A huge congratulations to Ms Qi Lihua, PhD Student in Prof Daniel Tenen’s lab, and Dr Madhura Kulkarni, Research Fellow in Prof Yoshiaki Ito’s lab, for receiving the Outstanding Poster Award in the 5th annual Frontiers in Cancer Science 2013 Poster Competition.
With more than 90 local and international scientists as well as students taking part in the competition, posters were critically assessed by a panel of judges across Singapore’s top medical institutes. CSI Singapore is delighted to have its participants bag two of the four awards presented for the competition.
Extensive A-to-I RNA Editing In 3’UTR And Its Involvement In Hepatocellular Carcinoma Development
Lihua QI1, Tim Hon Man CHAN1, Leilei CHEN1, Daniel G.TENEN1,2
1Cancer Science Institute of Singapore, 2 Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine, Boston MA
Adenosine to inosine (A-to-I) editing is the most common type of RNA editing, and catalyzed by Adenosine Deaminases that act on RNA (ADAR) protein family. The function of A-to-I RNA editing depends on where it occurs. In coding region, A-to-I editing can cause protein recoding. Conversely in non-coding region, A-to-I RNA editing can lead to alternative splicing, nuclear retention or targeted RNA degradation. The discovery of A-to-I RNA editing events is greatly advanced by next-generation sequencing; however the functional study is limited to A-to-I editing happened in coding region. In this study, we made use of RNA-seq to identify A-to-I RNA editing in hepatocellular carcinoma (HCC). We found A-to-I editing was significantly enriched in 3’UTR. The 3’UTR editing profile was greatly distorted during HCC development. Extensive 3’UTR A-to-I RNA editing led to reduced expression of a novel tumor suppressor protein through increased nuclear retention of target mRNA. The nuclear retention was shown mediated by a nuclear protein complex containing P54nrb. Furthermore, specific editing site in 3’UTR of this tumor suppressor gene can be used as a marker to predict disease-free survival of HCC patients. Our study represents the first one to reveal the involvement of 3’UTR A-to-I RNA editing in HCC development.
Interplay of YAP and RUNX3 in modulating transformation phenotypes
Madhura Kulkarni, Qiao Yiting, Yoshiaki Ito
Cancer Science Institute of Singapore, Singapore
RUNX3 belongs to a Runt-related transcription factor family, expressed in T- cells, dorsal ganglion neurons and epithelial cells. Many cancer studies have revealed RUNX3 inactivation either by promoter-methylation or deletion. RUNX3 functions as a transcription factor and its transcriptional activity is known to be modulated by its interacting partners like CBF- and Groucho/TLE. RUNX3 is known to interact with many proteins, with little explored functional significance. One of these proteins is a hippo pathway effector protein, YAP65, Yes-associated protein (Yagi 1999).
YAP an effector of Hippo tumor suppressor pathway; functions as an oncoprotein to drive increased proliferation and migratory phenotypes in number of human cancers, e.g. hepatocellular carcinomas (HCC), breast cancers, glioblastomas, colon cancers. RUNX3’s role as a tumor suppressor has been indicated in these tumors, by methylation and deletion studies.
Our preliminary co-relation analysis from a cohort of HCC RNA sequencing samples shows better patient survival when RUNX3 is expressed at higher levels along with higher YAP expression, compared to lower or no RUNX3 expression. This co-relation does not exist, in patients with lower YAP expression, indicating that RUNX3 shows a putative tumor suppressor activity only in the context of high YAP expressing tumor samples.
Immortalized mammary epithelial cell lines, with co-expressed YAP and RUNX3 also show suppression of migration and Mammosphere formation compared with YAP alone over-expression. Our in vitro studies, recapitulate the co-relation observed from the patient survival data analysis. Here, we are studying the functional relevance of the interaction between tumor suppressor-RUNX3 and oncoprotein-YAP. The aim is to dissect the molecular mechanisms behind the co-relation observed in the patient samples. This understanding may lead us to design a strategy to extend patient survival by restoring RUNX3’s function in HCC patients with high YAP expression.