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Cited by 45Gut microbiota and healthGenetic factors in colorectal cancerEscherichia coli research studies

Bacterially-Associated Transcriptional Remodelling in a Distinct Genomic Subtype of Colorectal Cancer Provides a Plausible Molecular Basis for Disease Development

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Lennard, Katie S., Goosen, Ryan W., Blackburn, Jonathan M.·2016·PLOS ONE
DOI 10.1371/journal.pone.0166282PMC PMC5112903
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Abstract

The relevance of specific microbial colonisation to colorectal cancer (CRC) disease pathogenesis is increasingly recognised, but our understanding of possible underlying molecular mechanisms that may link colonisation to disease in vivo remains limited. Here, we investigate the relationships between the most commonly studied CRC-associated bacteria (Enterotoxigenic Bacteroides fragilis, pks+ Escherichia coli, Fusobacterium spp., afaC+ E. coli, Enterococcus faecalis & Enteropathogenic E. coli) and altered transcriptomic and methylation profiles of CRC patients, in order to gain insight into the potential contribution of these bacteria in the aetiopathogenesis of CRC. We show that colonisation by E. faecalis and high levels of Fusobacterium is associated with a specific transcriptomic subtype of CRC that is characterised by CpG island methylation, microsatellite instability and a significant increase in inflammatory and DNA damage pathways. Analysis of the significant, bacterially-associated changes in host gene expression, both at the level of individual genes as well as pathways, revealed a transcriptional remodeling that provides a plausible mechanistic link between specific bacterial colonisation and colorectal cancer disease development and progression in this subtype; these included upregulation of REG3A, REG1A and REG1P in the case of high-level colonization by Fusobacterium, and CXCL10 and BMI1 in the case of colonisation by E. faecalis. The enrichment of both E. faecalis and Fusobacterium in this CRC subtype suggests that polymicrobial colonisation of the colonic epithelium may well be an important aspect of colonic tumourigenesis.

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  • F. nucleatum was associated with CIMP+, MSI CRC subtype.

    “Our results were also in line with previous reports that F. nucleatum was associated with CIMP+, MSI CRC subtype47, both of which were features of SFM-C.”

    From A tumor microenvironment-specific gene expression signature predicts chemotherapy resistance in colorectal cancer patients (2021) · cites this paper as [47]

    The Results sections on B-group CRCs report enrichment for CIMP+ and MSI+ tumours and greater high-level colonisation by Fusobacterium spp. in a related inflammatory/goblet-like cluster (page not supplied). This supports an association at the genus level, but the copy does not establish that F. nucleatum specifically was associated with the CIMP+, MSI subtype. (LLM, conf=0.85)

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Research works printed but not linked: 46

  1. [1]Swidsinski A, Khilkin M, Kerjaschki D, Schreiber S, Ortner M, Weber J, et al Association Between Intraepithelial Escerichia coli and Colorectal Cancer. Gastroenterology. 1998; 115: 281– 286. 9679033
  2. [3]Sadanandam A, Lyssiotis CA, Homicsko K, Collisson EA, Gibb WJ, Wullschleger S, et al A colorectal cancer classification system that associates cellular phenotype and responses to therapy. Nat Med. Nature Publishing Group; 2013; 19: 619– 25. 10.1038/nm.3175 23584089 PMC3774607 · DOI · Paper page
  3. [4]De Sousa E Melo F, Wang X, Jansen M, Fessler E, Trinh A, de Rooij LPMH, et al Poor-prognosis colon cancer is defined by a molecularly distinct subtype and develops from serrated precursor lesions. Nat Med. Nature Publishing Group; 2013; 19: 614– 8. 10.1038/nm.3174 23584090 · DOI · Paper page
  4. [5]Hinoue T, Weisenberger DJ, Lange CPE, Res G, Shen H, Byun H, et al Genome-scale analysis of aberrant DNA methylation in colorectal cancer. Genome Res. 2012; 10.1101/gr.117523.110 21659424 PMC3266034 · DOI
  5. [6]Jorissen RN, Lipton L, Gibbs P, Chapman M, Desai J, Jones IT, et al DNA Copy-Number Alterations Underlie Gene Expression Differences between Microsatellite Stable and Unstable Colorectal Cancers. Clin Cancer Res. 2008; 14: 8061– 8069. 10.1158/1078-0432.CCR-08-1431 19088021 PMC2605660 · DOI
  6. [7]Vaske CJ, Benz SC, Sanborn JZ, Earl D, Szeto C, Zhu J, et al Inference of patient-specific pathway activities from multi-dimensional cancer genomics data using PARADIGM. Bioinformatics. 2010; 26: i237– 45. 10.1093/bioinformatics/btq182 20529912 PMC2881367 · DOI · Paper page
  7. [8]Viljoen KS, Blackburn JM. Quality assessment and data handling methods for Affymetrix Gene 1.0 ST arrays with variable RNA integrity. BMC Genomics; 2013; 14: 14 10.1186/1471-2164-14-14 23324084 PMC3557148 · DOI
  8. [9]Houseman EA, Christensen BC, Yeh R-F, Marsit CJ, Karagas MR, Wrensch M, et al Model-based clustering of DNA methylation array data: a recursive-partitioning algorithm for high-dimensional data arising as a mixture of beta distributions. BMC Bioinformatics. 2008; 9: 365 10.1186/1471-2105-9-365 18782434 PMC2553421 · DOI
  9. [10]Johnson WE, Li C. Adjusting batch effects in microarray expression data using empirical Bayes methods. Biostatistics. 2007; 8: 118– 127. 10.1093/biostatistics/kxj037 16632515 · DOI · Paper page
  10. [11]Siegmund KD, Laird PW, Laird-Offringa IA. A comparison of cluster analysis methods using DNA methylation data. Bioinformatics. 2004; 20: 1896– 1904. 10.1093/bioinformatics/bth176 15044245 · DOI
  11. [12]Sadanandam A, Wang X, Melo FDSE, Gray JW, Vermeulen L, Hanahan D. Reconciliation of classification systems defining molecular subtypes of colorectal cancer. Cell Cycle. 2014; 13: 353– 357. 10.4161/cc.27769 24406433 PMC3956531 · DOI
  12. [13]Banerjea A, Ahmed S, Hands RE, Huang F, Han X, Shaw PM, et al Colorectal cancers with microsatellite instability display mRNA expression signatures characteristic of increased immunogenicity. Mol Cancer. 2004; 3: 21 10.1186/1476-4598-3-21 15298707 PMC514528 · DOI
  13. [14]Schwitalle Y, Kloor M, Eiermann S, Linnebacher M, Kienle P, Knaebel HP, et al Immune response against frameshift-induced neopeptides in HNPCC patients and healthy HNPCC mutation carriers. Gastroenterology. 2008; 134: 988– 97. 10.1053/j.gastro.2008.01.015 18395080 · DOI
  14. [15]Kloor M, Michel S, von Knebel Doeberitz M. Immune evasion of microsatellite unstable colorectal cancers. Int J Cancer. 2010; 127: 1001– 10. 10.1002/ijc.25283 20198617 · DOI
  15. [16]Balamurugan R, Rajendiran E, George S, Samuel GV, Ramakrishna BS. Real-time polymerase chain reaction quantification of specific butyrate-producing bacteria, Desulfovibrio and Enterococcus faecalis in the feces of patients with colorectal cancer. J Gastroenterol Hepatol. 2008; 23: 1298– 303. 10.1111/j.1440-1746.2008.05490.x 18624900 · DOI
  16. [17]Wang X, Allen TD, May RJ, Lightfoot S, Houchen CW, Huycke MM. Enterococcus faecalis induces aneuploidy and tetraploidy in colonic epithelial cells through a bystander effect. Cancer Res. 2008; 68: 9909– 17. 10.1158/0008-5472.CAN-08-1551 19047172 PMC2596646 · DOI
  17. [18]Wang X, Huycke MM. Extracellular superoxide production by Enterococcus faecalis promotes chromosomal instability in mammalian cells. Gastroenterology. 2007; 132: 551– 61. 10.1053/j.gastro.2006.11.040 17258726 · DOI
  18. [19]Huycke MM, Abrams V, Moore DR. Enterococcus faecalis produces extracellular superoxide and hydrogen peroxide that damages colonic epithelial cell DNA. Carcinogenesis. 2002; 23: 529– 536. 11895869
  19. [20]Kayaoglu G, Orstavik D. Virulence Factors of Enterococcus Faecalis: Relationship To Endodontic Disease. Crit Rev Oral Biol Med. 2004; 15: 308– 320. 10.1177/154411130401500506 15470268 · DOI
  20. [21]Barnett MPG, McNabb WC, Cookson AL, Zhu S, Davy M, Knoch B, et al Changes in colon gene expression associated with increased colon inflammation in interleukin-10 gene-deficient mice inoculated with Enterococcus species. BMC Immunol. 2010; 11: 39 10.1186/1471-2172-11-39 20630110 PMC2912833 · DOI
  21. [22]Hoffmann M, Kim SC, Sartor RB, Haller D. Enterococcus faecalis Strains Differentially Regulate Alix / AIP1 Protein Expression and ERK 1 / 2 Activation in Intestinal Epithelial Cells in the Context of Chronic Experimental Colitis. J Proteome Res. 2009; 8: 1183– 1192. 10.1021/pr800785m 19166300 · DOI
  22. [23]Tateishi K, Ohta M, Kanai F, Guleng B, Tanaka Y, Asaoka Y, et al Dysregulated expression of stem cell factor Bmi1 in precancerous lesions of the gastrointestinal tract. Clin Cancer Res. 2006; 12: 6960– 6. 10.1158/1078-0432.CCR-06-0449 17145814 · DOI
  23. [24]Li D, Tang H, Fan J, Yan D, Zhou C, Li S, et al Expression level of Bmi-1 oncoprotein is associated with progression and prognosis in colon cancer. J Cancer Res Clin Oncol. 2010; 136: 997– 1006. 10.1007/s00432-009-0745-7 20024662 PMC11827799 · DOI
  24. [25]Pun JCS, Chan JYJ, Chun BKM, Ng KW, Tsui SYK, Wan TMH, et al Plasma Bmi1 mRNA as a potential prognostic biomarker for distant metastasis in colorectal cancer patients. Mol Clin Oncol. 2014; 2: 817– 820. 10.3892/mco.2014.321 25054051 PMC4106668 · DOI
  25. [26]Du J, Li Y, Li J, Zheng J. Polycomb group protein Bmi1 expression in colon cancers predicts the survival. Med Oncol. 2010; 27: 1273– 6. 10.1007/s12032-009-9373-y 19957112 · DOI
  26. [27]Warren L, Freeman JD, Dreolini L, Castellarin M, Krzywinski M, Strauss J, et al Fusobacterium nucleatum infection is prevalent in human colorectal carcinoma. Genome Res. 2012; 22: 299– 306. 10.1101/gr.126516.111 22009989 PMC3266037 · DOI · Paper page
  27. [28]Kostic AD, Gevers D, Pedamallu CS, Michaud M, Duke F, Earl AM, et al Genomic analysis identifies association of Fusobacterium with colorectal carcinoma. Genome Res. 2012; 22: 292– 8. 10.1101/gr.126573.111 22009990 PMC3266036 · DOI · Paper page
  28. [29]Tahara T, Yamamoto E, Suzuki H, Maruyama R, Chung W, Garriga J, et al Fusobacterium in colonic flora and molecular features of colorectal carcinoma. Cancer Res. 2014; 74: 1311– 8. 10.1158/0008-5472.CAN-13-1865 24385213 PMC4396185 · DOI · Paper page
  29. [30]Kolenbrander PE, London J. Adhere Today, Here Tomorrow: Oral Bacterial Adherence. J Bacteriol. 1993; 175: 3247– 3252. 8501028 PMC204720
  30. [31]Rickard AH, Gilbert P, High NJ, Kolenbrander PE, Handley PS. Bacterial coaggregation: an integral process in the development of multi-species biofilms. Trends Microbiol. 2003; 11: 94– 100. 10.1016/S0966-842X(02)00034-3 12598132 · DOI · Paper page
  31. [32]Allen-Vercoe E, Jobin C. Fusobacterium and Enterobacteriaceae: Important players for CRC? Immunol Lett. Elsevier B.V.; 2014; 1– 8. 10.1016/j.imlet.2014.05.014 24972311 PMC4259803 · DOI
  32. [33]Johnson EM, Flannagan SE, Sedgley CM. Coaggregation Interactions Between Oral and Endodontic Enterococcus faecalis and Bacterial Species Isolated From Persistent Apical Periodontitis. J Endod. 2006; 32: 946– 950. 10.1016/j.joen.2006.03.023 16982270 · DOI
  33. [35]Diaz PI, Zilm PS, Rogers AH. The response to oxidative stress of Fusobacterium nucleatum grown in continuous culture. FEMS Microbiol Lett. 2000; 187: 31– 4. 10828396
  34. [36]Steeves CH, Potrykus J, Barnett DA, Bearne SL. Oxidative stress response in the opportunistic oral pathogen Fusobacterium nucleatum. Proteomics. 2011; 11: 2027– 2037. 10.1002/pmic.201000631 21563313 · DOI
  35. [37]Silva VL, Diniz CG, Cara DC, Santos SG, Nicoli JR, Carvalho MAR, et al Enhanced pathogenicity of Fusobacterium nucleatum adapted to oxidative stress. Microb Pathog. 2005; 39: 131– 8. 10.1016/j.micpath.2005.07.002 16125361 · DOI
  36. [38]Strauss J, Kaplan GG, Beck PL, Rioux K, Panaccione R, Devinney R, et al Invasive potential of gut mucosa-derived Fusobacterium nucleatum positively correlates with IBD status of the host. Inflamm Bowel Dis. 2011; 17: 1971– 8. 10.1002/ibd.21606 21830275 · DOI
  37. [39]van Beelen Granlund A, Østvik AE, Brenna Ø, Torp SH, Gustafsson BI, Sandvik AK. REG gene expression in inflamed and healthy colon mucosa explored by in situ hybridisation. Cell Tissue Res. 2013; 352: 639– 46. 10.1007/s00441-013-1592-z 23519454 PMC3663985 · DOI
  38. [40]Rechreche H, Montalto G, Mallo GV, Vasseur S, Marasa L, Soubeyran P, et al pap, reg Ialpha and reg Ibeta mRNAs are concomitantly up-regulated during human colorectal carcinogenesis. Int J Cancer. 1999; 81: 688– 94. 10328217
  39. [41]Cavard C, Terris B, Grimber G, Christa L, Audard V, Radenen-Bussiere B, et al Overexpression of regenerating islet-derived 1 alpha and 3 alpha genes in human primary liver tumors with beta-catenin mutations. Oncogene. 2006; 25: 599– 608. 10.1038/sj.onc.1208860 16314847 · DOI
  40. [42]Yoshino N, Ishihara S, Rumi MAK, Ortega-Cava CF, Yuki T, Kazumori H, et al Interleukin-8 regulates expression of Reg protein in Helicobacter pylori-infected gastric mucosa. Am J Gastroenterol. 2005; 100: 2157– 66. 10.1111/j.1572-0241.2005.41915.x 16181363 · DOI
  41. [43]Rubinstein MR, Wang X, Liu W, Hao Y, Cai G, Han YW. Fusobacterium nucleatum promotes colorectal carcinogenesis by modulating E-cadherin/β-catenin signaling via its FadA adhesin. Cell Host Microbe. Elsevier Inc.; 2013; 14: 195– 206. 10.1016/j.chom.2013.07.012 23954158 PMC3770529 · DOI · Paper page
  42. [44]Kostic AD, Chun E, Robertson L, Glickman JN, Gallini CA, Michaud M, et al Fusobacterium nucleatum potentiates intestinal tumorigenesis and modulates the tumor-immune microenvironment. Cell Host Microbe. Elsevier Inc.; 2013; 14: 207– 15. 10.1016/j.chom.2013.07.007 23954159 PMC3772512 · DOI · Paper page
  43. [45]Astrosini C, Roeefzaad C, Dai Y-Y, Dieckgraefe BK, Jöns T, Kemmner W. REG1A expression is a prognostic marker in colorectal cancer and associated with peritoneal carcinomatosis. Int J Cancer. 2008; 123: 409– 13. 10.1002/ijc.23466 18452172 · DOI
  44. [46]Ak S, Tunca B, Yilmazlar T, Tezcan G, Cecener G, Egeli U, et al Microsatellite instability status affects gene expression profiles in early onset colorectal cancer patients. J Surg Res. 2013; 185: 626– 37. 10.1016/j.jss.2013.07.014 23992855 · DOI
  45. [47]Chan AT, Ogino S, Fuchs CS. Aspirin and the risk of colorectal cancer in relation to expression of COX-2. N Engl J Med. 2007; 356: 2131– 2142. 10.1056/NEJMoa067208 17522398 · DOI
  46. [48]Wang D, DuBois RN. The role of anti-inflammatory drugs in colorectal cancer. Annu Rev Med. 2013; 64: 131– 44. 10.1146/annurev-med-112211-154330 23020877 · DOI

Cited by

Sorted by citations

Authors
Lennard, K. S., Goosen, R. W., & Blackburn, J. M.
Affiliations
University of Cape Town (ZA)
Corresponding author
  • Lennard, Katie S.
  • Goosen, Ryan W.
  • Blackburn, Jonathan M.
ORCID
Venue
PLOS ONE
Publisher
Public Library of Science (PLoS)
Published
2016-11-15
Volume
11
Issue
11
Pages
e0166282
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0166282
PMC
PMC5112903
OpenAlex
W2552700837
Cited by
45
References
2
Citations by year
2025: 2 · 2024: 4 · 2023: 8 · 2022: 5 · 2021: 7 · 2020: 4 · 2019: 8 · 2018: 3 · 2017: 3
FWCI
2.43
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Cancer Association of South Africa (research grant)
  • National Research Foundation (South African Research Chair grant)
  • Harry Crossley Foundation (PhD bursary)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Escherichia coli research studies
Keywords
colorectal cancer, gut microbiota, Enterococcus faecalis, Fusobacterium, enterotoxigenic Bacteroides fragilis, enteropathogenic Escherichia coli, CpG island methylation, microsatellite instability, DNA damage pathway, inflammatory signaling, REG1A, REG3A, CXCL10, BMI1, host gene expression
MeSH terms
Pancreatitis-Associated Proteins, Adult, Aged, Antigens, Neoplasm, Bacteroides fragilis, Female, Fusobacterium, Humans, Intestinal Mucosa, Male, Middle Aged, Enterococcus faecalis, Biomarkers, Tumor, Colony Count, Microbial, Colorectal Neoplasms, Gene Expression Regulation, Neoplastic, CpG Islands, DNA Methylation, Genomics, Lectins, C-Type, Lithostathine, Microsatellite Instability, Enteropathogenic Escherichia coli, Chemokine CXCL10, Host-Pathogen Interactions, Transcriptome, Polycomb Repressive Complex 1

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