LATS Dance: Molecular Choreography Between a Chronic Human Pathogen and Its Host

Abstract

astric adenocarcinoma is the third leading cause of Gcancer-related death in the world, with 5-year survival rates of less than 30%. Recently, the Cancer Genome Atlas Network identified 4 molecular subtypes of gastric cancer; however, in all anatomic regions of the stomach, chromosomal instability tumors with intestinal-type histology predominate. This subtype progresses through a series of well-orchestrated histologic steps from normal mucosa to nonatrophic gastritis and atrophic gastritis (lesions with high potential for reversibility), to intestinal metaplasia and dysplasia (typically irreversible lesions), and, ultimately, adenocarcinoma. The annual incidence of gastric cancer is estimated to be 0.1% for patients with atrophy, but increases 2.5-fold for patients with intestinal metaplasia, underscoring the premalignant potential of this lesion. Helicobacter pylori is the strongest known risk factor for gastric adenocarcinoma; however, only a subset of infected persons ever develop cancer. Contact between H pylori and gastric epithelial cells is critical for inducing injury, and a strain-specific bacterial determinant that augments cancer risk is the cag type IV secretion system, which translocates the oncoprotein Cytotoxin-associated gene A (CagA) into epithelial cells. After translocation, CagA undergoes tyrosine phosphorylation and activates a eukaryotic phosphatase Src homology region 2 (SH2)-containing protein tyrosine phosphatase 2 (SHP-2), leading to carcinogenic cellular responses. Nonphosphorylated CagA also exerts pathologic effects via induction of proinflammatory signaling, activation of b-catenin, and disruption of apical–junctional complexes. Importantly, CagA can activate intracellular molecular pathways that regulate gastric-to-intestinal cell transdifferentiation. In addition to promoting carcinogenesis, H pylori has cleverly evolved mechanisms to suppress the host immune response, which facilitates its chronic lifestyle. For example, H pylori flagellin is a noninflammatory molecule in terms of its ability to activate Toll-like receptor 5. H pylori lipopolysaccharide contains an anergic lipid A core that induces an attenuated Toll-like receptor 4–mediated response. Finally, activation of the intracellular receptor Nucleotide-binding oligomerization domain containing 1 (NOD1) by H pylori suppresses subsequent nuclear factor-kB–dependent signaling via activation of a NOD1-dependent negative feedback loop. In this issue of Cellular andMolecular Gastroenterology andHepatology, Castro et al provide fresh insights into the molecular underpinnings that regulate both H pylori–induced premalignant lesions and microbial persistence within the stomach. By using a panel of in vitro cell culture systems, Castro et al reported that H pylori up-regulates Large tumor suppresor kinase 2 (LATS2), a critical constituent of the Hippo signaling