Digestive Diseases
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Progress Report 進度報告 2019 Progress Report 進度報告 2019 DIGESTIVE Research Progress Summary Colorectal Cancer: DISEASES Gut microbiota: 1. The team led by Professor Jun Yu demonstrated tumour-associated neutrophils, which are that Peptostreptococcus anaerobius, an anaerobic associated with chronic infl ammation and tumour gut bacterium, could adhere to colon mucosa progression were observed in P. anaerobius- Min/+ and accelerates CRC development in mice. They treated Apc mice. Blockade of integrin α2/ϐ1 by further identifi ed that a P. anaerobius surface RGDS peptide, small interfering RNA or antibodies protein, putative cell wall binding repeat 2 all impaired P. anaerobius attachment and 01 (PCWBR2), directly interacts with colonic cell abolished P. anaerobius-mediated oncogenic Principal Investigator response in vitro and in vivo. They determined lines via α2/ϐ1 integrin. Interaction between PCWBR2 and integrin α /ϐ induced the activation that P. anaerobius drives CRC via a PCWBR2- Professor Jun Yu 2 1 of the PI3K–Akt pathway in CRC cells, leading to integrin α2/ϐ1-PI3K–Akt–NF-κB signalling axis increased cell proliferation and nuclear factor and that the PCWBR2-integrin α2/ϐ1 axis is a Team kappa-light-chain-enhancer of activated B potential therapeutic target for CRC (Nature cells (NF-κB) activation. Signifi cant expansion Communication 2019 ). Joseph Sung | Francis Chan | Henry Chan | Vincent Wong | of myeloid-derived suppressor cells, tumour- Dennis Wong | Jessie Liang | Olabisi Coker associated macrophages and granulocytic 84 85 Progress Report 進度報告 2019 Progress Report 進度報告 2019 2. The team profi led fecal shotgun metagenomic microbiota-related carcinogenesis, the potential Gastric Cancer: cohort of 42 patients with intestinal metaplasia (a sequences of 184 patients with CRC, 197 patients of utilising the microbiota as CRC biomarkers, precancerous lesion of GC) treated with a COX-2 with adenoma and 204 control subjects from and the prospect for modulating the microbiota Molecular pathogenesis: specifi c inhibitor Rofecoxib or placebo for 2 years, Hong Kong, to elucidate the contribution of for CRC prevention or treatment. They identifi ed they found that COX-2 inhibitor down-regulated 1. Using human genome comparative genomic enteric gut fungi to CRC, principal component that the modulation of gut microbiota is a overall DNA methylation levels (P=0.009). hybridisation microarray to profi le the copy analysis revealed separate clusters for CRC promising strategy to enhance treatment Finally, they demonstrated that pharmacological number variations in gastric cancer patients, patients and control, with distinct fungi effi cacy and reduce adverse effects of CRC inhibition of COX-2 and DNMT synergistically the team observed frequent amplifi cation of composition in early-stage and late-stage CRC. therapies (Nature Reviews Gastroenterology & inhibited GC growth. This work indicated that 8q24, in particular for C8orf76, a novel gene with Basidiomycota to Ascomycota ratio was higher Hepatology 2019 ). PGE induces DNA methylation in GC, and that unknown function. C8orf76 is up-regulated in GC 2 in CRC with increase in Malasseziomycetes co-targeting of PGE and DNMT inhibits GC and patients with high C8orf76 suffer from poor 2 and decrease in Saccharomycetes and Molecular pathogenesis: (Theranostics 2019 ). survival. In GC cell lines, C8orf76 possesses pro- Pneumocystidomycetes. Abundances of 14 fungal 1. Using whole-genome methylation analysis, tumourigenic and pro-metastatic functions, and biomarkers distinguished CRC from controls Non-alcoholic Fatty Liver Disease Associated they revealed that Tripartite motif 67 (TRIM67) it promotes tumour growth and metastasis in with an area under the receiver-operating Hepatocellular Carcinoma (NAFLD-HCC): is a novel tumour suppressor in CRC. TRIM67, mice models. They revealed that C8orf76 binds characteristic curve (AUC) of 0.93 which was was silenced in CRC and its downregulation was to promoter region of lncRNA DUSP5P1 and Molecular pathogenesis: validated with AUCs of 0.82 in independent Hong associated with poor survival. They generated induces MAPK/ERK cascade to promote gastric Kong validation cohort 1 and 0.74 in a European TRIM67 knockout mice and showed that tumourigenesis. Collectively, C8orf76 plays pivotal 1. The team found that macrophage-specifi c cohort. These indicated that gut fungi alterations colon-specifi c knockout of TRIM67 signifi cantly oncogenic role in gastric carcinogenesis and is p38 mitogen-activated protein kinases plays a are associated with CRC. They further observed accelerated CRC development. In terms of its an independent prognostic factor for GC patients critical role in pathogenesis of non-alcoholic enhanced intrafungal co-occurrence and molecular mechanism, RNA-seq showed that (Clinical Cancer Research 2019 ). steatohepatitis (NASH). p38α was upregulated bacteria–fungi co-exclusive relationships in CRC anti-tumour effect of TRIM67 was mediated by in the liver tissues of patients with NAFLD. They compared with control; which were validated in activation of the p53 signalling pathway. TRIM67 2. To unravel genome-wide signatures in GC, they established macrophage-specifi c p38α knockout independent Hong Kong validation cohort 1 and ΔMΦ fl/fl forms a self-amplifying loop with p53 to boost performed whole genome sequencing in 168 GC (p38α ) and wild-type (p38α ) mice and a European cohort. These results suggested a p53-induced cell growth inhibition and apoptosis. Of patients. Their data demonstrated diverse models evaluated its impact on NASH models, including complex relationship between fungi and bacteria note, TRIM67 reactivation restored p53 activation of complex structural variations operative in GC, high-fat diet (HFD), high-fat/high-cholesterol diet in the gut, in which their antagonistic relationship and sensitised CRC cells to chemotherapy. TRIM67 leading to high-level amplifi cation of oncogenes. (HFHC), and methionine-and choline-defi cient diet may contribute to colorectal tumourigenesis ΔMΦ thus functions as a tumour suppressor and is They identifi ed hotspots of tandem-duplications (MCD) models. p38α mice exhibited less severe (Gut 2019 ). a potential target for improving chemotherapy (TDs) involving well-established cancer genes steatohepatitis and insulin resistance compared such as CCND1, ERBB2 and MYC. Importantly, to wild-type mice. Mechanistically, macrophage 3. They developed a new method, Bayesian responsiveness (Clinical Cancer Research 2019 ). they nominated a novel hotspot involving super- p38α promotes steatohepatitis by inducing pro- Dirichlet-multinomial regression meta-analysis 2. Whole genome copy number profi ling in primary enhancer of ZFP36L2 that is present in ~10% of infl ammatory cytokine secretion (CXCL2, IL-1ϐ, (BDMMA), to simultaneously model batch colorectal tumour tissues have unravelled TTPAL GC from independent patient cohorts. Functional CXCL10 and IL-6) and M1 polarisation, suggesting effects and detect microbial taxa associated with as a top amplifi ed gene CRC. They demonstrated effects of this novel hotspot were validated using that macrophage p38α as a therapeutic target phenotypes, in microbiome studies. Combining that copy number gain of TTPAL leads to gene experimental studies. Collectively, their fi ndings in NASH. Indeed, pharmacological p38 inhibitors microbial data in meta-analysis is challenging overexpression in CRC in 2 independent cohorts. suggested that TDs might serve as an important suppressed HFHC-induced steatohepatitis. due to the variations between experiments. They also showed that TTAPL is an oncogene mechanism for cancer gene activation and Collectively, specifi c p38α inhibition in BDMMA automatically models dependence by promoting cell proliferation, migration and provide a novel signature for stratifi cation (Nature macrophages by p38 inhibitors might provide among microbial taxa and is robust to the invasion in vitro and animal models. TTPAL Communication 2019 ). a new approach for the treatment of high dimensionality of microbiome and their was found to activate activated Wnt/ϐ-catenin steatohepatitis (Journal of Hepatology 2019 ). association sparsity. Their method was validated 3. Prostaglandin E (PGE ) is a pro-infl ammatory signalling, a key oncogenic pathway in CRC. 2 2 using simulation and real data analysis. They TTPAL mediates its effect through stabilisation eicosanoid up-regulated in GC, but its role in showed that BDMMA can successfully adjust batch of TRIP6, which in turn, displaced ϐ-catenin from epigenetic regulation is unknown. The team effects and substantially reduce false discoveries revealed that PGE up-regulated DNA methylating the tumour suppressor MAGI1 via competitive 2 in microbial meta-analyses (Bioinformatics 2019 ). binding. This allows ϐ-catenin to enter the nucleus enzymes in GC cells, leading to genome wide promoter hypermethylation. Consistently, Cox-2 4. The team was invited to write a review of their and promote oncogenic Wnt/ϐ-catenin. Finally, (rate-limiting enzyme for PGE biosynthesis) research works and other recent relevant studies TTPAL expression also serves as an independent 2 transgenic expression in mice elevated DNMT about the role of gut microbiome in colorectal prognostic marker for CRC patients (Cancer expression and DNA methylation. In a patient neoplasia, including relevant mechanisms in Research 2019 ). 86 87 Progress Report 進度報告 2019 Progress Report 進度報告 2019 Research and Scholarship Research Awards and Recognitions Member’s Full Name Details Jun