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116. Enteric fungal microbiota dysbiosis and ecological alterations in colorectal cancer

Author

Coker, Olabisi Oluwabukola, Nakatsu, Geicho, Dai, Rudin Zhenwei, Wu, William Ka Kei, Wong, Sunny Hei, Ng, Siew Chien, Chan, Francis Ka Leung, Sung, Joseph Jao Yiu, and Yu, Jun

Abstract

ObjectivesBacteriome and virome alterations are associated with colorectal cancer (CRC). Nevertheless, the gut fungal microbiota in CRC remains largely unexplored. We aimed to characterise enteric mycobiome in CRC.DesignFaecal shotgun metagenomic sequences of 184 patients with CRC, 197 patients with adenoma and 204 control subjects from Hong Kong were analysed (discovery cohort: 73 patients with CRC and 92 control subjects; validation cohort: 111 patients with CRC, 197 patients with adenoma and 112 controls from Hong Kong). CRC-associated fungal markers and ecological changes were also validated in additional independent cohorts of 90 patients with CRC, 42 patients with adenoma and 66 control subjects of published repository sequences from Germany and France. Assignment of taxonomies was performed by exact k-mer alignment against an integrated microbial reference genome database.ResultsPrincipal component analysis revealed separate clusters for CRC and control (p<0.0001), with distinct mycobiomes in early-stage and late-stage CRC (p=0.0048). Basidiomycota:Ascomycota ratio was higher in CRC (p=0.0042), with increase in Malasseziomycetes (p<0.0001) and decrease in Saccharomycetes (p<0.0001) and Pneumocystidomycetes (p=0.0017). Abundances of 14 fungal biomarkers distinguished CRC from controls with an area under the receiver-operating characteristic curve (AUC) of 0.93 and validated AUCs of 0.82 and 0.74 in independent Chinese cohort V1 and European cohort V2, respectively. Further ecological analysis revealed higher numbers of co-occurring fungal intrakingdom and co-exclusive bacterial–fungal correlations in CRC (p<0.0001). Moreover, co-occurrence interactions between fungi and bacteria, mostly contributed by fungal Ascomycota and bacterial Proteobacteria in control, were reverted to co-exclusive interplay in CRC (p=0.00045).ConclusionsThis study revealed CRC-associated mycobiome dysbiosis characterised by altered fungal composition and ecology, signifying that the gut mycobiome might play a role in CRC.

Published
2019
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118. Metagenomic analysis of faecal microbiome as a tool towards targeted non-invasive biomarkers for colorectal cancer

Author

Yu, Jun, primary, Feng, Qiang, additional, Wong, Sunny Hei, additional, Zhang, Dongya, additional, Liang, Qiao yi, additional, Qin, Youwen, additional, Tang, Longqing, additional, Zhao, Hui, additional, Stenvang, Jan, additional, Li, Yanli, additional, Wang, Xiaokai, additional, Xu, Xiaoqiang, additional, Chen, Ning, additional, Wu, William Ka Kei, additional, Al-Aama, Jumana, additional, Nielsen, Hans Jørgen, additional, Kiilerich, Pia, additional, Jensen, Benjamin Anderschou Holbech, additional, Yau, Tung On, additional, Lan, Zhou, additional, Jia, Huijue, additional, Li, Junhua, additional, Xiao, Liang, additional, Lam, Thomas Yuen Tung, additional, Ng, Siew Chien, additional, Cheng, Alfred Sze-Lok, additional, Wong, Vincent Wai-Sun, additional, Chan, Francis Ka Leung, additional, Xu, Xun, additional, Yang, Huanming, additional, Madsen, Lise, additional, Datz, Christian, additional, Tilg, Herbert, additional, Wang, Jian, additional, Brünner, Nils, additional, Kristiansen, Karsten, additional, Arumugam, Manimozhiyan, additional, Sung, Joseph Jao-Yiu, additional, and Wang, Jun, additional

Published
2015
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123. A Zoom-Focus algorithm (ZFA) to locate the optimal testing region for rare variant association tests.

Author

Maggie Haitian Wang, Haoyi Weng, Rui Sun, Jack Lee, Wu, William Ka Kei, Ka Chun Chong, and Benny Chung-Ying Zee

Subjects
GENOMIC information retrieval, KERNEL (Mathematics), MENDEL'S law, STATISTICAL methods in genetic markers, NUMERIC databases, METABOLIC disorders
Abstract

Motivation: Increasing amounts of whole exome or genome sequencing data present the challenge of analysing rare variants with extremely small minor allele frequencies. Various statistical tests have been proposed, which are specifically configured to increase power for rare variants by conducting the test within a certain bin, such as a gene or a pathway. However, a gene may contain from several to thousands of markers, and not all of them are related to the phenotype. Combining functional and non-functional variants in an arbitrary genomic region could impair the testing power. Results: We propose a Zoom-Focus algorithm (ZFA) to locate the optimal testing region within a given genomic region. It can be applied as a wrapper function in existing rare variant association tests to increase testing power. The algorithm consists of two steps. In the first step, Zooming, a given genomic region is partitioned by an order of two, and the best partition is located. In the second step, Focusing, the boundaries of the zoomed region are refined. Simulation studies showed that ZFA substantially increased the statistical power of rare variants' tests, including the SKAT, SKAT-O, burden test and the W-test. The algorithm was applied on real exome sequencing data of hypertensive disorder, and identified biologically relevant genetic markers to metabolic disorders that were undetectable by a gene-based method. The proposed algorithm is an efficient and powerful tool to enhance the power of association study for whole exome or genome sequencing data. [ABSTRACT FROM AUTHOR]

Published
2017
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124. Protective roles of melatonin in central nervous system diseases by regulation of neural stem cells.

Author

Yu, Xin, Li, Zheng, Zheng, Heyi, Ho, Jeffery, Chan, Matthew T.V., and Wu, William Ka Kei

Subjects
CENTRAL nervous system diseases, NEURAL stem cells, MELATONIN, TUMOR suppressor genes, GENETIC regulation, CELL differentiation, DEVELOPMENTAL neurobiology
Abstract

Neural stem cells ( NSCs) are immature precursors of the central nervous system (CNS), with self-renewal and multipotential differentiation abilities. Their proliferation and differentiation are dynamically regulated by hormonal and local factors. Alteration in neurogenesis is associated with many neurological disorders. Increasing evidence suggests that modulation of NSCs can be a promising therapeutic approach for neural injury and neurodegenerative disorders. Melatonin, a pineal gland-derived hormone, regulates the neuroimmuno-endocrine axis and is functionally important to the circadian rhythm, tumour suppression and immunity. In the CNS, melatonin exerts neuroprotective effects in many diseases, such as Parkinson's disease, Alzheimer's disease and ischaemic brain injury. Emerging evidence suggests that it might also mediate such protective action by influencing proliferation and differentiation of NSCs. In this article, we review the current literature concerned with effects of melatonin on NSCs in different physiological and pathological conditions. [ABSTRACT FROM AUTHOR]

Published
2017
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125. Micro RNA-379 suppresses osteosarcoma progression by targeting PDK1.

Author

Li, Zheng, Shen, Jianxiong, Chan, Matthew T. V., and Wu, William Ka Kei

Subjects
MICRORNA, OSTEOSARCOMA, DISEASE progression, XENOGRAFTS, CELL proliferation
Abstract

Osteosarcoma is the most common primary bone tumour. Increasing evidence has demonstrated the pathogenic role of micro RNA (mi RNAs) dysregulation in tumour development. miR-379 was previously reported to function as an oncogenic or tumour-suppressing mi RNA in a tissue-dependent manner. However, its function in osteosarcoma remains unknown. In this study, we found that the expression of miR-379 was downregulated in osteosarcoma tissues and cell lines. Further functional characterization revealed that miR-379 suppressed osteosarcoma cell proliferation and invasion in vitro and retarded the growth of osteosarcoma xenografts in vivo. Mechanistically, PDK1 was identified as the direct target of miR-379 in osteosarcoma, in which PDK1 expression was up-regulated and showed inverse correlation with miR-379. Enforced expression of PDK1 promoted osteosarcoma cell proliferation and rescued the anti-proliferative effect of miR-379. These data suggest that miR-379 could function as a tumour-suppressing mi RNA via targeting PDK1 in osteosarcoma. [ABSTRACT FROM AUTHOR]

Published
2017
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126. The role of micro RNAs in intrahepatic cholangiocarcinoma.

Author

Li, Zheng, Shen, Jianxiong, Chan, Matthew T.V., and Wu, William Ka Kei

Subjects
CHOLANGIOCARCINOMA, MICRORNA, GENETICS, DIAGNOSIS, PROGNOSIS, THERAPEUTICS
Abstract

Intrahepatic cholangiocarcinoma ( ICC) is the second most common primary hepatic malignancy with poor prognosis. Despite improvements in its diagnosis and therapy, the prognosis for ICC patients remains poor. An improved understanding of ICC pathogenesis and consequential identification of novel therapeutic targets would improve the prognosis of ICC patients. Micro RNAs (mi RNAs) are a class of highly conserved, endogenous, small non-coding RNA molecules of 18-23 nucleotides in length, which regulate gene expression through complementary base-pairing with target messenger RNAs and subsequent gene silencing. Several studies have shown deregulated expression of mi RNAs in ICC cell lines and tissues, in which these mi RNAs play important roles in ICC apoptosis, cell proliferation, invasion, migration and metastasis. In this review, we illustrate the potential role of mi RNA in the pathogenesis of ICC and explore the possibilities of using mi RNAs as prognostic and diagnostic markers, as well as therapeutic targets in ICC. [ABSTRACT FROM AUTHOR]

Published
2017
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128. Vascular-targeted TNFα and IFNγ inhibits orthotopic colorectal tumor growth.

Author

Jing Shen, Zhi Jie Li, Long Fei Li, Lan Lu, Zhan Gang Xiao, William Ka Kei Wu, Lin Zhang, Ming Xing Li, Wei Hu, Kam Ming Chan, Chi Hin Cho, Shen, Jing, Li, Zhi Jie, Li, Long Fei, Lu, Lan, Xiao, Zhan Gang, Wu, William Ka Kei, Zhang, Lin, Li, Ming Xing, and Hu, Wei

Subjects
TUMOR necrosis factors, WESTERN immunoblotting, ANTINEOPLASTIC antibiotics, CYTOMETRY, PROTEIN expression, THERAPEUTIC use of interferons, ANIMAL experimentation, ANIMALS, ANTINEOPLASTIC agents, APOPTOSIS, BIOLOGICAL models, CELL lines, CELL physiology, COLON tumors, INTERFERONS, MICE, PEPTIDES, RECTUM tumors, PATHOLOGIC neovascularization, PHARMACODYNAMICS, THERAPEUTICS
Abstract

Background: Tumor necrosis factor alpha (TNFα) and interferon gamma (IFNγ) were originally identified to show potent anti-tumor activity and immunomodulatory capability. Unfortunately, several clinical studies of relevant cancer therapy did not observe significant response in maximum tolerated dose whether given alone or in combination. We have identified a tumor vasculature homing peptide (TCP-1 peptide) which targets only the vasculature of colorectal tumors but not normal blood vessels in animals and humans. In the current study, the antitumor effect of TCP-1/TNFα and TCP-1/IFNγ alone or in combination was studied in orthotopic colorectal tumor model.Methods: TCP-1/TNFα and TCP-1/IFNγ recombinant proteins were prepared and i.v. injected to study the in vivo anticancer effect in orthotopic colorectal tumor model. Tumor apoptosis was determined by TUNEL staining and cleaved caspase-3 immunofluorescent staining. Tumor infiltrating lymphocytes were analyzed by immunofluorescent staining and flow cytometry. Western-blot was performed to examine the expression of proteins. Cell apoptosis was measured by Annexin V/PI flow cytometry.Results: Targeted delivery of TNFα or IFNγ by TCP-1 peptide exhibited better antitumor activity than unconjugated format by inducing more tumor apoptosis and also enhancing antitumor immunity shown by increased infiltration of T lymphocytes inside the tumor. More importantly, combination therapy of TCP-1/TNFα and TCP-1/IFNγ synergistically suppressed tumor growth and alleviated systematic toxicity associated with untargeted therapy. This combination therapy induced massive apoptosis/secondary necrosis in the tumor.Conclusions: Taken together, our data demonstrate TCP-1 is an efficient drug carrier for targeted therapy of colorectal cancer (CRC). TCP-1/TNFα combined with TCP-1/IFNγ is a promising combination therapy for CRC. [ABSTRACT FROM AUTHOR]

Published
2016
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136. Macroautophagy and ERK phosphorylation counteract the anti-proliferative effect of proteasome inhibitor in gastric cancer cells

Author

Wu, William Ka Kei, primary, Cho, Chi Hin, additional, Lee, Chung Wa, additional, Wu, Ya Chun, additional, Yu, Le, additional, Li, Zhi Jie, additional, Wong, Clover Ching Man, additional, Li, Hai Tao, additional, Lin, Zhang, additional, Ren, Shun Xiang, additional, Che, Chun Tao, additional, Wu, Kaichun, additional, Fan, Daiming, additional, Yu, Jun, additional, and Sung, Joseph Jao Yiu, additional

Published
2010
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