HKU Bulletin June 2013 (Vol. 14 No. 3)

We are just at the very beginning and are putting together a puzzle that still has many missing pieces. The next step is to find other previously unidentified editing events in hepatocellular carcinoma (HCC) – now that we have discovered AZIN1, there may be other genes or micro-RNA or uncoding regions affected by RNA editing.” “Moreover, we need to dig more deeply into the mechanisms of RNA editing. For example, what kind of molecules regulate this editing process, are there any co-factors, are there any etiologic factors affecting this process? Most importantly, we intend to test some small molecules which may target the RNA editing process to try to rectify the malfunction of that editing.” Far-reaching implications The implications of the findings are far- reaching. Liver cancer is the third leading cause of cancer death in Hong Kong with over 1,800 new cases and more 1,500 deaths in 2010 (HKSAR Department of Health statistics). Every year, around half a million new cases are diagnosed worldwide, and more than half of those new cases come from China. “Furthermore,” says Professor Guan, “liver cancer is notoriously asymptomatic and therefore tends to be diagnosed at an advanced stage. The prognosis is very poor, especially for advanced stage patients whose therapeutic choices are also limited because surgical resection, liver transplantation and percutaneous techniques are no longer available.” “The response rate to chemotherapy is extremely low and Sorafenib, a multikinase inhibitor, is the only molecular medicine clinically adopted now. So there is a great need to develop novel molecular targets to enhance management of the disease. Hopefully our new finding about RNA editing will provide novel and effective therapeutic targets for liver cancer, and even for other types of cancer.” Medical scientists around the world are currently engaged in developing drugs which target epigenetic mechanisms (epigenetic is a big concept and includes methylation, Ribonucleic acid editing is a previously untouched field in cancer research. We are just at the very beginning and are putting together a puzzle that still has many missing pieces. ¡ ¢ £ ¤ ¥ ¦ § ¨ ¡ © © ª « ¨ ¥ ¤ ¬ ¡ ¥ ¦ § ¨ ¡ ¤ ¤ ¤ ® ¯ FRQIRUPDWLRQDO FKDQJH RI WKH $=,1 SURWHLQ 7KH DERYH ¿JXUHV VKRZ WKH $=,1 SURWHLQ VWUXFWXUH SUHGLFWHG E\ VRIWZDUH « ¨ ¥ ¤ ª ° ± ² ³ ´ µ µ ² ± ¶ · ¸ ¹ º » ¹ ¼ · ¸ ¹ Research Researchers used the next-generation Transcriptome Sequencing Technique to search the RNAs. Samples from 200 local and Mainland liver cancer patients were examined by liver cells culture in-vitro and in experimental mouse models. Initially they discovered that a gene named AZIN1 was frequently excessively edited in tumour cells, but rarely 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 altered the protein coding sequence of AZIN1, making it 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 reduced chances of survival for the patient, and that it transformed normal liver cells into tumour cells. Research leader and Professor of the Department of Clinical Oncology Professor Guan Xinyuan says: “RNA editing is a previously untouched field in cancer research. A team from HKU’s Cancer Genetic Laboratory has discovered for the first time a ribonucleic acid (RNA) editing event which triggers the formation of liver cancer by transforming normal liver cells into tumour cells. Until now, there has been a great deal of focus on DNA mutations in tumour genesis and progression, but this breakthrough is the first to highlight the role of transcriptional changes in RNA in cancer. Unlike some genetic mutations which are irreversible, RNA editing is potentially adjustable and therefore potentially rectifiable, offering the possibility of new hope to patients of liver cancer. histone modification, RNA editing). Professor Guan cites the treatment of myelodysplastic syndromes as one of the successful examples of this, but adds that for RNA editing itself there is no currently available medicine as it is such a new area of cancer research. “However, some scientists have already proved in the laboratory that the inhibition of RNA editing at a specific gene is possible by using therapeutic oligonucleotides (a kind of small molecule which would usually be used as molecular medicine),” he adds. “When and whether these oligonucleotides can be applied to clinical trial is unknown right now – they need to be strictly tested before being applied to animal models or human beings.” Professor Guan and his team collaborated on the research with the Cancer Science Institute of the National University of Singapore. M Editing Hope Cancer Genetic Laboratory’s discovery that ribonucleic acid editing can cause liver cancer gives new hope to patients. © ¤ ½ © ¤ © ¾ ¿ © ¤ £ 17 The University of Hong Kong Bulletin June 2013