Helicobacter pylori‐induced YAP1 nuclear translocation promotes gastric carcinogenesis by enhancing IL‐1β expression

Abstract

Gastric cancer (GC) is one of the most common and malignant pathologies, and a significant portion of GC incidences develops from Helicobacter pylori (Hp) ‐induced chronic gastritis. Although the exact mechanisms of GC are complex and poorly understood, gastric carcinogenesis is a good model to investigate how inflammation and infection collaboratively promote tumorigenesis. Yes‐associated protein 1 (YAP1) is the key effector of the Hippo pathway, which is silenced in most human cancers. Herein, we verified the tumor‐promoting effect of YAP1 in vitro, in vivo, and in human specimens. We revealed that YAP1 displays nuclear translocation and works with TEAD to activate transcription of the crucial inflammatory cytokine IL‐1β in gastric cells infected with Hp . As IL‐1ß accounts for inflammation‐associated tumorigenesis, this process can lead to gastric carcinogenesis. Thus, in addition to activating proliferation genes, YAP1 also plays a major role in inflammation amplification by activating inflammatory cytokine genes. Excitingly, our research demonstrates that transfection of mutant plasmid YAP‐5SA/S94A or addition of the drug verteporfin, both of which are thought to disrupt the YAP1‐TEAD interaction, can arrest the carcinogenesis process. These findings can provide new approaches to GC treatment.

TAZ Controls Helicobacter pylori-Induced Epithelial–Mesenchymal Transition and Cancer Stem Cell-Like Invasive and Tumorigenic Properties

“…We previously reported that cag A-positive carcinogenic strains of H. pylori upregulate the expression of the Hippo tumor suppressor LATS2 and its oncogenic target YAP in a biphasic kinetic manner [ 30 ]. Other studies have also reported an upregulation of YAP in response to H. pylori [ 50 , 51 ]. Although YAP and TAZ are paralogues, most studies in the field of H. pylori and GC have focused on YAP in such a way that the direct implication of TAZ remained unexplored in the context of H. pylori -induced gastric carcinogenesis.…”

Leukemia inhibitory factor promotes gastric cancer cell proliferation, migration, and invasion via the LIFR–Hippo–YAP pathway

“…LIF also enhanced NPC dissemination and invasion through promotion of nuclear YAP accumulation 39 . In GC, some factors were found to promote carcinogenesis by increasing nuclear YAP 33,40,41 . The Hippo signaling pathway can phosphorylate YAP and suppress its translocation to the nucleus and attenuate target gene expression 20 .…”

“…The mechanism of GC development, progression, and metastasis remains unclear because of the complicated multistep process of gene mutations, epigenetic changes, and various signaling events. Inflammation can contribute to GC progression, 33 and LIF is involved in the process of gastric carcinogenesis as an inflammatory factor. The expression of LIF was significantly elevated in GC tissues compared with gastritis tissues and it was found to be associated with Helicobacter pylori infection in a previous study 34 .…”

Mechanisms of the Epithelial–Mesenchymal Transition and Tumor Microenvironment in Helicobacter pylori-Induced Gastric Cancer

“…Overexpression of the oncogenic YAP1 is associated with aggressiveness and poor prognosis [155]. Gastric cancer development and progression are further promoted by the dysregulated YAP1/SLC35B4 axis; another mechanism involves altered IL-1β levels [156,157]. These findings show that YAP might become a potential target in gastric cancer treatment.…”