The main focus of Dr Chen Leilei’s group is to study the transcriptome instability of human cancers, particularly hepatocellular carcinoma (HCC), the major malignancy of the liver and the third leading cause of cancer-related deaths globally. 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. One type of epigenetic change is RNA editing, defined as an alteration of RNA sequences. Using integrative genomic approaches, her group recently highlighted a link between transcriptome instabilities in the form of excessive or defective RNA editing activity and cancer development. She currently places focus on the regulators of A-to-I RNA editing and the crosstalk between RNA editing and alternative splicing-the two main processes contributing to transcriptome diversity. This work will provide important insights into the regulation of tumorigenesis by transcriptome instability, in turn translating these findings into diagnoses or even treatment.
RNA editing is an integral step in generating the diversity and plasticity of cellular RNA signatures. In humans, the most frequent type of editing is the conversion of adenosine (A) to inosine (I), which is catalyzed by the double-stranded RNA (dsRNA)-specific ADAR (Adenosine DeAminase that act on RNA) family of protein. This process of recoding of translated exons, widespread editing of repetitive sequence elements and sequence modification of microRNA (miRNA) can lead to specific amino acid substitutions, alternative splicing and changes in gene expression levels. With the advent of high-throughput transcriptome sequencing, many editing sites potentially associated with cancer development have been identified. Our laboratory for the first time demonstrated that unlike other types of cancers, which are associated with a general decrease or increase in RNA editing activity, hepatocellular carcinoma (HCC) displays a more complicated RNA editome, with a disrupted A-to-I editing balance. We also reported that A-to-I editing of antizyme inhibitor 1 (AZIN1) gene, which is specially catalyzed by a RNA editing enzyme ADAR1, displays a high modification rate in HCC specimens. As a consequence of RNA editing in AZIN1 transcript, AZIN1 protein undergoing the serine-to-glycine substitution at residue 367, induces a cytoplasmic-to-nuclear translocation, and confers tumor initiating potential and more aggressive behavior (see attached figure). In addition, we are pursuing work on the biological importance of editing sites within 3-untranslational region (3-UTR) during cancer development, such as the effects of editing on transcript stability, microRNA targeting and the subsequent protein expression. Because ADAR enzyme expression imbalances, with consequent editing dysregulation, characterizes many human cancers and, adar1-/- mice are embryonic lethal (at E11.5-12.5) mainly due to defective hematopoiesis and liver disintegration, another focus is to study the role of RNA editing enzyme ADARs and their specific targets in hemoatopoiesis and acute myeloid leukemia (AML).
- Hong H, An Ő, Chan TH, Ng VHE, Kwok HS, Lin JS, Qi L, Han J, Tay DJ, Tang SJ, Yang H, Song YY, Molias FB, Tenen DG, Chen L. Bidirectional regulation of adenosine-to-inosine (A-to-I) RNA editing by DEAH box helicase 9 (DHX9) in cancer. Nucleic Acids Res, 2018 May 18
- Qi L, Song Y, Chan TH, Yang H, Lin CH, Tay ST, Hong H, Tang SJ, Tan KT, Huang XX, Lin JS, Ng VHE, Maury JJP, Tenen DG, Chen L. An RNA editing/dsRNA binding-independent gene regulatory mechanism of ADARs and its clinical implication in cancer. Nucleic Acids Research, 2017 Jul 29.
- Chan TH, Qamra A, Tan KT, Guo J, Yang H, Qi L, Lin JS, Ng VH, Song Y, Hong HQ, Tay ST, Liu Y, Lee J, Rha SY, Feng Z, So JB, Tean TB, Guan YK, Rozen S, Tenen DG, Tan P, Chen L. ADAR-mediated RNA editing predicts progression and prognosis of Gastric Cancer. Gastroenterology. 2016, 151(4):637-650.
- Hong HQ, Lin JS, Chen L. Regulatory factors governing Adenosine-to-Inosine (A-to-I) RNA editing. Biosci Rep. 2015, 35(2).
- Qin YR, Qiao JJ, Chan TH, Zhu YH, Li FF, Liu HB, Fei J, Li Y, Guan XY, Chen L. Adenosine-to-inosine RNA editing mediated by ADARs in Esophageal squamous cell carcinoma (ESCC). Cancer Res. 2014 74(3):840-851.
- Chan TH, Lin CH, Qi L, Fei J, Li Y, Yong KJ, Liu M, Song Y, Chow RK, Ng VH, Yuan YF, Tenen DG, Guan XY, Chen L. A disrupted RNA editing balance mediated by ADARs (Adenosine DeAminases that act on RNA) in human hepatocellular carcinoma. Gut. 2014, 63(5):832-43.
- Qi LH, Chan HM, Tenen DG, Chen L. RNA editome imbalance in hepatocellular carcinoma. Cancer Res, 2014,74(5):1301-1306.
- Qiao JJ, Chan TH, Qin YR, Chen L. ADAR1: a promising new biomarker for Esophageal Squamous Cell Carcinoma. Expert Rev Anticancer Ther, 2014, 14(8):865-868.
- Chen L., Li Y, Lin C, 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. Nature Med, 2013, 19(2):209-16.
- Chen L., Yuan YF, Li Y, Chan TH, Zheng BJ, Huang J, Guan XY. Clinical significance of CHD1L in hepatocellular carcinoma and therapeutic potentials of virus-mediated CHD1L depletion. Gut. 2011, 60(4):534-43.
|Name||CHEN Leilei Polly|
|Affiliations||Principal Investigator, Cancer Science Institute of Singapore
President’s Assistant Professor, Department of Anatomy, NUS
|Institute||Degree (if applicable)||Year(s)|
|Medical College of Jiangsu University, China||M.D. (First-Class Honor)||2002|
|The University of Hong Kong||Ph.D.||2010|
|•||Editorial Board member, Journal of Human Transcriptome||2013 – present|
|•||Research Fellow in Clinical Oncology, the University of Hong Kong (Laboratory of Prof. Xin-Yuan Guan)||2010 – 2012|
|•||Associate Member, American Association for Cancer Research (AACR)||2009 – present|
|•||Clinician, Department of Obstetrics and Gynaecology of Nanjing Drum Tower Hospital, China||2005 – 2006|
Transcriptome analysis of cancer RNA-sequencing datasets.
Elucidating the functional roles of ADAR co-factors in A-to-I RNA editing.
Fernando Bellido MOLIAS
Assessing the impact of ADAR1 expression on the genomic DNA.
Investigate RNA editing in Hepatocellular Carcinoma and Liver Differentiation
TANG Sze Jing
Study Alternative Splicing in Hepatocellular Carcinoma.
Research Assistant/PhD student
Elucidating the functional roles of ADAR co-factors in A-to-I RNA editing.
Daryl Jin Tai TAY
Targeting RNA Editing by Triplex-Forming Oligonucleotides (TFOs) or Peptide Nucleic Acid (PNA).
Vanessa Hui En NG
Senior Laboratory Executive
The role of COG3 editing event in human HCC.
LEONG Ka Wai
Understanding the substrate selectivity and sensitivity of ADARs.
|•||Yong Loo Lin School of Medicine Young Research Of the Year Award||2017|
|•||President Assistant Professorship, National University of Singapore||2015|
|•||Science and Technology Award of Higher Education of China (Second Class), Ministry of Education, China||2014|
|•||NUS Young Scientist Award, National University of Singapore||2014|
|•||Finalist in 2014 National Research Fellowship (NRF), Prime Minister’s Office, Singapore||2014|
|•||Li Ka Shing Prize 2009/2010, Hong Kong||2010|