ORCID Profile
0000-0002-3354-9310
Current Organisation
Nanyang Technological University
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Publisher: BMJ
Date: 25-07-2023
DOI: 10.1136/GUTJNL-2023-330291
Abstract: Roseburia intestinalis is a probiotic species that can suppress intestinal inflammation by producing metabolites. We aimed to study the role of R. intestinalis in colorectal tumourigenesis and immunotherapy. R. intestinalis abundance was evaluated in stools of patients with colorectal cancer (CRC) (n=444) and healthy controls (n=575). The effects of R. intestinalis were studied in Apc Min/+ or azoxymethane (AOM)-induced CRC mouse models, and in syngeneic mouse xenograft models of CT26 (microsatellite instability (MSI)-low) or MC38 (MSI-high). The change of immune landscape was evaluated by multicolour flow cytometry and immunohistochemistry staining. Metabolites were profiled by metabolomic profiling. R. intestinalis was significantly depleted in stools of patients with CRC compared with healthy controls. R. intestinalis administration significantly inhibited tumour formation in Apc Min/+ mice, which was confirmed in mice with AOM-induced CRC. R. intestinalis restored gut barrier function as indicated by improved intestinal permeability and enhanced expression of tight junction proteins. Butyrate was identified as the functional metabolite generated by R. intestinalis. R. intestinalis or butyrate suppressed tumour growth by inducing cytotoxic granzyme B + , interferon (IFN)-γ + and tumour necrosis factor (TNF)-α + CD8 + T cells in orthotopic mouse models of MC38 or CT26. R. intestinalis or butyrate also significantly improved antiprogrammed cell death protein 1 (anti-PD-1) efficacy in mice bearing MSI-low CT26 tumours. Mechanistically, butyrate directly bound to toll-like receptor 5 (TLR5) receptor on CD8 + T cells to induce its activity through activating nuclear factor kappa B (NF-κB) signalling. R. intestinalis protects against colorectal tumourigenesis by producing butyrate, which could also improve anti-PD-1 efficacy by inducing functional CD8 + T cells. R. intestinalis is a potential adjuvant to augment anti-PD-1 efficacy against CRC.
Publisher: American Association for Cancer Research (AACR)
Date: 15-09-2225
DOI: 10.1158/0008-5472.22431556
Abstract: Supplementary Table from Single-Hit Inactivation Drove Tumor Suppressor Genes Out of the X Chromosome during Evolution
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22431559
Abstract: Supplementary Table from Single-Hit Inactivation Drove Tumor Suppressor Genes Out of the X Chromosome during Evolution
Publisher: Springer Science and Business Media LLC
Date: 11-04-2018
Publisher: BMJ
Date: 24-10-2016
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22431556.V1
Abstract: Supplementary Table from Single-Hit Inactivation Drove Tumor Suppressor Genes Out of the X Chromosome during Evolution
Publisher: Informa UK Limited
Date: 16-01-2020
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22431571
Abstract: Supplementary Figure from Single-Hit Inactivation Drove Tumor Suppressor Genes Out of the X Chromosome during Evolution
Publisher: Elsevier BV
Date: 12-2017
DOI: 10.1053/J.GASTRO.2017.08.022
Abstract: Altered gut microbiota is implicated in development of colorectal cancer (CRC). Some intestinal bacteria have been reported to potentiate intestinal carcinogenesis by producing genotoxins, altering the immune response and intestinal microenvironment, and activating oncogenic signaling pathways. We investigated whether stool from patients with CRC could directly induce colorectal carcinogenesis in mice. We obtained stored stool s les from participants in a metagenome study performed in Hong Kong. Conventional (male C57BL/6) mice were given azoxymethane to induce colon neoplasia after receiving a course of antibiotics in drinking water. Mice were gavaged twice weekly with stool from 5 patients with CRC or 5 healthy in iduals (controls) for 5 weeks. Germ-free C57BL/6 mice were gavaged once with stool from 5 patients with CRC or 5 controls. We collected intestinal tissues from mice and performed histology, immunohistochemistry, expression microarray, quantitative polymerase chain reaction, immunoblot, and flow cytometry analyses. We performed 16S ribosomal RNA gene sequencing analysis of feces from mice. Significantly higher proportions of conventional mice fed with stool from in iduals with CRC than control stool developed high-grade dysplasia (P < .05) and macroscopic polyps (P < .01). We observed a higher proportion of proliferating (Ki-67-positive) cells in colons of germ-free mice fed with stool from patients with CRC vs those fed with stool from controls (P < .05). Feces from germ-free and conventional mice fed with stool from patients with CRC vs controls contained different microbial compositions, with lower richness in mice fed with stool from patients with CRC. Intestines collected from conventional and germ-free mice fed with stool from patients with CRC had increased expression of cytokines that modulate inflammation, including C-X-C motif chemokine receptor 1, C-X-C motif chemokine receptor 2, interleukin 17A (IL17A), IL22, and IL23A. Intestines from conventional and germ-free mice fed with stool from patients with CRC contained higher proportions of T-helper 1 (Th1) cells (2.25% vs 0.44%) and Th17 cells (2.08% vs 0.31%) (P < .05 for each) than mice fed with stool from controls. Real-time polymerase chain reaction arrays revealed up-regulation of genes involved in cell proliferation, stemness, apoptosis, angiogenesis, invasiveness, and metastasis in mice fed with stool from patients with CRC. We fed stool s les from patients with CRC and heathy in iduals to germ-free mice and conventional mice with azoxymethane. We found stool from patients with CRC to increase the numbers of polyps, levels of intestinal dysplasia and proliferation, markers of inflammation, and proportions of Th1 and Th17 cells in colon, compared with stool from in iduals without CRC. This study provides evidence that the fecal microbiota from patients with CRC can promote tumorigenesis in germ-free mice and mice given a carcinogen.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22431553
Abstract: Supplementary Table from Single-Hit Inactivation Drove Tumor Suppressor Genes Out of the X Chromosome during Evolution
Publisher: Springer Science and Business Media LLC
Date: 03-04-2018
DOI: 10.1038/S41388-018-0220-5
Abstract: Zinc-finger protein 471 (ZNF471) was preferentially methylated in gastric cancer using promoter methylation array. The role of ZNF471 in human cancer is unclear. Here we elucidated the functional significance, molecular mechanisms and clinical impact of ZNF471 in gastric cancer. ZNF471 mRNA was silenced in 15 out of 16 gastric cancer cell lines due to promoter hypermethylation. Significantly higher ZNF471 promoter methylation was also observed in primary gastric cancers compared to their adjacent normal tissues ( P 0.001). ZNF471 promoter CpG-site hypermethylation correlated with poor survival of gastric cancer patients ( n = 120, P = 0.001). Ectopic expression of ZNF471 in gastric cancer cell lines (AGS, BGC823, and MKN74) significantly suppressed cell proliferation, migration, and invasion, while it induced apoptosis in vitro and inhibited xenograft tumorigenesis in nude mice. Transcription factor AP-2 Alpha (TFAP2A) and plastin3 (PLS3) were two crucial downstream targets of ZNF471 demonstrated by bioinformatics modeling and ChIP-PCR assays. ZNF471 directly bound to the promoter of TFAP2A and PLS3 and transcriptionally inhibited their expression. TFAP2A and PLS3 showed oncogenic functions in gastric cancer cell lines. Moreover, ZNF471 recruited KAP1 to the promoter of the target genes, thereby inducing H3K9me3 enrichment for transcriptional repression and inhibition of oncogenic TFAP2A and PLS3. In conclusion, ZNF471 acts as a tumor suppressor in gastric cancer by transcriptionally inhibiting downstream targets TFAP2A and PLS3. KAP1 is a co-repressor of ZNF471 at the promoter of the target genes. The promoter CpG-site methylation is an independent prognostic factor for overall survival of gastric cancer patients.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22431565.V1
Abstract: Supplementary Table from Single-Hit Inactivation Drove Tumor Suppressor Genes Out of the X Chromosome during Evolution
Publisher: Wiley
Date: 28-03-2023
DOI: 10.1111/JGH.16182
Publisher: Wiley
Date: 22-04-2020
DOI: 10.1111/JGH.15053
Publisher: Hindawi Limited
Date: 31-01-2022
DOI: 10.1155/2022/8803862
Abstract: Background. Evidence regarding the use of proton-pump inhibitors (PPIs) in COVID-19 patients remains elusive. Aim. To examine the potential effects of PPI use on the clinical outcomes of COVID-19 patients in a territory-wide cohort. Methods. A retrospective cohort study was performed using data from a territory-wide database in Hong Kong. Patients diagnosed with COVID-19 from 23 January 2020 to 1 January 2021 were identified by virological results. The primary endpoint was a composite of intensive care unit admission, use of invasive mechanical ventilation, and/or death. PPI users were identified by PPI use within 12 months prior to their diagnosis of COVID-19. Results. We identified 8,675 COVID-19 patients (mean age 46 years, 49% male, 97.6% of all reported cases in Hong Kong), of which 579 (6.7%) patients had used PPI. PPI users were found to be older, more likely to have comorbidities, concomitant medications and unfavourable laboratory parameters than nonusers. Of the 8,675 COVID-19 patients, 500 (5.8%) developed the primary endpoint. After propensity score (PS) balancing for patients’ demographics, comorbidities, laboratory parameters, and use of medications, PPI use was not found to be associated with the development of primary endpoint in PS weighting (weighted hazard ratio (HR) 1.10, 95% confidence interval (CI) 0.82–1.46, P = 0.529 ), and PS matching analysis (weighted HR 0.79, 95% CI 0.56–1.13, P = 0.198 ). Consistent nonassociation was observed after multivariable adjustment (adjusted HR 0.84, 95% CI 0.67–1.06, P = 0.142 ), and in subgroups of current and past PPI users. Conclusion. PPI use is not found to be associated with adverse clinical outcomes in COVID-19 patients. The result remains robust after PS weighting, PS matching, and multivariable adjustment.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22431559.V1
Abstract: Supplementary Table from Single-Hit Inactivation Drove Tumor Suppressor Genes Out of the X Chromosome during Evolution
Publisher: Springer Science and Business Media LLC
Date: 06-05-2022
DOI: 10.1038/S41388-022-02343-5
Abstract: Cancer-related genes have evolved specific genetic and genomic features to favor tumor suppression. Previously we reported that tumor suppressor genes (TSGs) acquired high promoter CpG dinucleotide frequencies during evolution to maintain high expression in normal tissues and resist cancer-specific downregulation. In this study, we investigated whether 3'untranslated regions (3'UTRs) of TSGs have evolved specific features to carry out similar functions. We found that 3'UTRs of TSGs, especially those involved in multiple histological types and pediatric cancers, are longer than those of non-cancer genes. 3'UTRs of TSGs also exhibit higher density of binding sites for RNA-binding proteins (RBPs), particularly those having high affinities to C-rich motifs. Both longer 3'UTR length and RBP binding sites enrichment are correlated with higher gene expression in normal tissues across tissue types. Moreover, both features together with the correlated N
Publisher: Springer Science and Business Media LLC
Date: 30-10-2015
DOI: 10.1038/NCOMMS9727
Abstract: Gut microbial dysbiosis contributes to the development of colorectal cancer (CRC). Here we catalogue the microbial communities in human gut mucosae at different stages of colorectal tumorigenesis. We analyse the gut mucosal microbiome of 47 paired s les of adenoma and adenoma-adjacent mucosae, 52 paired s les of carcinoma and carcinoma-adjacent mucosae and 61 healthy controls. Probabilistic partitioning of relative abundance profiles reveals that a metacommunity predominated by members of the oral microbiome is primarily associated with CRC. Analysis of paired s les shows differences in community configurations between lesions and the adjacent mucosae. Correlations of bacterial taxa indicate early signs of dysbiosis in adenoma, and co-exclusive relationships are subsequently more common in cancer. We validate these alterations in CRC-associated microbiome by comparison with two previously published data sets. Our results suggest that a taxonomically defined microbial consortium is implicated in the development of CRC.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22431553.V1
Abstract: Supplementary Table from Single-Hit Inactivation Drove Tumor Suppressor Genes Out of the X Chromosome during Evolution
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22431568
Abstract: Supplementary Table from Single-Hit Inactivation Drove Tumor Suppressor Genes Out of the X Chromosome during Evolution
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.C.6513940.V1
Abstract: Abstract Cancer-related genes are under intense evolutionary pressure. In this study, we conjecture that X-linked tumor suppressor genes (TSG) are not protected by the Knudson's two-hit mechanism and are therefore subject to negative selection. Accordingly, nearly all mammalian species exhibited lower TSG-to-noncancer gene ratios on their X chromosomes compared with nonmammalian species. Synteny analysis revealed that mammalian X-linked TSGs were depleted shortly after the emergence of the XY sex-determination system. A phylogeny-based model unveiled a higher X chromosome-to-autosome relocation flux for human TSGs. This was verified in other mammals by assessing the concordance/discordance of chromosomal locations of mammalian TSGs and their orthologs in i Xenopus tropicalis /i . In humans, X-linked TSGs are younger or larger in size. Consistently, pan-cancer analysis revealed more frequent nonsynonymous somatic mutations of X-linked TSGs. These findings suggest that relocation of TSGs out of the X chromosome could confer a survival advantage by facilitating evasion of single-hit inactivation. Significance: This work unveils extensive trafficking of TSGs from the X chromosome to autosomes during evolution, thus identifying X-linked TSGs as a genetic Achilles' heel in tumor suppression. /
Publisher: American Association for Cancer Research (AACR)
Date: 03-03-2022
DOI: 10.1158/0008-5472.CAN-21-3458
Abstract: This work unveils extensive trafficking of TSGs from the X chromosome to autosomes during evolution, thus identifying X-linked TSGs as a genetic Achilles' heel in tumor suppression.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22431571.V1
Abstract: Supplementary Figure from Single-Hit Inactivation Drove Tumor Suppressor Genes Out of the X Chromosome during Evolution
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22431562
Abstract: Supplementary Table from Single-Hit Inactivation Drove Tumor Suppressor Genes Out of the X Chromosome during Evolution
Publisher: Springer Science and Business Media LLC
Date: 19-02-2018
DOI: 10.1038/S41598-018-21573-W
Abstract: MicroRNAs are frequently dysregulated in human neoplasms, including gastrointestinal cancers. Nevertheless, the global influence of microRNA dysregulation on cellular signaling is still unknown. Here we sought to elucidate cellular signaling dysregulation by microRNAs in gastrointestinal cancers at the systems biology level followed by experimental validation. Signature dysregulated microRNAs in gastric, colorectal and liver cancers were defined based on our previous studies. Targets of signature dysregulated miRNAs were predicted using multiple computer algorithms followed by gene enrichment analysis to identify biological processes perturbed by dysregulated microRNAs. Effects of microRNAs on endocytosis were measured by epidermal growth factor (EGF) internalization assay. Our analysis revealed that, aside from well-established cancer-related signaling pathways, several novel pathways, including axon guidance, neurotrophin/nerve growth factor signaling, and endocytosis, were found to be involved in the pathogenesis of gastrointestinal cancers. The regulation of EGF receptor (EGFR) endocytosis by two predicted miRNAs, namely miR-17 and miR-145, was confirmed experimentally. Functionally, miR-145, which blocked EGFR endocytosis, prolonged EGFR membrane signaling and altered responsiveness of colon cancer cells to EGFR-targeting drugs. In conclusion, our analysis depicts a comprehensive picture of cellular signaling dysregulation, including endocytosis, by microRNAs in gastrointestinal cancers.
Publisher: The American Association of Immunologists
Date: 15-02-2016
Abstract: The antimicrobial peptide cathelicidin is critical for protection against different kinds of microbial infection. This study sought to elucidate the protective action of cathelicidin against Helicobacter pylori infection and its associated gastritis. Exogenous cathelicidin was found to inhibit H. pylori growth, destroy the bacteria biofilm, and induce morphological alterations in H. pylori membrane. Additionally, knockdown of endogenous cathelicidin in human gastric epithelial HFE-145 cells markedly increased the intracellular survival of H. pylori. Consistently, cathelicidin knockout mice exhibited stronger H. pylori colonization, higher expression of proinflammatory cytokines IL-6, IL-1β, and ICAM1, and lower expression of the anti-inflammatory cytokine IL-10 in the gastric mucosa upon H. pylori infection. In wild-type mice, H. pylori infection also stimulated gastric epithelium-derived cathelicidin production. Importantly, pretreatment with bioengineered Lactococcus lactis that actively secretes cathelicidin significantly increased mucosal cathelicidin levels and reduced H. pylori infection and the associated inflammation. Moreover, cathelicidin strengthened the barrier function of gastric mucosa by stimulating mucus synthesis. Collectively, these findings indicate that cathelicidin plays a significant role as a potential natural antibiotic for H. pylori clearance and a therapeutic agent for chronic gastritis.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22431565
Abstract: Supplementary Table from Single-Hit Inactivation Drove Tumor Suppressor Genes Out of the X Chromosome during Evolution
Publisher: Elsevier BV
Date: 10-2020
Publisher: BMJ
Date: 24-08-2022
DOI: 10.1136/GUTJNL-2022-327377
Abstract: The Asia-Pacific region has the largest number of cases of colorectal cancer (CRC) and one of the highest levels of mortality due to this condition in the world. Since the publishing of two consensus recommendations in 2008 and 2015, significant advancements have been made in our knowledge of epidemiology, pathology and the natural history of the adenoma-carcinoma progression. Based on the most updated epidemiological and clinical studies in this region, considering literature from international studies, and adopting the modified Delphi process, the Asia-Pacific Working Group on Colorectal Cancer Screening has updated and revised their recommendations on (1) screening methods and preferred strategies (2) age for starting and terminating screening for CRC (3) screening for in iduals with a family history of CRC or advanced adenoma (4) surveillance for those with adenomas (5) screening and surveillance for sessile serrated lesions and (6) quality assurance of screening programmes. Thirteen countries/regions in the Asia-Pacific region were represented in this exercise. International advisors from North America and Europe were invited to participate.
Publisher: Springer Science and Business Media LLC
Date: 08-01-2022
DOI: 10.1038/S41418-021-00916-7
Abstract: A recent mutation analysis suggested that Non-Structural Protein 6 (NSP6) of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a key determinant of the viral pathogenicity. Here, by transcriptome analysis, we demonstrated that the inflammasome-related NOD-like receptor signaling was activated in SARS-CoV-2-infected lung epithelial cells and Coronavirus Disease 2019 (COVID-19) patients’ lung tissues. The induction of inflammasomes yroptosis in patients with severe COVID-19 was confirmed by serological markers. Overexpression of NSP6 triggered NLRP3/ASC-dependent caspase-1 activation, interleukin-1β/18 maturation, and pyroptosis of lung epithelial cells. Upstream, NSP6 impaired lysosome acidification to inhibit autophagic flux, whose restoration by 1α,25-dihydroxyvitamin D 3 , metformin or polydatin abrogated NSP6-induced pyroptosis. NSP6 directly interacted with ATP6AP1, a vacuolar ATPase proton pump component, and inhibited its cleavage-mediated activation. L37F NSP6 variant, which was associated with asymptomatic COVID-19, exhibited reduced binding to ATP6AP1 and weakened ability to impair lysosome acidification to induce pyroptosis. Consistently, infection of cultured lung epithelial cells with live SARS-CoV-2 resulted in autophagic flux stagnation, inflammasome activation, and pyroptosis. Overall, this work supports that NSP6 of SARS-CoV-2 could induce inflammatory cell death in lung epithelial cells, through which pharmacological rectification of autophagic flux might be therapeutically exploited.
Publisher: Springer Science and Business Media LLC
Date: 11-01-2023
Publisher: Wiley
Date: 28-07-2020
DOI: 10.1002/EHF2.12952
Abstract: The present Perspective examined the latest evidence on the association between the use of angiotensin‐converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) and the incidence/mortality of coronavirus disease 2019 (COVID‐19). Our critical appraisal from existing literature does not support discontinuation of ACEIs/ARBs in clinical practice as there is absence of solid evidence. However, we do recommend future research perspective in formulation and implementation of practice‐changing guidelines.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22431568.V1
Abstract: Supplementary Table from Single-Hit Inactivation Drove Tumor Suppressor Genes Out of the X Chromosome during Evolution
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22431562.V1
Abstract: Supplementary Table from Single-Hit Inactivation Drove Tumor Suppressor Genes Out of the X Chromosome during Evolution
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Sunny Wong.