adjustable and reversible epigenetic mechanism, therefore this study represents a major breakthrough in the field of cancer therapy and brings new idea for developing targeted drugs. The research was recently published in Nature Medicine, the international leading scientific journal on basic medical research.

One of the key researchers, Professor Guan Xin-yuan, the Department of Clinical Oncology of HKU Li Ka Shing Faculty of Medicine says, “Cancer researchers have long focused on the influence of genetic mutation to the formation of tumours while failed to recognise the importance of RNA editing during cancer development. Genetic mutation and RNA editing bring forth similar results as both of them may change protein sequences and functions. Genetic mutations, out of its specification and uniqueness in nature, usually account for a small proportion of cancer cases only. In contrast, the phenomenon of RNA editing deregulation frequently occurs in a wide range of patients, which indicates therapies targeted against RNA editing might be efficacious to the majority of the liver cancer patients.”

About RNA editing
Genes specify various biological traits in humans and store this kind of instructions in the heredity material called deoxyribonucleic acid (DNA). Acting as a messenger, RNA passes the genetic information held in the DNA to protein synthesis machinery and guides protein production. Proteins are responsible for executing the necessary functions of the human body. The biological traits or functions will be changed if DNA information is mutated, RNA is wrongly transcribed, or protein is produced against construction drawing. In certain cases, although the DNA information is faithfully transcribed into RNA, the correct information will be further edited, which is referred to as RNA editing. RNA editing modifies the RNA information, leading to variation of the protein formation, and leaves mysteries of its consequences and meanings.
Research methods and findings

To unravel the mysteries, HKU researchers adopted the next-generation Transcriptome Sequencing Technique to conduct a search of RNAs. They examined 200 local and mainland liver cancer patients’ samples by liver cells culture in vitro and in experimental mouse models. A gene named AZIN1 was frequently found to be excessively edited in tumour cells, while this phenomenon was barely detected in normal liver, blood and other organs. Further studies revealed that the RNA editing machinery, known as ADAR1, was deregulated in liver cells, which wrongly edited AZIN1 at high levels. This editing event altered protein coding sequence of AZIN1 and be capable of undergoing significant protein conformation and functional change. Clinicopathological data showed that RNA editing was significantly associated with the presence of liver cirrhosis, tumour recurrence, and poorer survival. The research also proved RNA editing triggered the transformation of normal liver cells into tumour cells. HKU research team believes the tumour transformation process might be reversed if the RNA editing deregulated machinery could be promptly fixed, or if the wrongly edited AZIN1 gene could be corrected.

Research Implications
The research proved for the first time that RNA editing of AZIN1 triggered the formation of cancer. It is of prime importance in the field of sciences as it leads us to examine the cancer mechanism from a totally new visual angle. There will certainly be a stirring of interest in RNA editing research studies. Hopefully this will provide novel and effective therapeutic targets for liver cancer, or even other types of cancer. Compared with those irreversible genetic mutations, RNA editing is a potentially adjustable and reversible epigenetic mechanism. Indeed, there is great general excitement in the cancer field of developing drugs which target epigenetic mechanisms. These drugs bring new hopes to patients. Treatment of myelodysplastic syndromes is one of the successful examples.

About Liver cancer
Primary liver cancer refers to malignant tumour that originates in the livers. It is one of the most common malignant tumours. According to statistics compiled by the Department of Health, HKSAR government, liver cancer is the third leading cause of cancer death in Hong Kong, with over 1,800 new cases and over 1,500 deaths recorded in 2009. Annually, there are over 0.5 million new patients worldwide and more than half of the new cases occur in China. Surgical resection is the best curative therapy for primary liver cancer at early stage. However, patients are usually diagnosed at mid or late stage ascribed to its unconspicuous signs and symptoms at the early stage. Moreover, its high malignancy as well as poor prognosis renders the treatment difficult and ineffective. As a result, most patients die within 6 to 20 months after diagnosis.

About the research team
The study was led by Professor Guan Xin-yuan from the Cancer Genetic Laboratory of HKU Department of Clinical Oncology, in collaboration with the Cancer Science Institute of National Singapore University. Other key researchers included Dr Chen Leilei, Dr Li Yan from HKU and Professor DG Tenen from Cancer Science Institute of National Singapore University. The research was supported by grants from Hong Kong Research Grant Council grants.

SOURCE / The University of Hong Kong