RESEARCH NEWS STORY
11 July 2023
New Study Throws Light on Mechanisms Underlying Helicobacter pyloriInduced Gastric Cancer
Researchers from Japan show how oncoprotein CagA from Helicobacter pylori disrupts
Wnt/PCP signaling and promotes gastric carcinogenesis
Helicobacter pylori cagA+ strains cause gastric inflammation, ulcers, and cancer. Previous
reports have shown that the cagA gene-encoded protein “CagA” plays a crucial role ingastric carcinogenesis. However, the underlying mechanisms remain to be fully elucidated.
Researchers from Japan used animal models and laboratory-cultured human gastricepithelial cells to demonstrate that CagA works by disrupting the Wnt/Planar Cell Polarity(PCP) signaling pathway.
Helicobacter pylori (H. pylori) infections are commonly associated with abdominal pain,
bloating, and acidity. Clinical evidence suggests that infection with H. pylori cagA+ strains
dramatically increases the risk of developing gastric cancer. A specialized protein delivered byH. pylori to the host, oncoprotein “CagA,” has been shown to interact with multiple hostproteins and promote gastric carcinogenesis (transformation of normal cells to cancer cells).
However, the underlying mechanisms associated with its biochemical activity have not been
fully determined yet.
A new study published in Science Signaling on 18 July 2023 shares insights into the additional
mechanism of oncogenic CagA action. “CagA interacts with multiple host proteins within thegastric epithelial cells, thereby inducing pathways associated with oncogenesis and promoting
gastric carcinogenesis. We were curious to find out which pathways were involved in thisprocess,’ says Dr. Atsushi Takahashi-Kanemitsu, lead author of the study and AssistantProfessor, Department of Biochemistry & Systems Biomedicine, Juntendo University, as hestates the motivation behind pursuing this study.
In order to carry out their study, the researchers expressed oncoprotein CagA in threedifferent models—embryos of Xenopus laevis (lab frog), adult mouse stomach, and cultured
human gastric epithelial cells—and tried to understand its effect on the host cells andpathways.
The team noted that the expression of the CagA oncoprotein in X. laevis embryos led toimpairment of convergent extension movements—cell movements observed duringembryonic development that are involved in shaping or elongating organismal tissues andorgans. This impairment further interfered with subsequent key embryonic development
processes, including body axis formation.
Similarly, the team performed an experiment using adult mice. They generated geneticallymodified (transgenic) mice that specifically express the CagA oncoprotein in the stomach
epithelial cells in response to tamoxifen treatment.
The researchers observed that CagA expression in the stomach of adult mice caused anincrease in the depth of pyloric glands—secretory glands that facilitate digestion/stomach
function—and also triggered abnormal/excessive cell multiplication, which is a phenomenon
remarkably observed in various types of cancers. This also led to the displacement of theproteins “VANGL1/2”—members of the Van Gogh-like (VANGL) protein family, which play key
roles in various biological processes—from the plasma membrane to the cytoplasm. CagA
expression also resulted in fewer differentiated enteroendocrine cells, which are specialized
cells in the gastrointestinal tract that aid in digestion.
Finally, the team expressed the CagA oncoprotein in cultured human gastric epithelial cells.
The experiments clearly demonstrated that a small region of the CagA oncoprotein wasinteracting with amino acid residues from the proteins VANGL1/2, thus leading to its
displacement (a phenomenon also observed in the mouse model) and resulting in disruptionof the Wnt/PCP pathway—a key biological ‘relay’ that affects organismal development.
Corresponding author Masanori Hatakeyama, Laboratory Head, Institute of Microbial
Chemistry, Microbial Chemistry Research Foundation, says, “Perturbation of Wnt/PCP
signaling by the H. pylori CagA-VANGL interaction induces hyperplastic changes, along with
impaired cell differentiation in gastric pyloric glands. This, in conjunction with other oncogenic
CagA actions, may contribute to the development of gastric cancer.”
In summary, the researchers conclude that through this study, they were able to elucidate
the molecular mechanisms involved in gastric carcinogenesis induced by H. pylori, gain
insights into the role of the Wnt/PCP pathway in carcinogenesis, and propose it as a potential
target for clinical interventions against H. pylori cagA+ infections.
This research project was conducted by Atsushi Takahashi-Kanemitsu (Juntendo University),
Masanori Hatakeyama (Institute of Microbial Chemistry, Hokkaido University and The
University of Tokyo), and Mengxue Lu (The University of Tokyo) in collaboration withChristopher T. Knight (The University of Tokyo), Takayoshi Yamamoto (The University ofTokyo), Takuo Hayashi (Juntendo University), Yusuke Mii (National Institute for Basic Biology,
ExCELLS, and JST), Masanori Taira (Chuo University), Etsuo A. Susaki (Juntendo University),
Nick Barker (A*STAR Singapore, Kanazawa University, and National University of Singapore),
Takuya Ooki (Institute of Microbial Chemistry), Ippei Kikuchi (Institute of Microbial Chemistry),and Akira Kikuchi (Osaka University).
ReferenceAuthors

Atsushi Takahashi-Kanemitsu1,2, Mengxue Lu1, Christopher Takaya
Knight1, Takayoshi Yamamoto3,4, Takuo Hayashi5, Yusuke Mii6,7,
Takuya Ooki1,8, Ippei Kikuchi1,8, Akira Kikuchi9,10, Nick Barker 11,12,13,
Etsuo A. Susaki2, Masanori Taira3,14, and Masanori Hatakeyama1,8,15

Title of original paper

The Helicobacter Pylori CagA Oncoprotein Disrupts Wnt/PCP
Signaling and Promotes Hyperproliferation of Pyloric Gland BaseCells

JournalScience Signaling

DOI

10.1126/scisignal.abp9020

Affiliations

1

Department of Microbiology, Graduate School of Medicine, The
University of Tokyo, Japan.
2
Department of Biochemistry and Systems Biomedicine, Juntendo
University Graduate School of Medicine, Japan.
3
Department of Biological Sciences, Graduate School of Science, The
University of Tokyo, Japan.
4
Department of Life Sciences, Graduate School of Arts and Sciences,
The University of Tokyo, Japan.
5
Department of Human Pathology, Juntendo University Graduate
School of Medicine, Japan.
6
National Institute for Basic Biology and Exploratory Research Center
on Life and Living Systems (ExCELLS), National Institutes of NaturalSciences, Japan.
7Japan Science and Technology Agency, PRESTO, Japan.
8
Laboratory of Microbial Carcinogenesis, Institute of Microbial
Chemistry, Microbial Chemistry Research Foundation, Japan.
9Department of Molecular Biology and Biochemistry, Graduate
School of Medicine, Osaka University, Japan.
10Center for Infectious Disease Education and Research (CiDER),
Osaka University, Japan.
11
Institute of Molecular and Cell Biology (IMCB), Agency for Science,
Technology and Research (A*STAR), Singapore.
12
Department of Physiology, Yong Loo Lin School of Medicine,National University of Singapore, Singapore.
13
Division of Epithelial Stem Cell Biology, Cancer Research Institute,Kanazawa University, Japan.
14
Department of Biological Sciences, Faculty of Science andEngineering, Chuo University, Japan.
15
Research Center of Microbial Carcinogenesis, Institute for GeneticMedicine, Hokkaido University, Japan.

Additional information for EurekAlert
Latest Article Publication Date: 18 July 2023
Method of Research: Experimental study
Subject of Research: Animals

Conflict of Interest Statement: None

Infographic:

Image Title: The Mechanism Underlying Helicobacter pylori Oncoprotein CagA Action and Development ofGastric Cancer
Image Caption: The disruption of Wnt/PCP signaling by the oncoprotein CagA seems to promote gastriccarcinogenesis.
Image Credit: Atsushi Takahashi-Kanemitsu, Juntendo University Graduate
School of Medicine
Image Source Link to be added in the Image Credit Section of EA form: Not applicable
License Type: Original content

About Atsushi Takahashi-Kanemitsu, Ph.D
Dr. Atsushi Takahashi-Kanemitsu works as an Assistant Professor at the Department ofBiochemistry & Systems Biomedicine (Professor Etsuo A. Susaki’s Lab.), Juntendo University
Graduate School of Medicine since 2022. He studied at the Division of Molecular Oncology,
Institute for Genetic Medicine, Hokkaido University and received his Ph.D. in Chemistry fromthe Graduate School of Science, Hokkaido University in 2011. He then worked as a postdoctoral researcher and a research associate at Division of Microbiology, Graduate School ofMedicine, The University of Tokyo (both of which are Professor Masanori Hatakeyama’s Labs)
till 2021. He received the Research Fellowship for Young Scientists from Japan Society for thePromotion of Science (2007), and Annual Research Award from Japanese Association forProtein Phosphatase Research (2011). Google Scholar. Researchmap. ResearchGate. Twitter.

About Professor Masanori Hatakeyama
Dr. Masanori Hatakeyama (Professor emeritus, The University of Tokyo) concurrently holds
the position of Laboratory Head, Institute of Microbial Chemistry, Microbial Chemistry
Research Foundation and Specially Appointed Professor at the Institute for Genetic Medicine,
Hokkaido University. He received his MB (Bachelor of Medicine) from the School of Medicine,
Hokkaido University in 1981 and passed the national examination for medical practitioners in
1981. He received his Ph.D degree from the Graduate School of Medicine, Hokkaido University
in 1986. He then carried out his post-doctoral research at the Whitehead Institute,
Massachusetts Institute of Technology (MIT), under the supervision of Professor Robert A.
Weinberg. He is serving as Editor-in-Chief of Cancer Science, the official journal of theJapanese Cancer Association (JCA). He has been the recipient of many prizes and awards suchas the Incitement Award by the Japanese Cancer Association (1991), JCA-Mauvernay Award(2006), Sagawa Special Award (2011), Medical Award of the Japan Medical Association (2014),
Hideyo Noguchi Memorial Medical Prize (2016), Medal of Honor with Purple Ribbon (2019),
Tomizo Yoshida Prize (2019), Princess Takamatsu Cancer Research Fund Prize (2022), andTakeda Prize for Medical Science (2022).
Further information
Dr. Atsushi Takahashi-Kanemitsu
Department of Biochemistry & Systems Biomedicine
Juntendo University Graduate School of Medicine
Email: atkane@juntendo.ac.jp
Prof. Masanori Hatakeyama
Institute of Microbial Chemistry
Microbial Chemistry Research Foundation
Email: mhatakeyama@bikaken.or.jp
Media contact
Yoshitaka Nakashima
Juntendo University Research Promotion Center
E-mail: y.nakashima.gd@juntendo.ac.jp
Website: https://en.juntendo.ac.jp/
Katsuhisa Yamazaki
Department of Intellectual Property and Public Relations
Institute of Microbial Chemistry
Microbial Chemistry Research Foundation
Email: yamazakik@bikaken.or.jp
Website: https://www.bikaken.or.jp/english/

Twitter posts
Post 1.
In a new @scisignal study, researchers found that the disruption of Wnt/PCP signaling by the#oncoprotein CagA may lead to #gastriccancer #carcinogenesis #biochemistry #medicine#research Read more here: <Insert shortened link>

Post 2.
A new @scisignal study reveals the likely mechanism of action of the oncoprotein CagA andshows how the disruption of Wnt/PCP signaling promotes #gastric #cancer. #biochemistry#medicine Read more here: <Insert the shortened link here>