Abdominal pain, bloating, and acidity are frequently linked to Helicobacter pylori ( H. pneumoniae ) infections. Clinical research indicates that the risk of developing gastric cancer is significantly increased by infection with H. pylori cagA + strains. It has been demonstrated that the oncoprotein” CagA ,” a specialized protein delivered by H. pylori to the host, interacts with numerous host proteins and promotes gastric carcinogenesis( the transformation of healthy cells into cancer cells ). The underlying mechanisms that underlie its biochemical activity, though, have not yet been fully identified.
Insights into the additional mechanism of oncogenic CagA action are provided in a new study that was published in Science Signaling on July 18, 2023. ” CagA interacts with a number of host proteins in the gastric epithelial cells, stimulating oncogenesis pathways and promoting oncology.” Dr. says,” We were interested to learn which pathways were involved in this process. Atsushi Takahashi – Kanemitsu, the study’s lead author and assistant professor at Juntendo University ‘ Department of Biochemistry & amp, Systems Biomedicine, explains why he decided to conduct this study.
In order to conduct their study, the researchers expressed oncoprotein CagA in three different models: adult mouse stomachs, Xenopus laevis embryos( lab frog ), and cultured human gastric epithelial cells. They also attempted to comprehend how this protein affected the host cells and pathways.
The researchers discovered that the CagA oncoprotein’s expression in X. laevis embryos impaired convergent extension movements, which are cell movements seen during embryonic development and are responsible for forming or lengthening organismal tissues and organs. This impairment further hampered the formation of the body axis and other crucial embryonic development processes.
In a similar vein, the team used adult mice in an experiment. In response to tamoxifen treatment, they created genetically modified( transgenic ) mice that specifically express the CagA oncoprotein in the stomach epithelial cells.
The researchers found that CagA expression in adult mice’s stomachs increased the depth of pyloric glands, which are secretories that help with digestion and stomach function, and also triggered abnormal / excessive cell multiplication, a phenomenon that is remarkably common in many different types of cancers. Additionally, as a result of this, the proteins” VANGL1 / 2″-, which are part of the Van Gogh protein family and are essential to many biological processes, were moved from the plasma membrane to the cytoplasm. Less differentiated enteroendocrine cells, which are specialized cells in the gastrointestinal tract that support digestion, were also produced as a result of cagA expression.
Finally, the team used cultured human gastric epithelial cells to express the CagA oncoprotein. The experiments amply showed that a small portion of the CagA oncoprotein was interacting with amino acid residues from the proteins VANGL1 / 2, causing its displacement( a phenomenon also seen in the mouse model ) and disrupting the Wnt / PCP pathway, an important biological” relay” that influences organismal development.
The H. pylori CagA – VANGL interaction perturbs Wnt / PCP signaling, which results in hyperplastic changes as well as impaired cell differentiation in gastric polymeric glands, according to corresponding author Masanori Hatakeyama, laboratory head at the Institute of Microbial Chemistry, MRC. This could help the development of gastric cancer along with other oncogenic CagA actions.
In summary, the researchers come to the conclusion that this study helped them understand the molecular mechanisms underlying H. pylori-induced gastric carcinogenesis, gain knowledge of the Wnt / PCP pathway’s function in cancer, and suggest it as a potential target for clinical interventions against the disease.
In collaboration with Christopher T. Knight( The University of Tokyo ), Takayoshi Yamamoto( Juntendo University ), Yusuke Mii( National Institute for Basic Biology, ExCELLS, and JST ), Atsushi Takahashi – Kanemitsu, Masanori Hatakeyama( Institute of Microbial Chemistry, Hokkaido Universities and The University Of Tokyo) and Nick Barker( A * STAR Singapore, Kanazawa University, Takuya Ooki