Study reveals molecular mechanisms of H. pylori-induced gastric carcinogenesis

Helicobacter pylori (H. pylori) infections are commonly related to abdominal pain, bloating, and acidity. Clinical evidence suggests that infection with H. pylori cagA⁺ strains dramatically increases the danger of developing gastric cancer. A specialized protein delivered by H. pylori to the host, oncoprotein “CagA,” has been shown to interact with multiple host proteins and promote gastric carcinogenesis (transformation of normal cells to cancer cells). Nonetheless, the underlying mechanisms related to its biochemical activity haven’t been fully determined yet.

A brand new study published in Science Signaling on 18 July 2023 shares insights into the extra mechanism of oncogenic CagA motion. “CagA interacts with multiple host proteins throughout the gastric epithelial cells, thereby inducing pathways related to oncogenesis and promoting gastric carcinogenesis. We were curious to search out out which pathways were involved on this process,’ says Dr. Atsushi Takahashi-Kanemitsu, lead creator of the study and Assistant Professor, Department of Biochemistry & Systems Biomedicine, Juntendo University, as he states the motivation behind pursuing this study.

In an effort to perform their study, the researchers expressed oncoprotein CagA in three different models-;embryos of Xenopus laevis (lab frog), adult mouse stomach, and cultured human gastric epithelial cells-;and tried to grasp its effect on the host cells and pathways.

The team noted that the expression of the CagA oncoprotein in X. laevis embryos led to impairment of convergent extension movements-;cell movements observed during embryonic development which might be involved in shaping or elongating organismal tissues and organs. 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 genetically modified (transgenic) mice that specifically express the CagA oncoprotein within the stomach epithelial cells in response to tamoxifen treatment.

The researchers observed that CagA expression within the stomach of adult mice caused a rise within the depth of pyloric glands-;secretory glands that facilitate digestion/stomach function-;and in addition triggered abnormal/excessive cell multiplication, which is a phenomenon remarkably observed in various kinds of cancers. This also led to the displacement of the proteins “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, that are specialized cells within 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 was interacting with amino acid residues from the proteins VANGL1/2, thus resulting in its displacement (a phenomenon also observed within the mouse model) and leading to disruption of the Wnt/PCP pathway-;a key biological ‘relay’ that affects organismal development.

Corresponding creator 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, together with impaired cell differentiation in gastric pyloric glands. This, together with other oncogenic CagA actions, may contribute to the event of gastric cancer.”

In summary, the researchers conclude that through this study, they were in a position 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 possible goal 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 with Christopher T. Knight (The University of Tokyo), Takayoshi Yamamoto (The University of Tokyo), 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).