title: Hemolytic E. coli Promotes Colonic Tumorigenesis in Females.
abstract: Bacterial infection is linked to colorectal carcinogenesis, but the species that contribute to a protumorigenic ecology are ill-defined. Here we report evidence that α-hemolysin-positive (hly(+)) type I Escherichia coli (E. coli) drives adenomagenesis and colorectal cancer in human females but not males. We classified E. coli into four types using a novel typing method to monitor fimH mutation patterns of fecal isolates from adenoma patients (n= 59), colorectal cancer patients (n= 83), and healthy subjects (n= 85). hly(+) type I E. coli was found to be relatively more prevalent in stools from females with adenoma and colorectal cancer, correlating with poor survival in colorectal cancer patients. In mechanistic studies in female mice, we found that hly(+) type 1 E. coli activated expression of the glucose transporter GLUT1 and repressed expression of the tumor suppressor BIM. hly-encoded alpha hemolysin partially accounted for these effects by elevating the levels of HIF1α. Notably, colon tumorigenesis in mice could be promoted by feeding hly(+) type I E. coli to female but not male subjects. Collectively, our findings point to hemolytic type I E. coli as a candidate causative factor of colorectal cancer in human females, with additional potential as a biomarker of disease susceptibility. Cancer Res; 76(10); 2891-900. ©2016 AACR.
authors.affiliation: Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong. yejin@cuhk.edu.hk jjysung@cuhk.edu.hk junyu@cuhk.edu.hk.
authors.forename: Ye
authors.initials: Y
authors.lastname: Jin
authors.affiliation: Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Senwei
authors.initials: S
authors.lastname: Tang
authors.affiliation: Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Weilin
authors.initials: W
authors.lastname: Li
authors.affiliation: Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Siew Chien
authors.initials: SC
authors.lastname: Ng
authors.affiliation: Department of Life Science, National Chung Cheng University, Min-Hsiung, Chia, Taiwan.
authors.forename: Michael W Y
authors.initials: MW
authors.lastname: Chan
authors.affiliation: Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong. yejin@cuhk.edu.hk jjysung@cuhk.edu.hk junyu@cuhk.edu.hk.
authors.forename: Joseph J Y
authors.initials: JJ
authors.lastname: Sung
authors.affiliation: Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong. yejin@cuhk.edu.hk jjysung@cuhk.edu.hk junyu@cuhk.edu.hk.
authors.forename: Jun
authors.initials: J
authors.lastname: Yu
mesh_terms: D000236:Adenoma / Q000378:metabolism / Q000382:microbiology / Q000473:pathology*; D000818:Animals; D017209:Apoptosis; D000072224:Bcl-2-Like Protein 11 / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000378:metabolism / Q000382:microbiology / Q000473:pathology*; D004926:Escherichia coli; D004927:Escherichia coli Infections / Q000378:metabolism / Q000382:microbiology / Q000473:pathology*; D005243:Feces / Q000382:microbiology; D005260:Female; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism; D006460:Hemolysin Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009367:Neoplasm Staging; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000072224:Bcl-2-Like Protein 11; D051272:Glucose Transporter Type 1; C497442:HIF1A protein, human; D006460:Hemolysin Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; C495677:SLC2A1 protein, human