Leilei Chen
Email Address
csicl@nus.edu.sg
Organizational Units
YONG LOO LIN SCH OF MEDICINE
faculty
ANATOMY
dept
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Publication Overexpression of GPR39 contributes to malignant development of human esophageal squamous cell carcinoma(BioMed Central Ltd., 2011) Xie F.; Liu H.; Zhu Y.-H.; Qin Y.-R.; Dai Y.; Zeng T.; Chen L.; Nie C.; Tang H.; Li Y.; Fu L.; Guan X.-Y.; ANATOMYPublication Maelstrom promotes hepatocellular carcinoma metastasis by inducing epithelial-mesenchymal transition by way of Akt/GSK-3β/Snail signaling(John Wiley and Sons Inc., 2014) Liu, L; Dai, Y; Chen, J; Zeng, T; Li, Y; Chen, L; Zhu, Y.-H; Li, J; Li, Y; Ma, S; Xie, D; Yuan, Y.-F; Guan, X.-Y; ANATOMYAmplification of 1q is one of the most frequent chromosomal alterations in human hepatocellular carcinoma (HCC). In this study we identified and characterized a novel oncogene, Maelstrom (MAEL), at 1q24. Amplification and overexpression of MAEL was frequently detected in HCCs and significantly associated with HCC recurrence (P = 0.031) and poor outcome (P = 0.001). Functional study demonstrated that MAEL promoted cell growth, cell migration, and tumor formation in nude mice, all of which were effectively inhibited when MAEL was silenced with short hairpin RNA (shRNAs). Further study found that MAEL enhanced AKT activity with subsequent GSK-3? phosphorylation and Snail stabilization, finally inducing epithelial-mesenchymal transition (EMT) and promoting tumor invasion and metastasis. In addition, MAEL up-regulated various stemness-related genes, multidrug resistance genes, and cancer stem cell (CSC) surface markers at the messenger RNA (mRNA) level. Functional study demonstrated that overexpression of MAEL increased self-renewal, chemoresistance, and tumor metastasis. Conclusion: MAEL is an oncogene that plays an important role in the development and progression of HCC by inducing EMT and enhancing the stemness of HCC. © 2013 by the American Association for the Study of Liver Diseases.Publication SPOCK1 is regulated by CHD1L and blocks apoptosis and promotes HCC cell invasiveness and metastasis in mice(2013-01) Li, Y.; Chen, L.; Chan, T.H.M.; Liu, M.; Kong, K.-L.; Qiu, J.-L.; Yuan, Y.-F.; Guan, X.-Y.; CANCER SCIENCE INSTITUTE OF SINGAPOREBackground & Aims: Chromodomain helicase/adenosine triphosphatase DNA binding protein 1-like (CHD1L) is an SNF2-like transcription factor involved in the development of human hepatocellular carcinoma (HCC). Sparc/osteonectin, cwcv, and kazal-like domains proteoglycan 1 (SPOCK1) is up-regulated by CHD1L; we investigated its role in hepatocellular carcinogenesis. Methods: We investigated interactions between SPOCK1 and CHD1L using electrophoretic mobility shift and luciferase reporter assays. Levels of SPOCK1 messenger RNA (mRNA) and protein were measured in samples of HCC and adjacent nontumor liver tissues (135 pairs) and compared using Pearson correlation coefficients. Effects of SPOCK1 overexpression and silencing were determined in HCC cell lines (QGY-7703, PLC-8024, BEL-7402, and QGY-7701). Results: The CHD1L protein bound directly to the promoter region (nt-1662 to +34) of SPOCK1 and activated transcription. Levels of SPOCK1 mRNA and protein were increased in 60% of human HCC samples, compared with nontumor live tissues, and was associated significantly with clinical stage. Levels of SPOCK1 mRNA were increased among tumors that became metastatic, compared with those that did not, and among patients with shorter overall and disease-free survival times. Ectopic expression of SPOCK1 in HCC cells increased proliferation, foci formation, and colony formation in soft agar; these cells also formed larger xenograft tumors, more rapidly, in nude mice than control HCC cells. Silencing SPOCK1 expression with short hairpin RNA had the opposite effects. We found that SPOCK1 prevents apoptosis of HCC cells by activating Akt, to block release of cytochrome c and activation of caspase-9 and caspase-3; these effects were reversed with an Akt inhibitor. HCC cells that overexpressed SPOCK1 expressed higher levels of matrix metallopeptidase 9, were more invasive in Matrigel assays, and formed more metastatic nodules in immunodeficient mice than control HCC cells. Conclusions: CHD1L activates expression of SPOCK1, which activates Akt signaling to block apoptosis and invasion by HCC cells, in culture and in mice. Levels of SPOCK1 increase with progression of human HCC. SPOCK1 might be used as a prognostic factor or therapeutic target. © 2013 AGA Institute.Publication RNA Editome imbalance in hepatocellular carcinoma(2014-03-01) Qi, L.; Chan, T.H.M.; Tenen, D.G.; Chen, L.; MEDICINEAdenosine-to-inosine conversion (A-to-I editing), a posttranscriptional modification on RNA, contributes to extensive transcriptome diversity. A-to-I editing is a hydrolytic deamination process, catalyzed by adenosine deAminase acting on double-stranded RNA (ADAR) family of enzymes. ADARs are essential for normal mammalian development, and disturbance in RNA editing has been implicated in various pathologic disorders, including cancer. Thanks to next-generation sequencing, rich databases of transcriptome evolution for cancer development at the resolution of single nucleotide have been generated. Extensive bioinformatic analysis revealed a complex picture of RNA editing change during transformation. Cancer displayed global hypoediting of Alurepetitive elements with gene-specific editing pattern. In particular, hepatocellular carcinoma editome is severely disrupted and characterized by hyper- and hypoediting of different genes, such as hyperedited AZIN1 (antizyme inhibitor 1) and FLNB (filamin B, b) and hypoedited COPA (coatomer protein complex, subunit a). In hepatocellular carcinoma, not only the recoding editing in exons, but also the editing in noncoding regions (e.g., Alu-repetitive elements and microRNA) displays such complex editing pattern with site-specific editing trend. In this review, we will discuss current research progress on the involvement of abnormal A-to-I editing in cancer development, more specifically on hepatocellular carcinoma. © 2013 American Association for Cancer Research.Publication A disrupted RNA editing balance mediated by ADARs (Adenosine DeAminases that act on RNA) in human hepatocellular carcinoma(2014-05-01) Chan, T.H.M.; Lin, C.H.; Qi, L.; Fei, J.; Li, Y.; Yong, K.J.; Liu, M.; Song, Y.; Chow, R.K.K.; Ng, V.H.E.; Yuan, Y.-F.; Tenen, D.G.; Guan, X.-Y.; Chen, L.; MEDICINEObjective: Hepatocellular carcinoma (HCC) is a heterogeneous tumour displaying a complex variety of genetic and epigenetic changes. In human cancers, aberrant post-transcriptional modifications, such as alternative splicing and RNA editing, may lead to tumour specific transcriptome diversity. Design: By utilising large scale transcriptome sequencing of three paired HCC clinical specimens and their adjacent non-tumour (NT) tissue counterparts at depth, we discovered an average of 20 007 inferred A to I (adenosine to inosine) RNA editing events in transcripts. The roles of the double stranded RNA specific ADAR (Adenosine DeAminase that act on RNA) family members (ADARs) and the altered gene specific editing patterns were investigated in clinical specimens, cell models and mice. Results: HCC displays a severely disrupted A to I RNA editing balance. ADAR1 and ADAR2 manipulate the A to I imbalance of HCC via their differential expression in HCC compared with NT liver tissues. Patients with ADAR1 overexpression and ADAR2 downregulation in tumours demonstrated an increased risk of liver cirrhosis and postoperative recurrence and had poor prognoses. Due to the differentially expressed ADAR1 and ADAR2 in tumours, the altered gene specific editing activities, which was reflected by the hyper-editing of FLNB (filamin B, β) and the hypo-editing of COPA (coatomer protein complex, subunit α), are closely associated with HCC pathogenesis. In vitro and in vivo functional assays prove that ADAR1 functions as an oncogene while ADAR2 has tumour suppressive ability in HCC. Conclusions: These findings highlight the fact that the differentially expressed ADARs in tumours, which are responsible for an A to I editing imbalance, has great prognostic value and diagnostic potential for HCC.Publication Chromosome 1q21 amplification and oncogenes in hepatocellular carcinoma(Wiley, 2010) Chen, L; Chan, T.H.M; Guan, X.-Y; ANATOMY; CANCER SCIENCE INSTITUTE OF SINGAPOREHepatocellular carcinoma (HCC) is among the most lethal of human malignancies. During human multistep hepatocarcinogenesis, genomic gain represents an important mechanism in the activation of proto-oncogenes. In many circumstances, activated oncogenes hold clinical implications both as prognostic markers and targets for cancer therapeutics. Gain of chromosome 1q copy is one of the most frequently detected alterations in HCC and 1q21 is the most frequent minimal amplifying region (MAR). A better understanding of the physiological and pathophysiological roles of target genes within 1q21 amplicon will significantly improve our knowledge in HCC pathogenesis, and may lead to a much more effective management of HCC bearing amplification of 1q21. Such knowledge has long term implications for the development of new therapeutic strategies for HCC treatment. Our research group and others, focused on the identification and characterization of 1q21 target genes such as JTB, CKS1B, and CHD1L in HCC progression. In this review, we will summarize the current scientific knowledge of known target genes within 1q21 amplicon and the precise oncogenic mechanisms of CHD1L will be discussed in detail. © 2010 CPS and SIMM All rights reserved.Publication RBMS3 at 3p24 Inhibits Nasopharyngeal Carcinoma Development via Inhibiting Cell Proliferation, Angiogenesis, and Inducing Apoptosis(Public Library of Science (PLoS), 2012) Chen J.; Kwong D.L.-W.; Zhu C.-L.; Chen L.-L.; Dong S.-S.; Zhang L.-Y.; Tian J.; Qi C.-B.; Cao T.-T.; Wong A.M.G.; Kong K.-L.; Li Y.; Liu M.; Fu L.; Guan X.-Y.; ANATOMYPublication Red Blood Cell-Derived Extracellular Vesicles Display Endogenous Antiviral Effects and Enhance the Efficacy of Antiviral Oligonucleotide Therapy(AMER CHEMICAL SOC, 2023-10-18) Jayasinghe, Migara K; Gao, Chang; Yap, Gracemary; Yeo, Brendon Zhi Jie; Vu, Luyen Tien; Tay, Douglas Jie Wen; Loh, Wen Xiu; Aw, Zhen Qin; Chen, Huixin; Phung, Dai Cao; Hoang, Dong Van; Prajogo, Rebecca Carissa; Hooi, Lissa; Lim, Fang Qing; Pirisinu, Marco; Mok, Chee Keng; Lim, Kah Wai; Tang, Sze Jing; Tan, Kai Sen; Chow, Edward Kai-Hua; Chen, Leilei; Phan, Anh Tuan; Chu, Justin Jang Hann; Le, Minh TN; Dr Yan Ling Ng; PHARMACOLOGY; DEAN'S OFFICE (MEDICINE); SURGERY; ANATOMY; MICROBIOLOGY AND IMMUNOLOGY; CANCER SCIENCE INSTITUTE OF SINGAPOREThe COVID-19 pandemic has resulted in a large number of fatalities and, at present, lacks a readily available curative treatment for patients. Here, we demonstrate that unmodified red blood cell-derived extracellular vesicles (RBCEVs) can inhibit SARS-CoV-2 infection in a phosphatidylserine (PS) dependent manner. Using T cell immunoglobulin mucin domain-1 (TIM-1) as an example, we demonstrate that PS receptors on cells can significantly increase the adsorption and infection of authentic and pseudotyped SARS-CoV-2 viruses. RBCEVs competitively inhibit this interaction and block TIM-1-mediated viral entry into cells. We further extend the therapeutic efficacy of this antiviral treatment by loading antisense oligonucleotides (ASOs) designed to target conserved regions of key SARS-CoV-2 genes into RBCEVs. We establish that ASO-loaded RBCEVs are efficiently taken up by cells in vitro and in vivo to suppress SARS-CoV-2 replication. Our findings indicate that this RBCEV-based SARS-CoV-2 therapeutic displays promise as a potential treatment capable of inhibiting SARS-CoV-2 entry and replication.Publication CAV1 - GLUT3 signaling is important for cellular energy and can be targeted by Atorvastatin in Non-Small Cell Lung Cancer(NLM (Medline), 2019) Ali, A.; Levantini, E.; Fhu, C.W.; Teo, J.T.; Clohessy, J.G.; Goggi, J.L.; Wu, C.-S.; Chen, L.; Chin, T.M.; Tenen, D.G.; MEDICINE; ANATOMY; CANCER SCIENCE INSTITUTE OF SINGAPOREBackground: The development of molecular targeted therapies, such as EGFR-TKIs, has positively impacted the management of EGFR mutated NSCLC. However, patients with innate and acquired resistance to EGFR-TKIs still face limited effective therapeutic options. Statins are the most frequently prescribed anti-cholesterol agents and have been reported to inhibit the progression of various malignancies, including in lung. However, the mechanism by which statin exerts its anti-cancer effects is unclear. This study is designed to investigate the anti-proliferative effects and identify the mechanism-of-action of statins in NSCLC. Methods: In this study, the anti-tumoral properties of Atorvastatin were investigated in NSCLC utilizing cell culture system and in vivo models. Results: We demonstrate a link between elevated cellular cholesterol and TKI-resistance in NSCLC, which is independent of EGFR mutation status. Atorvastatin suppresses growth by inhibiting Cav1 expression in tumors in cell culture system and in in vivo models. Subsequent interrogations demonstrate an oncogenic physical interaction between Cav1 and GLUT3, and glucose uptake found distinctly in TKI-resistant NSCLC and this may be due to changes in the physical properties of Cav1 favoring GLUT3 binding in which significantly stronger Cav1 and GLUT3 physical interactions were observed in TKI-resistant than in TKI-sensitive NSCLC cells. Further, the differential effects of atorvastatin observed between EGFR-TKI resistant and sensitive cells suggest that EGFR mutation status may influence its actions. Conclusions: This study reveals the inhibition of oncogenic role of Cav1 in GLUT3-mediated glucose uptake by statins and highlights its potential impact to overcome NSCLC with EGFR-TKI resistance.Publication Hepatocellular carcinoma: Transcriptome diversity regulated by RNA editing(2013) Li, Y.; Chen, L.; Chan, T.H.M.; Guana, X.-Y.; CANCER SCIENCE INSTITUTE OF SINGAPOREHepatocellular carcinoma (HCC) can be envisioned as a prolonged multi-stage process accumulating genetic and epigenetic changes. In the past years, DNA alterations lent us important clues to the com-prehension of molecular pathways involved in HCC. However, as an increasing number of RNAs were identified to be subject to A-to-I modifications, it has become apparent that RNA editing might be the causal basis of various human diseases. Recent evidence has strengthened this notion by correlating hyper-edited AZIN1 (antizyme inhibitor 1) protein with HCC onset and the mechanisms that regulate cell transformation. As we continue to demystify it, RNA editing astonishes us with its diverse substrates, esoteric functions, elaborate machinery and complex interaction with HBV/HCV viral infection. In this review, we examine the contribution of A-to-I RNA editing to caner onset/progression and explore its potential implications for cancer treatment advances. © 2013 Elsevier Ltd. All rights reserved.