title: CEACAM6 is upregulated by Helicobacter pylori CagA and is a biomarker for early gastric cancer.
abstract: Early detection of gastric cancers saves lives, but remains a diagnostic challenge. In this study, we aimed to identify cell-surface biomarkers of early gastric cancer. We hypothesized that a subset of plasma membrane proteins induced by the Helicobacter pylori oncoprotein CagA will be retained in early gastric cancers through non-oncogene addiction. An inducible system for expression of CagA was used to identify differentially upregulated membrane protein transcripts in vitro. The top hits were then analyzed in gene expression datasets comparing transcriptome of gastric cancer with normal tissue, to focus on markers retained in cancer. Among the transcripts enriched upon CagA induction in vitro, a significant elevation of CEACAM6 was noted in gene expression datasets of gastric cancer. We used quantitative digital immunohistochemistry to measure CEACAM6 protein levels in tissue microarrays of gastric cancer. We demonstrate an increase in CEACAM6 in early gastric cancers, when compared to matched normal tissue, with an AUC of 0.83 for diagnostic validity. Finally, we show that a fluorescently conjugated CEACAM6 antibody binds avidly to freshly resected gastric cancer xenograft samples and can be detected by endoscopy in real time. Together, these results suggest that CEACAM6 upregulation is a cell surface response to H. pylori CagA, and is retained in early gastric cancers. They highlight a novel link between CEACAM6 expression and CagA in gastric cancer, and suggest CEACAM6 to be a promising biomarker to aid with the fluorescent endoscopic diagnosis of early neoplastic lesions in the stomach.
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Rony K
authors.initials: RK
authors.lastname: Roy
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Michal M
authors.initials: MM
authors.lastname: Hoppe
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Supriya
authors.initials: S
authors.lastname: Srivastava
authors.affiliation: Department of Chemistry, National University of Singapore, Singapore.
authors.forename: Animesh
authors.initials: A
authors.lastname: Samanta
authors.affiliation: Division of Gastroenterology and Hepatology, National University Hospital, Singapore.
authors.forename: Neel
authors.initials: N
authors.lastname: Sharma
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Kar Tong
authors.initials: KT
authors.lastname: Tan
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Henry
authors.initials: H
authors.lastname: Yang
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Dominic C
authors.initials: DC
authors.lastname: Voon
authors.affiliation: Department of Pathology, National University Hospital, Singapore.
authors.forename: Brendan
authors.initials: B
authors.lastname: Pang
authors.affiliation: Department of Pathology, National University Hospital, Singapore.
authors.forename: Ming
authors.initials: M
authors.lastname: Teh
authors.affiliation: University of Tokyo, Tokyo, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Murata-Kamiya
authors.affiliation: University of Tokyo, Tokyo, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Hatakeyama
authors.affiliation: Department of Chemistry, National University of Singapore, Singapore.
authors.forename: Young-Tae
authors.initials: YT
authors.lastname: Chang
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.|Singapore Gastric Cancer Consortium, National University of Singapore, Singapore.
authors.forename: Wei Peng
authors.initials: WP
authors.lastname: Yong
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.|Singapore Gastric Cancer Consortium, National University of Singapore, Singapore.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Ito
authors.affiliation: Department of Chemistry, National University of Singapore, Singapore.|Singapore Gastric Cancer Consortium, National University of Singapore, Singapore.
authors.forename: Khek Yu
authors.initials: KY
authors.lastname: Ho
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.|Singapore Gastric Cancer Consortium, National University of Singapore, Singapore.
authors.forename: Patrick
authors.initials: P
authors.lastname: Tan
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Richie
authors.initials: R
authors.lastname: Soong
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.|Department of Chemistry, National University of Singapore, Singapore.
authors.forename: Phillip H
authors.initials: PH
authors.lastname: Koeffler
authors.affiliation: Department of Chemistry, National University of Singapore, Singapore.|Singapore Gastric Cancer Consortium, National University of Singapore, Singapore.
authors.forename: Khay Guan
authors.initials: KG
authors.lastname: Yeoh
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.|Singapore Gastric Cancer Consortium, National University of Singapore, Singapore.
authors.forename: Anand D
authors.initials: AD
authors.lastname: Jeyasekharan
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000502:physiology*; D015703:Antigens, CD / Q000032:analysis*; D001426:Bacterial Proteins / Q000502:physiology*; D014408:Biomarkers, Tumor / Q000032:analysis*; D015815:Cell Adhesion Molecules / Q000032:analysis*; D005455:Fluorescent Antibody Technique; D058851:GPI-Linked Proteins / Q000032:analysis; D016481:Helicobacter Infections / Q000378:metabolism; D006801:Humans; D051379:Mice; D013274:Stomach Neoplasms / Q000175:diagnosis*; D015854:Up-Regulation
chemical_list: D000942:Antigens, Bacterial; D015703:Antigens, CD; D001426:Bacterial Proteins; D014408:Biomarkers, Tumor; C504117:CEACAM6 protein, human; D015815:Cell Adhesion Molecules; D058851:GPI-Linked Proteins; C080866:cagA protein, Helicobacter pylori
keywords: CEACAM6; Helicobacter pylori; biomarker; endoscopy; gastric cancer