Humphrey Oei Institute of Cancer Research

Humphrey, Singapore

Humphrey Oei Institute of Cancer Research

Humphrey, Singapore
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Sabapathy K.,Humphrey Oei Institute of Cancer Research | Sabapathy K.,National University of Singapore
Progress in Molecular Biology and Translational Science | Year: 2012

The c-Jun-NH 2-terminal kinase (JNK) signaling pathway plays a critical role in regulating cell fate, being implicated in a multitude of diseases ranging from cancer to neurological and immunological/inflammatory conditions. Not surprisingly, therefore, it has been sought after for therapeutic intervention, and its inhibition has been shown to ameliorate many pathological conditions in experimental systems, paving the way for initial clinical trials. However, the fundamental problem in fully harnessing the potential provided by the JNK pathway has been the lack of specificity, due to the multiple JNK forms that are involved in multiple cellular processes in various cell types. Moreover, lack of sufficient knowledge of all JNK-interacting proteins and substrates has also hindered progress. This review will therefore focus on the role of the JNKs in human diseases and appraise the efforts to inhibit JNK signaling to ameliorate disease conditions, assessing potential challenges and providing insights into possible future directions to efficiently target this pathway for therapeutic use. © 2012 Elsevier Inc.


Dulloo I.,Humphrey Oei Institute of Cancer Research | Hooi P.B.,Humphrey Oei Institute of Cancer Research | Sabapathy K.,Humphrey Oei Institute of Cancer Research | Sabapathy K.,National University of Singapore
Cell Cycle | Year: 2015

P73, the homolog of p53, exists in 2 major forms: either as a pro-apoptotic TAp73 or an amino-terminally truncated DNp73, the latter lacking the first transactivation domain. While TAp73s tumor suppressive functions have been established, DNp73 is an anti-apoptotic protein conferring chemoresistance and is associated with poor survival. However, both forms are variably overexpressed in many human cancers. In this context, we have recently demonstrated that TAp73 is stabilized by hypoxia, a tumor-relevant condition that is associated with cell survival, via HIF-1α-mediated suppression of Siah1 E3 ligase that degrades TAp73. Consequently, hypoxic signals lead to TAp73-mediated activation of several angiogenic genes and blood vessel formation, thereby supporting tumorigenesis. We show here that, similar to TAp73, DNp73 is stabilized by hypoxia in a HIF-1α-dependent manner, which otherwise is degraded by Siah1. Moreover, DNp73 is capable of inducing the expression of Vegf-A, the prototypic angiogenic gene, and loss of DNp73 expression results in reduction in tumor vasculature and size. These data therefore indicate a common mode of regulation for both p73 forms by hypoxia, resulting in the promotion of angiogenesis and tumor growth, highlighting common functionality of these antagonistic proteins under specific physiological contexts. © Iqbal Dulloo, Phang Beng Hooi, and Kanaga Sabapathy.


Xia H.,Humphrey Oei Institute of Cancer Research | Ooi L.L.P.J.,The Surgical Center | Ooi L.L.P.J.,Singapore General Hospital | Hui K.M.,Humphrey Oei Institute of Cancer Research | And 2 more authors.
Hepatology | Year: 2013

Tumor recurrence and metastases are the major obstacles to improving the prognosis of patients with hepatocellular carcinoma (HCC). To identify novel risk factors associated with HCC recurrence and metastases, we have established a panel of recurrence-associated microRNAs (miRNAs) by comparing miRNA expression in recurrent and nonrecurrent human HCC tissue samples using microarrays (recurrence is defined as recurrent disease occurring within a 2-year time point of the original treatment). Among the panel, expression of the miR-216a/217 cluster was consistently and significantly up-regulated in HCC tissue samples and cell lines associated with early tumor recurrence, poor disease-free survival, and an epithelial-mesenchymal transition (EMT) phenotype. Stable overexpression of miR-216a/217-induced EMT increased the stem-like cell population, migration, and metastatic ability of epithelial HCC cells. Phosphatase and tensin homolog (PTEN) and mothers against decapentaplegic homolog 7 (SMAD7) were subsequently identified as two functional targets of miR-216a/217, and both PTEN and SMAD7 were down-regulated in HCC. Ectopic expression of PTEN or SMAD7 partially rescued miR-216a/217-mediated EMT, cell migration, and stem-like properties of HCC cells. Previously, SMAD7 was shown to be a transforming growth factor beta (TGF-β) type 1 receptor antagonist. Here, we further demonstrated that overexpression of miR-216a/217 acted as a positive feedback regulator for the TGF-β pathway and the canonical pathway involved in the activation of phosphoinositide 3-kinase/protein kinase K (PI3K/Akt) signaling in HCC cells. Additionally, activation of the TGF-β- and PI3K/Akt-signaling pathways in HCC cells resulted in an acquired resistance to sorafenib, whereas blocking activation of the TGF-β pathway overcame miR-216a/217-induced sorafenib resistance and prevented tumor metastases in HCC. Conclusion: Overexpression of miR-216a/217 activates the PI3K/Akt and TGF-β pathways by targeting PTEN and SMAD7, contributing to hepatocarcinogenesis and tumor recurrence in HCC. © 2013 by the American Association for the Study of Liver Diseases.


Wang Y.,National University of Singapore | Lee C.G.,National University of Singapore | Lee C.G.,Humphrey Oei Institute of Cancer Research | Lee C.G.,11 Hospital Drive
Epigenomics | Year: 2011

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide, characterized by high mortality rate and poor prognosis. Our understanding of the HCC pathology is still very much fragmented and little progress has been made to improve the clinical outcome of HCC patients. While recently discovered microRNA deregulation in HCC has added to the complexity of our understanding of HCC, it has also presented promising novel approaches to understand, diagnose and treat HCC. Here, we highlight one miRNA, miR-224, which has been more consistently reported to be upregulated in HCC than other miRNAs. We will discuss the validated and predicted functional roles of this miRNA in HCC, speculate on the possible mechanism for its upregulation in HCC and explore the potential of miR-224 as an exciting novel biomarker for the early detection of liver malignancies as well as a novel therapeutic target for HCC treatment. © 2011 Future Medicine Ltd.


Slagle B.L.,Baylor College of Medicine | Andrisani O.M.,Purdue University | Bouchard M.J.,Drexel University | Lee C.G.L.,National University of Singapore | And 3 more authors.
Hepatology | Year: 2015

Chronic infection with hepatitis B virus (HBV) is a risk factor for developing hepatocellular carcinoma (HCC). The life cycle of HBV is complex and has been difficult to study because HBV does not infect cultured cells. The HBV regulatory X protein (HBx) controls the level of HBV replication and possesses an HCC cofactor role. Attempts to understand the mechanism(s) that underlie HBx effects on HBV replication and HBV-associated carcinogenesis have led to many reported HBx activities that are likely influenced by the assays used. This review summarizes experimental systems commonly used to study HBx functions, describes limitations of these experimental systems that should be considered, and suggests approaches for ensuring the biological relevance of HBx studies. © 2014 by the American Association for the Study of Liver Diseases.


Gao Y.,Humphrey Oei Institute of Cancer Research | Gao Y.,Liaoning Medical University | Theng S.S.,National University of Singapore | Zhuo J.,Humphrey Oei Institute of Cancer Research | And 4 more authors.
Carcinogenesis | Year: 2014

FAT10 (HLA-F-adjacent transcript 10) is an ubiquitin-like modifier, which has been implicated in immune response and cancer development. In particular, the hypothesis of FAT10 as a mediator of tumorigenesis stems from its ability to associate with a spindle checkpoint protein Mad2 during mitosis and cause aneuploidy, a hallmark of cancer cells. Furthermore, FAT10 is overexpressed in several carcinomas types, including that of liver and colon. Nevertheless, direct evidence linking FAT10 to cell malignant transformation and progression is lacking. Here, we demonstrate that high FAT10 expression enhanced the proliferative, invasive, migratory and adhesive functions of the transformed cell line, HCT116. These observations were consistently demonstrated in an immortalized, non-tumorigenic liver cell line NeHepLxHT. Importantly, FAT10 can induce malignant transformation as evidenced from the anchorage-independent growth as well as in vivo tumor-forming abilities of FAT10-overexpressing NeHepLxHT cells, whereas in rapidly proliferating HCT116, increased FAT10 further augmented tumor growth. FAT10 was found to activate nuclear factor-κB (NFκB), which in turn upregulated the chemokine receptors CXCR4 and CXCR7. Importantly, small interfering RNA depletion of CXCR7 and CXCR4 attenuated cell invasion of FAT10-overexpressing cells, indicating that the CXCR4/7 is crucial for the FAT10-dependent malignant phenotypes. Taken together, our data reveal novel functions of FAT10 in malignant transformation and progression, via the NFκB-CXCR4/7 pathway. © The Author 2013. Published by Oxford University Press. All rights reserved.


Ho I.A.W.,Cancer Therapy and Research Center | Toh H.C.,Cancer Therapy and Research Center | Ng W.H.,National Neuroscience Institute | Teo Y.L.,Cancer Therapy and Research Center | And 6 more authors.
Stem Cells | Year: 2013

Tumor tropism of human bone marrow-derived mesenchymal stem cells (MSC) has been exploited for the delivery of therapeutic genes for anticancer therapy. However, the exact contribution of these cells in the tumor microenvironment remains unknown. In this study, we examined the biological effect of MSC on tumor cells. The results showed that MSC inhibited the growth of human glioma cell lines and patient-derived primary glioma cells in vitro. Coadministration of MSC and glioma cells resulted in significant reduction in tumor volume and vascular density, which was not observed when glioma was injected with immortalized normal human astrocytes. Using endothelial progenitor cells (EPC) from healthy donors and HUVEC endothelial cells, the extent of EPC recruitment and capacity to form endothelial tubes was significantly impaired in conditioned media derived from MSC/glioma coculture, suggesting that MSC suppressed tumor angiogenesis through the release of antiangiogenic factors. Further studies using antibody array showed reduced expression of platelet-derived growth factor (PDGF)-BB and interleukin (IL)-1β in MSC/glioma coculture when compared with controls. In MSC/glioma coculture, PDGF-BB mRNA and the corresponding proteins (soluble and membrane bound forms) as well as the receptors were found to be significantly downregulated when compared with that of glioma cocultured with normal human astrocytes or glioma monoculture. Furthermore, IL-1β, phosphorylated Akt, and cathepsin B proteins were also reduced in MSC/glioma. Taken together, these data indicated that the antitumor effect of MSC may be mediated through downregulation of PDGF/PDGFR axis, which is known to play a key role in glioma angiogenesis. © AlphaMed Press.


Xia H.,Humphrey Oei Institute of Cancer Research | Ooi L.L.P.J.,Singapore General Hospital | Hui K.M.,Humphrey Oei Institute of Cancer Research | Hui K.M.,National University of Singapore | Hui K.M.,Institute of Molecular and Cell Biology
PLoS ONE | Year: 2012

The down-regulation of miR-214 has previously been observed in human hepatocellular carcinoma (HCC). Here, we demonstrated the down-regulation of miR-214 is associated with cell invasion, stem-like traits and early recurrence of HCC. Firstly, we validated the suppression of miR-214 in human HCC by real-time quantitative RT-PCR (qRT-PCR) in 20 paired tumor and non-tumor liver tissues of HCC patients and 10 histologically normal liver tissues from colorectal cancer patients with liver metastases. Further qRT-PCR analysis of 50 HCC tissues from an independent cohort of HCC patients of whom 29 with early recurrent disease (<2 years) and 21 with late recurrent disease demonstrated that the suppression of miR-214 was significantly more suppressed in samples from HCC patients with early recurrent disease compared those from patients with no recurrence. Re-expression of miR-214 significantly suppressed the growth of HCC cells in vitro and reduced their tumorigenicity in vivo. The enhancer of zeste homologue 2 (EZH2) and β-catenin (CTNNB1) was identified as two potential direct downstream targets of miR-214 through bioinformatics analysis and experimentally validated the miRNA-target interactions with a dual-firefly luciferase reporter assay. In corroborate with this, both EZH2 and CTNNB1 are found to be significantly overexpressed in human HCC biopsies. Since EZH2 can regulate CTNNB1, CTNNB1 can also be an indirect target of miR-214 through EZH2. Silencing EZH2 or CTNNB1 expression suppressed the growth and invasion of HCC cells and induced E-cadherin (CDH1), known to inhibit cell invasion and metastasis. Furthermore, the silencing of miR-214 or overexpression of EZH2 increased EpCAM+ stem-like cells through the activation of CTNNB1. Interestingly, the up-regulation of EZH2, CTNNB1 and the down-regulation of CDH1 in HCC patients correlated with early recurrent disease and can be an independent predictor of poor survival. Therefore, miR-214 can directly or indirectly target CTNNB1 to modulate the β-catenin signaling pathway in HCC. © 2012 Xia et al.


Wang Q.-E.,Ohio State University | Han C.,Ohio State University | Zhang B.,Ohio State University | Sabapathy K.,Humphrey Oei Institute of Cancer Research | Wani A.A.,Ohio State University
Cancer Research | Year: 2012

XPC protein is a critical DNA damage recognition factor in nucleotide excision repair for which genetic deficiency confers a predisposition to cancer. In this study, we show that XPC has a function that is independent of its canonical function in DNA repair, potentially altering the interpretation of how XPC deficiency leads to heightened cancer susceptibility. XPC enhances apoptosis induced by DNA damage in a p53 nullizygous background, acting downstream of mitochondrial permeabilization and upstream of caspase-9 activation in the DNA damage-induced apoptosis cascade. We found that deficiency in XPC upregulated production of the short isoform of caspase-2 (casp-2S). This upregulation occurred at both protein and mRNA levels through repression of the caspase-2 promoter by XPC protein. Targeted RNAi-mediated downregulation of casp-2S-enhanced UV-induced apoptosis as well as activation of caspase-9 and caspase-6 in XPC-deficient cells, but not in XPC-proficient cells. In addition, XPC overexpression in various p53-deficient cancer cells resistant to cisplatin improved their sensitivity to cisplatin-induced apoptosis. Given that casp-2S functions as an antiapoptotic protein, our findings suggest that XPC enhances DNA damage-induced apoptosis through inhibition of casp-2S transcription. Together, these findings offer a mechanistic foundation to overcome the resistance of highly prevalent p53-deficient tumors to cell death induced by DNA-damaging therapeutic agents, by targeting strategies that inhibit the expression or function of casp-2S. ©2011 AACR.


Lal S.,Humphrey Oei Institute of Cancer Research
Pharmacogenomics Journal | Year: 2016

This study investigated the impact of ABCB5, ABCC5 and RLIP76 polymorphisms on doxorubicin pharmacokinetics in Asian breast cancer patients (N=62). Direct sequencing was performed to screen for previously identified ABCC5 polymorphisms as well as polymorphisms in the exons and exon–intron boundaries of ABCB5 and RLIP76 genes. Genotype–phenotype correlations were analyzed using Mann–Whitney U-test. The homozygous variant allele at the ABCC5 g.+7161G>A (rs1533682) locus was significantly associated with higher doxorubicin clearance (g.+7161AA vs g.+7161GG, CL/BSA (Lh-1m-2): 30.34 (25.41–33.60) vs 22.46 (15.04–49.4), P=0.04). Homozygosity for the reference allele at the ABCC5 g.-1679T>A locus was associated with significantly higher doxorubicinol exposure (g.-1679TT vs g.-1679TA, AUC0-∞/dose/BSA (hm-5): 15.48 (6.18–67.17) vs 8.88 (3.68–21.71), P=0.0001). No significant influence of the three newly identified ABCB5 polymorphisms (c.2T>C, c.343A>G and c.1573G>A) on doxorubicin pharmacokinetics was observed. No polymorphisms were identified in the RLIP76 gene. These findings suggest that ABCC5 polymorphisms may explain partially the interpatient variability in doxorubicin disposition.The Pharmacogenomics Journal advance online publication, 15 March 2016; doi:10.1038/tpj.2016.17. © 2016 Macmillan Publishers Limited

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