Sai Wah Tsao

The University of Hong Kong, Hong Kong, Hong Kong

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Publications (214)1036.27 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Epstein-Barr virus (EBV) infection is closely associated with undifferentiated nasopharyngeal carcinoma (NPC), strongly implicating a role for EBV in NPC pathogenesis; conversely, EBV infection is rarely detected in normal nasopharyngeal epithelial tissues. In general, EBV does not show a strong tropism for infecting human epithelial cells, and EBV infection in oropharyngeal epithelial cells is believed to be lytic in nature. To establish lifelong infection in humans, EBV has evolved efficient strategies to infect B cells and hijack their cellular machinery for latent infection. Lytic EBV infection in pharyngeal epithelial cells, though an infrequent event, is believed to be a major source of infectious EBV particles for salivary transmission. The biological events associated with nasopharyngeal epithelial cells are only beginning to be understood with the advancement of EBV infection methods and the availability of nasopharyngeal epithelial cell models for EBV infection studies. EBV infection in human epithelial cells is a highly inefficient process compared to that in B cells, which express the complement receptor type 2 (CR2) to mediate EBV infection. Although receptor(s) on the epithelial cell surface for EBV infection remain(s) to be identified, EBV infection in epithelial cells could be achieved via the interaction of glycoproteins on the viral envelope with surface integrins on epithelial cells, which might trigger membrane fusion to internalize EBV into cells. Normal nasopharyngeal epithelial cells are not permissive for latent EBV infection, and EBV infection in normal nasopharyngeal epithelial cells usually results in growth arrest. However, genetic alterations in premalignant nasopharyngeal epithelial cells, including p16 deletion and cyclin D1 overexpression, could override the growth inhibitory effect of EBV infection to support stable and latent EBV infection in nasopharyngeal epithelial cells. The EBV episome in NPC is clonal in nature, suggesting that NPC develops from a single EBV-infected nasopharyngeal epithelial cell, and the establishment of persistent and latent EBV infection in premalignant nasopharyngeal epithelium may represent an early and critical event for NPC development.
    Chinese journal of cancer. 09/2014;
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    ABSTRACT: Over 75% of nasopharyngeal carcinoma (NPC) patients have already developed local or regional spread at diagnosis, which hampers effective treatment and results in a poor prognosis. It is essential to characterize more sensitive and specific biomarkers for screening of high risk individuals and assessment of NPC treatment effectiveness. NPC is an EBV associated tumor in which only a few viral proteins but more than 20 BART microRNAs are detected, at abundant levels. We hypothesized that these BART microRNAs may be novel biomarkers for NPC. Systematic analysis of EBV BART microRNA expression profiles in EBV latently infected MutuI and Mutu III cell lines, EBV-harboring NPC and non-cancerous nasopharyngeal cells found that miR-BART3, miR-BART7 and miR-BART13 microRNAs are highly expressed and regularly secreted into the extracellular environment of NPC cells. These BART microRNAs were evaluated for used as potential NPC biomarkers. Analysis of plasma specimens obtained from NPC patients (n=89), and healthy (n=28) and non-NPC tumor patient controls (n=18) found levels of both miR-BART7 and miR-BART13, but not miR-BART3, to be distinctly presence among NPC patients, with elevated levels being particularly apparent among patients with advanced disease. ROC curve analysis combining miR-BART7 and miR-BART13 levels produces a 90% predictive value for the presence of NPC. Analysis of 41 NPC patients before and after radiotherapy showed that miR-BART7 and miR-BART13, but not miR-BART3, were diminished after treatment. These results indicate That EBV microRNAs, miR-BART7 and miR-BART13, may constitute useful new serological biomarkers for diagnosis of NPC and prediction of treatment efficacy. © 2014 Wiley Periodicals, Inc.
    International Journal of Cancer 09/2014; · 6.20 Impact Factor
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    ABSTRACT: Apart from regulating stem cell self-renewal, embryonic development and proliferation, Bmi-1 has been recently reported to be critical in the maintenance of genome integrity. In searching for novel mechanisms underlying the anticlastogenic function of Bmi-1, we observed, for the first time, that Bmi-1 positively regulates p21 expression. We extended the finding that Bmi-1 deficiency induced chromosome breaks in multiple cancer cell models. Interestingly, we further demonstrated that knockdown of cyclin E or ectopic overexpression of p21 rescued Bmi-1 deficiency-induced chromosome breaks. We therefore conclude that p21/cyclin E pathway is crucial in modulating the anticlastogenic function of Bmi-1. Because it is well-established that the overexpression of cyclin E potently induces genome instability and p21 suppresses the function of cyclin E, the novel and important implication from our findings is that Bmi-1 plays an important role in limiting genomic instability in cylin E-overexpressing cancer cells by positive regulation of p21. © 2014 Wiley Periodicals, Inc.
    International Journal of Cancer 08/2014; · 6.20 Impact Factor
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    ABSTRACT: The p38 mitogen-activated protein (MAP) kinase signal transduction pathway plays an important role in inflammatory and stress responses. MAP Kinase Kinase 6 (MKK6), a dual specificity protein kinase, is a p38 activator. Activation of the MKK6-p38 pathway is kept in check by multiple layers of regulations, including autoinhibition, dimerization, scaffold proteins and lysine 63 (K63)-linked polyubiquitination. However, the mechanisms underlying deactivation of MKK6-p38, which is crucial for maintaining magnitude and duration of signal transduction, are not well understood. Lysine 48 (K48)-linked ubiquitination, which marks substrates for proteasomal degradation, is an important negative post-translational regulatory machinery for signal pathway transduction. Here we report that the accumulation of F-box only protein 31 (FBXO31), a component of Skp1-Cul1-F-box protein (SCF) E3 ligase, negatively regulated p38 activation in cancer cells upon genotoxic stresses. Our results showed that FBXO31 binds to MKK6 and mediates its K48-linked polyubiquitination and degradation, thereby functioning as a negative regulator of MKK6-p38 signaling and protecting cells from stress-induced cell apoptosis. Taken together, our findings uncover a new mechanism of deactivation of MKK6/p38, and substantiate a novel regulatory role of FBXO31 in stress response.
    The Journal of biological chemistry. 06/2014;
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    ABSTRACT: To investigate the autocrine/endocrine role of Id1-induced insulin-like growth factor 2 (IGF2) in esophageal cancer, and evaluate the potential of IGF2- and IGF type 1 receptor (IGF1R)-targeted therapies. Antibody array-based screening was used to identify differentially secreted growth factors from Id1-overexpressing esophageal cancer cells. In vitro and in vivo assays were performed to confirm the induction of IGF2 by Id1, and to study the autocrine and endocrine effects of IGF2 in promoting esophageal cancer progression. Human esophageal cancer tissue microarray was analyzed for overexpression of IGF2 and its correlation with that of Id1 and phosphorylated AKT (p-AKT). The efficacy of intratumorally injected IGF2 antibody and intraperitoneally injected cixutumumab (fully human monoclonal IGF1R antibody) was evaluated using in vivo tumor xenograft and experimental metastasis models. Id1 overexpression induced IGF2 secretion which promoted cancer cell proliferation, survival and invasion by activating AKT in an autocrine manner. Overexpression of IGF2 was found in 21/35 (60%) esophageal cancer tissues and was associated with upregulation of Id1 and p-AKT. IGF2 secreted by Id1-overexpressing esophageal cancer xenograft could instigate the growth of distant esophageal tumors, as well as promote metastasis of circulating cancer cells. Targeting IGF2 and IGF1R had significant suppressive effects on tumor growth and metastasis in mice. Cixutumumab treatment enhanced the chemosensitivity of tumor xenografts to fluorouracil and cisplatin. The Id1-IGF2-IGF1R-AKT signaling cascade plays an important role in esophageal cancer progression. Blockade of IGF2/IGF1R signaling has therapeutic potential in the management of esophageal cancer.
    Clinical Cancer Research 03/2014; · 7.84 Impact Factor
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    ABSTRACT: Nasopharyngeal carcinoma (NPC) is a common disease among southern Chinese. The major etiological factors proposed for NPC pathogenesis include genetic susceptibility, environment factors and EBV infection. In the high risk population, genetic susceptibility to NPC has been mapped to the HLA loci and adjacent genes in MHC region on chromosome 6p21. Consumption of preserved food including salted fish has been implicated in its etiology in earlier studies. Its contribution to pathogenesis of NPC remains to be determined. A decreasing trend of NPC incidence was observed in Hong Kong, Taiwan and Singapore in recent years which may be accounted by a change of dietary habits. A comprehensive epidemiological study will help to elucidate the relative importance of various risk factors in the pathogenesis of NPC. Despite the close association of EBV infection with NPC, the etiological role of EBV in NPC pathogenesis remains enigmatic. EBV infection in primary nasopharyngeal epithelial cells is uncommon and difficult to achieve. EBV does not transform primary nasopharyngeal epithelial cells into proliferative clones, which contrasts greatly with the well-documented ability of EBV to transform and immortalize primary B cells. Genetic alterations identified in premalignant nasopharyngeal epithelium may play crucial roles to support stable EBV infection. Subsequently, latent and lytic EBV gene products may drive clonal expansion and transformation of premalignant nasopharyngeal epithelial cells into cancer cells. Stromal inflammation in nasopharyngeal mucosa is believed to play an important role in modulating the growth and possibly drive the malignant transformation of EBV-infected nasopharyngeal epithelial cells. Furthermore, there are increasing evidences supporting a role of EBV infection to evade host immune surveillance. EBV-infected cells may have selective growth advantages in vivo by acquiring a stress–resistance phenotype. Understanding the etiological factors and pathogenesis of NPC will contribute effectively to the prevention and treatment of this disease.
    Oral Oncology 01/2014; · 2.70 Impact Factor
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    ABSTRACT: Cortidis rhizoma (Huanglian) and its major therapeutic component, berberine, have drawn extensive attention in recent years for their anti-cancer properties. Growth inhibitory effects of berberine on multiple types of human cancer cells have been reported. Berberine inhibits invasion, induces cell cycle arrest and apoptosis in human cancer cells. The anti-inflammatory property of berberine, involving inhibition of Signal Transducer and Activator of Transcription 3 (STAT3) activation, has also been documented. In this study, we have examined the effects of berberine on tumorigenicity and growth of nasopharyngeal carcinoma (NPC) cells and their relationship to STAT3 signaling using both in vivo and in vitro models. Berberine effectively inhibited the tumorigenicity and growth of an EBV-positive NPC cell line (C666-1) in athymic nude mice. Inhibition of tumorigenic growth of NPC cells in vivo was correlated with effective inhibition of STAT3 activation in NPC cells inside the tumor xenografts grown in nude mice. In vitro, berberine inhibited both constitutive and IL-6-induced STAT3 activation in NPC cells. Inhibition of STAT3 activation by berberine induced growth inhibition and apoptotic response in NPC cells. Tumor-associated fibroblasts were found to secret IL-6 and the conditioned medium harvested from the fibroblasts also induced STAT3 activation in NPC cells. Furthermore, STAT3 activation by conditioned medium of tumor-associated fibroblasts could be blocked by berberine or antibodies against IL-6 and IL-6R. Our observation that berberine effectively inhibited activation of STAT3 induced by tumor-associated fibroblasts suggests a role of berberine in modulating the effects of tumor stroma on the growth of NPC cells. The effective inhibition of STAT3 activation in NPC cells by berberine supports its potential use in the treatment of NPC.
    BMC Cancer 12/2013; 13(1):619. · 3.33 Impact Factor
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    ABSTRACT: The humanized anti-HER2 monoclonal antibody (mAb) Herceptin (trastuzumab) effectively inhibits HER2-positive breast tumors. However, many patients responding to treatment often develop resistance. Crosstalk between IGF-IR and HER2 and elevated IGF-IR signaling have been implicated in tumor cell resistance to Herceptin therapy. Previously, we reported that the anti-IGF-IR mAb m590 inhibits proliferation and migration of breast cancer MCF-7 cells in vitro. Here, we generated a "knobs-into-holes" bispecific antibody (Bi-Ab) against HER2 and IGF-IR by engineering Herceptin and m590. We compared the effects of Bi-Ab treatment in vitro and in SKOV-3 HER2- and IGF-IR-overexpressing cancer xenograft mouse model with those of m590 and Herceptin treatment alone or in combination (Comb). Bi-Ab effectively inhibited proliferation of HER2- and IGF-IR-overexpressing ovarian cancer SKOV-3 cells in vitro by ablating receptor phosphorylation and downstream PI3K/Akt and MAPK signaling. Bi-Ab more effectively inhibited cancer growth in SKOV-3 HER2- and IGF-IR-overexpressing cancer xenograft mouse model than m590 and Herceptin alone or in combination. Mice bearing SKOV-3 HER2- and IGF-IR-overexpressing xenografts showed extensive and sustainable tumor regression when treated with Bi-Ab. Our results suggest that Bi-Ab has superior antitumor activity compared with monospecific antibodies, and co-targeting HER2 and IGF-IR may be clinically beneficial in minimizing the acquired resistance to Herceptin therapy.
    Molecular Cancer Therapeutics 11/2013; · 5.60 Impact Factor
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    ABSTRACT: Disintegrins and metalloproteinases with thrombospondin motifs (ADAMTSs) have been reported dysregulated in various cancers. Through refining a loss of heterozygosity locus at 11q25 by array-CGH, we identified ADAMTS8 as a novel candidate tumor suppressor gene. Although ADAMTS8 downregulation has been reported in several tumors, its biological function and underlying mechanism remain largely unknown. Here, we found that ADAMTS8 is broadly expressed in normal tissues but frequently downregulated or silenced by promoter methylation in common carcinoma cell lines, including nasopharyngeal, esophageal squamous cell, gastric and colorectal carcinomas. Pharmacological or genetic demethylation restored ADAMTS8 expression, indicating that promoter methylation mediates its silencing. Aberrant methylation of ADAMTS8 was also detected in several types of primary tumors but rarely in normal tissues. Further functional studies showed that restoring ADAMTS8 expression suppressed tumor cell clonogenicity through inducing apoptosis. ADAMTS8 as a secreted protease inhibited EGFR signaling along with decreased levels of phosphorylated MEK and ERK. We further found that ADAMTS8 disrupted actin stress fiber organization and inhibited tumor cell motility. Thus, our data demonstrate that ADAMTS8 metalloprotease acts as a functional tumor suppressor through antagonizing EGFR-MEK-ERK signaling, in addition to its previously reported anti-angiogenesis function, and is frequently methylated in common tumors. Implications: This study uncovers the tumor suppressive funciton of ADAMTS8, one of the ADAMTS8 family memebers,and its frequent methylation in certain tumors could be developed as a potential biomarker.
    Molecular Cancer Research 11/2013; · 4.35 Impact Factor
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    ABSTRACT: Epstein-Barr virus (EBV) encodes at least 44 mature microRNAs (miRNAs), some of which are abundantly expressed in nasopharyngeal carcinoma cells. EBV-encoded miR-BART6 miRNA is known to undergo A-to-I RNA editing that impacts processing and function. Whether additional EBV miRNAs might be A-to-I edited remains to be determined. In this study we reported on A-to-I editing of EBV miR-BART3. The A-to-I editing enzyme was abundantly expressed in EBV-infected epithelial carcinoma cells. pri-miR-BART3 was found to be edited at four sites in these cells and in nasopharyngeal carcinoma samples. Whereas editing of the second site located within the seed region abrogated the targeting of DICE1 mRNA, editing of the third site effectively cripples the biogenesis of mature miR-BART3. Thus, A-to-I editing perturbs biogenesis and targeting of miR-BART3 and might contribute to its differential expression and function in EBV-infected epithelial cells.
    Journal of General Virology 09/2013; · 3.13 Impact Factor
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    ABSTRACT: The dual PI3K-mTOR inhibitor BEZ235 was evaluated in preclinical models of nasopharyngeal carcinoma (NPC). The IC50 value of BEZ235 for growth was in the nanomolar range in vitro, induce G1 cycle arrest and apoptosis, and inhibited AKT and mTOR signaling in most NPC cell lines. No synergistic effect was observed when BEZ235 was combined with chemotherapy. BEZ235 increased MAPK activation in vitro but not in vivo. A daily schedule was more effective than a weekly schedule on tumor growth and inhibition of downstream mTOR signaling in vivo. The activity of BEZ235 maybe independent of the PIK3CA amplification and mutation status.
    Cancer letters 09/2013; · 4.86 Impact Factor
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    ABSTRACT: Nasopharyngeal carcinoma (NPC) is a rare but highly invasive cancer. As options of agents for effective combination chemoradiotherapy of advanced NPC are limited, novel therapeutic approaches are desperately needed. The ubiquitin ligase CHFR is known to target poly(ADP-ribose) polymerase 1 (PARP1) for degradation and is epigenetically inactivated in NPC. We present evidence that PARP1 protein is indeed overexpressed in NPC cells in comparison to immortalized normal nasopharyngeal epithelial cells. Tissue microarray analysis also indicated that PARP1 protein is significantly elevated in primary NPC tissues, with strong correlation with all stages of NPC development. We found that the PARP inhibitor AZD2281 (Olaparib) increased DNA damage, cell cycle arrest, and apoptosis in NPC cells challenged with ionizing radiation or temozolomide. Isobologram analysis confirmed that the cytotoxicity triggered by AZD2281 and DNA damaging agents was synergistic. Finally, AZD2281 also enhanced the tumor-inhibitory effects of ionizing radiation in animal xenograft models. These observations implicate that PARP1 overexpression is an early event in NPC development and provide a molecular basis of using PARP inhibitors to potentiate treatment of NPC with radiotherapy and chemotherapy.
    Molecular Cancer Therapeutics 08/2013; · 5.60 Impact Factor
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    ABSTRACT: Nasopharyngeal carcinoma (NPC) is a cancer with its highest prevalence among the southern Chinese and is rare elsewhere in the world. The main treatment modalities include chemotherapy and radiotherapy. However, tumor chemoresistance often limits the efficacy of NPC treatment and reduces survival rates. Thus, identifying new selective chemotherapeutic drugs for NPC treatment is needed. In this current study, the anti-tumor efficacy of a polo-like kinase inhibitor, Ro5203280, was investigated. Ro5203280 induces tumor suppression both in vitro and in vivo. An inhibitory effect was observed with the highly proliferating cancer cell lines tested, but not with the non-tumorigenic cell line. Real-time cell proliferation and FACS analysis, together with immunohistochemical (IHC), immunofluorescence (IF), and Annexin V staining assays were used to evaluate the impact of drug treatment on cell cycle and apoptosis. Ro5203280 induces G2/M cell cycle arrest and apoptosis. Western blotting shows it inhibits PLK1 phosphorylation and down-regulates the downstream signaling molecule, Cdc25c, and up-regulates two important mitosis regulators, Wee1 and Securin, as well as the DNA damage-related factor Chk2 in vitro and in vivo. In vivo tumorigenicity assays with Ro5203280 intravenous injection demonstrated its potent ability to inhibit tumor growth in mice, with no observable signs of toxicity. These findings suggest the potential usefulness of Ro5203280 as a chemotherapeutic targeting drug for NPC treatment.
    Molecular Cancer Therapeutics 05/2013; · 5.60 Impact Factor
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    ABSTRACT: Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV)-associated tumor prevalent in Southern China and Southeast Asia, with the 3p14-12 locus reported as a critical tumor suppressor gene (TSG) region during its pathogenesis. We identified a novel 3p14.2 TSG, FEZF2 (FEZ family zinc finger 2), for NPC. FEZF2 is readily expressed in normal tissues including upper respiratory epithelium, testis, brain and ovary tissues as well as immortalized nasopharyngeal epithelial cell line NP69, but completely silenced in NPC cell lines due to CpG methylation of its promoter, although no homozygous deletion of FEZF2 was detected. Aza treatment restored FEZF2 expression in NPC cell lines along with its promoter demethylation. FEZF2 was frequently downregulated in NPC tumors, with promoter methylation detected in 75.5% of tumors, but only in 7.1% of normal nasopharyngeal tissues. Restored FEZF2 expression suppressed NPC cell clonogenicity through inducing G2/M cell cycle arrest and apoptosis, and also inhibited NPC cell migration and stemness. FEZF2 acted as a HDAC-associated repressor downregulating multiple oncogenes including EZH2 and MDM2, through direct binding to their promoters. Concomitantly, overexpression of EZH2 was frequently detected in NPC tumors. Thus, we have identified FEZF2 as a novel 3p14.2 TSG frequently inactivated by promoter methylation in NPC, which functions as a repressor downregulating multiple oncogene expression.
    Carcinogenesis 05/2013; · 5.64 Impact Factor
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    ABSTRACT: A novel drug combination of a proteasome inhibitor, bortezomib and a histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA) was tested in nasopharyngeal carcinoma (NPC) both in vitro and in vivo. Dose-response of different concentrations of bortezomib and SAHA on inhibition of cell proliferation of NPC was determined. Mechanisms of apoptosis and effects on lytic cycle activation of Epstein-Barr virus (EBV) were investigated. Combination of bortezomib and SAHA (bortezomib/SAHA) synergistically induced killing of a panel of NPC cell lines. Pronounced increase in sub-G1, annexin V-positive and TUNEL-positive cell populations were detected after treatment with bortezomib/SAHA when compared with either drug alone. Concomitantly, markedly augmented proteolytic cleavage of PARP, caspase-3, -7, -8 and -9, reactive oxygen species (ROS) generation and caspase-8-dependent histone acetylation were observed. ROS scavenger, N-acetyl cysteine, diminished the apoptotic effects of bortezomib/SAHA while caspase inhibitor, Z-VAD-FMK, significantly suppressed the apoptosis without decreasing the generation of ROS. Bortezomib inhibited SAHA's induction of EBV replication and abrogated production of infectious viral particles in NPC cells. Furthermore, bortezomib/SAHA potently induced apoptosis and suppressed the growth of NPC xenografts in nude mice. In conclusion, the novel drug combination of bortezomib and SAHA is highly synergistic in the killing of NPC cells in vitro and in vivo. The major mechanism of cell death is ROS-driven caspase-dependent apoptosis. Bortezomib antagonizes SAHA's activation of EBV lytic cycle in NPC cells. This study provides a strong basis for clinical testing of the combination drug regimen in NPC patients.
    Molecular Cancer Therapeutics 03/2013; · 5.60 Impact Factor
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    ABSTRACT: Tumor-initiating cells (TICs), also known as cancer stem cells, are regarded widely as a specific subpopulation of cells needed for cancer initiation and progression. TICs have yet to be identified in esophageal tumors that have a rising incidence in developed countries. Here we report a CD90+ cell population found in esophageal squamous cell carcinoma (ESCC) which is endowed with stem cell-like properties and high tumorigenic and metastatic potential. mRNA profiling of these cells suggested pathways through which they drive tumor growth and metastasis, with deregulation of an Ets1-MMP signaling pathway and epithelial-mesenchymal transition figuring prominently. These cells possessed higher self-renewal activity and were sufficient for tumor growth, differentiation, metastasis and chemotherapeutic resistance. CD90+ TICs were isolated and characterized from ESCC clinical specimens as well as ESCC cell lines. In freshly resected clinical specimens, they represented a rare cell population the levels of which correlated with strong family histories and lymph node metastasis. Our results prompt further study of this CD90+ population of esophageal TICs as potential therapeutic targets.
    Cancer Research 02/2013; · 9.28 Impact Factor
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    ABSTRACT: Nasopharyngeal carcinoma (NPC) is common among southern Chinese including the ethnic Cantonese population living in Hong Kong. Epstein-Barr virus (EBV) infection is detected in all undifferentiated type of NPC in this endemic region. Establishment of stable and latent EBV infection in premalignant nasopharyngeal epithelial cells is an early event in NPC development and may contribute to its pathogenesis. Immortalized primary nasopharyngeal epithelial cells represent an important tool for investigation of EBV infection and its tumorigenic potential in this special type of epithelial cells. However, the limited availability and small sizes of nasopharyngeal biopsies have seriously restricted the establishment of primary nasopharyngeal epithelial cells for immortalization. A reliable and effective method to immortalize primary nasopharyngeal epithelial cells will provide unrestricted materials for EBV infection studies. An earlier study has reported that Bmi-1 expression could immortalize primary nasopharyngeal epithelial cells. However, its efficiency and actions in immortalization have not been fully characterized. Our studies showed that Bmi-1 expression alone has limited ability to immortalize primary nasopharyngeal epithelial cells and additional events are often required for its immortalization action. We have identified some of the key events associated with the immortalization of primary nasopharyngeal epithelial cells. Efficient immortalization of nasopharyngeal epithelial cells could be reproducibly and efficiently achieved by the combined actions of Bmi-1 expression, activation of telomerase and silencing of p16 gene. Activation of MAPK signaling and gene expression downstream of Bmi-1 were detected in the immortalized nasopharyngeal epithelial cells and may play a role in immortalization. Furthermore, these newly immortalized nasopharyngeal epithelial cells are susceptible to EBV infection and supported a type II latent EBV infection program characteristic of EBV-infected nasopharyngeal carcinoma. The establishment of an efficient method to immortalize primary nasopharyngeal epithelial cells will facilitate the investigation into the role of EBV infection in pathogenesis of nasopharyngeal carcinoma.
    PLoS ONE 01/2013; 8(10):e78395. · 3.53 Impact Factor
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    ABSTRACT: Activation of the stem cell transcriptional circuitry is an important event in cancer development. Although cancer cells demonstrate a stem cell-like gene expression signature, the epigenetic regulation of pluripotency-associated genes in cancers remains poorly understood. In this study, we characterized the epigenetic regulation of the pluripotency-associated genes NANOG, OCT4, c-MYC, KLF4, and SOX2 in a variety of cancer cell lines and in primary tumor samples, and investigated the re-activation of pluripotency regulatory circuits in cancer progression. Differential patterns of DNA methylation, histone modifications, and gene expression of pluripotent genes were demonstrated in different types of cancers, which may reflect their tissue origins. NANOG promoter hypomethylation and gene upregulation were found in metastatic human liver cancer cells and human hepatocellular carcinoma (HCC) primary tumor tissues. The upregulation of NANOG, together with p53 depletion, was significantly associated with clinical late stage of HCC. A pro-metastatic role of NANOG in colon cancer cells was also demonstrated, using a NANOG-overexpressing orthotopic tumor implantation mouse model. Demethylation of NANOG promoter was observed in CD133+(high) cancer cells. In accordance, overexpression of NANOG resulted in an increase in the population of CD133+(high) cells. In addition, we demonstrated a cross-regulation between OCT4 and NANOG in cancer cells via reprogramming of promoter methylation. Taken together, epigenetic reprogramming of NANOG can lead to the acquisition of stem cell-like properties. These results underscore the restoration of pluripotency circuits in cancer cells as a potential mechanism for cancer progression.
    PLoS ONE 01/2013; 8(9):e72435. · 3.53 Impact Factor
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    ABSTRACT: Nasopharyngeal carcinoma (NPC) is etiologically associated with Epstein-Barr virus (EBV) infection. However, the exact role of EBV in NPC pathogenesis remains elusive. Activation of signal transducer and activator of transcription 3 (STAT3) is common in human cancers including NPC and plays an important role in the pathogenesis and progression of human cancers. Interleukin-6 (IL-6), a major inflammatory cytokine, is a potent activator of STAT3. In this study, we report that EBV-infected immortalized nasopharyngeal epithelial (NPE) cells often acquire an enhanced response to IL-6-induced STAT3 activation to promote their growth and invasive properties. Interestingly, this enhanced IL-6/STAT3 response was mediated by overexpression of IL-6 receptor (IL-6R). Furthermore, IL-6R overexpression enhanced IL-6-induced STAT3 activation in uninfected immortalized NPE cells in vitro, and promoted growth and tumorigenicity of EBV-positive NPC cell line (C666-1) in vivo. Moreover, it is shown for the first time that IL-6R was overexpressed in clinical specimens of NPC. IL-6 expression could also be strongly detected in the stromal cells of NPC and a higher circulating level of IL-6 was found in the sera of advance-staged NPC patients compared to the control subjects. Therefore, IL-6R overexpression, coupled with enhanced IL-6/STAT3 signaling may facilitate the malignant transformation of EBV-infected premalignant NPE cells into cancer cells, and enhance malignant properties of NPC cells.
    PLoS ONE 01/2013; 8(5):e62284. · 3.53 Impact Factor
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    ABSTRACT: Latent infection with Epstein-Barr virus (EBV) is associated with several types of malignancies including nasopharyngeal carcinoma (NPC), which is particularly more prevalent in Southern China. EBV expresses at least 44 mature microRNAs (miRNAs) to modulate the activity of viral and cellular RNAs, but the targets of these EBV-encoded miRNAs in NPC are not well understood. In this report, we characterized DICE1 tumor suppressor to be a cellular target of EBV miR-BART3* miRNA. miR-BART3* was abundantly expressed in NPC cells. The target site of miR-BART3* located in the 3?-untranslated region of DICE1 transcript was identified and characterized. Enforced expression of miR-BART3* or its precursor pre-miR-BART3 led to down-regulation of endogenous DICE1 expression. Inhibition of endogenous miR-BART3* in NPC cells with anti-miR-BART3* oligonucleotide inhibitor resulted in increased expression of DICE1 protein. On the contrary, expression of miR-BART3* overcame the growth suppressive activity of DICE1 and stimulated cell proliferation. Consistent with its tumor suppressive function, DICE1 was underexpressed in EBV-expressing NPC tumor tissues. Taken together, our findings suggest that EBV encoded miR-BART3* miRNA targets DICE1 tumor suppressor to promote cellular growth and transformation in NPC. © 2012 Wiley Periodicals, Inc.
    International Journal of Cancer 12/2012; · 6.20 Impact Factor

Publication Stats

5k Citations
1,036.27 Total Impact Points

Institutions

  • 1998–2014
    • The University of Hong Kong
      • • Centre for Cancer Research
      • • Department of Surgery
      • • Department of Anatomy
      • • Department of Clinical Oncology
      • • Department of Pathology
      Hong Kong, Hong Kong
  • 2013
    • Capital Medical University
      Peping, Beijing, China
  • 2012–2013
    • Xi'an Jiaotong University
      Ch’ang-an, Shaanxi, China
  • 2005–2013
    • Lands Department of The Government of the Hong Kong Special Administrative Region
      Hong Kong, Hong Kong
  • 1991–2013
    • The Chinese University of Hong Kong
      • • Department of Clinical Oncology
      • • Prince of Wales Hospital
      • • Department of Anatomical and Cellular Pathology
      Hong Kong, Hong Kong
  • 2005–2012
    • The Hong Kong University of Science and Technology
      • Division of Life Science
      Kowloon, Hong Kong
  • 2010
    • French National Centre for Scientific Research
      Lutetia Parisorum, Île-de-France, France
  • 2008
    • Institut de Cancérologie Gustave Roussy
      • Department of Radiotherapy
      Île-de-France, France
    • University of Massachusetts Medical School
      Worcester, Massachusetts, United States
  • 2007–2008
    • Central South University
      • Cancer Research Institute
      Changsha, Hunan, China
  • 2003–2008
    • Queen Mary Hospital
      Hong Kong, Hong Kong
  • 2004
    • Harbin Medical University
      • Laboratory of Medical Genetics
      Charbin, Heilongjiang Sheng, China
  • 1997
    • Prince of Wales Hospital, Hong Kong
      Chiu-lung, Kowloon City, Hong Kong
  • 1991–1995
    • Brigham and Women's Hospital
      • • Department of Medicine
      • • Center for Brain Mind Medicine
      • • Department of Obstetrics and Gynecology
      Boston, MA, United States
  • 1990
    • Dana-Farber Cancer Institute
      Boston, Massachusetts, United States