Hippo pathway dysregulation in gastric cancer: from Helicobacter pylori infection to tumor promotion and progression

Abstract

The Hippo pathway plays a critical role for balancing proliferation and differentiation, thus regulating tissue homeostasis. The pathway acts through a kinase cascade whose final effectors are the Yes-associated protein (YAP) and its paralog transcriptional co‑activator with PDZ‑binding motif (TAZ). In response to a variety of upstream signals, YAP and TAZ activate a transcriptional program that modulates cellular proliferation, tissue repair after injury, stem cell fate decision, and cytoskeletal reorganization. Hippo pathway signaling is often dysregulated in gastric cancer and in Helicobacter pylori-induced infection, suggesting a putative role of its deregulation since the early stages of the disease. In this review, we summarize the architecture and regulation of the Hippo pathway and discuss how its dysregulation fuels the onset and progression of gastric cancer. In this setting, we also focus on the crosstalk between Hippo and other established oncogenic signaling pathways. Lastly, we provide insights into the therapeutic approaches targeting aberrant YAP/TAZ activation and discuss the related clinical perspectives and challenges.

Fig. 1. Hippo signaling pathway.

Schematic diagram for the Hippo pathway core components and signaling. When Hippo signaling is ON, the activated Mammalian sterile 20-like kinase 1 and 2 (MST1/2) bind Salvador homolog 1 (SAV1) and phosphorylate/activate Large tumor suppressor 1 and 2 (LATS1/2) and their cofactors MOB kinase activator 1A and 1B (MOB1A/B). The activated LATS/MOB phosphorylate YAP/TAZ which results in its cytoplasmic retention by 14-3-3 protein and proteasomal degradation. As a result, YAP/TAZ cannot interact with TEAD in an active transcriptional unit (targets OFF). When Hippo signaling is OFF, MST1/2 and LATS kinases are inactive. Unphosphorylated YAP/TAZ translocate into the nucleus and interact with TEAD (TEA Domain transcription factor) to induce the transcription of target genes (targets ON).

Fig. 2. Crosstalk of the Hippo pathway with other signaling networks.

A The functional connection between mTOR (regulating cell size) and Hippo (regulating proliferation) pathways is essential for the proper organ development. At the basis of this crosstalk, YAP can downregulate PTEN (Phosphatase and tensin homolog), whereas LATS1/2 (Large tumor suppressor kinase 1/2) can phosphorylate Raptor, resulting in inhibition of mTOR signaling. B Under energy stress condition, the AMP-activated protein kinase (AMPK) phosphorylates and stabilizes AMOTL1 (Angiomotin Like 1), together with inducing both direct and LATS-mediated YAP phosphorylation, leading to YAP inhibition. C In conditions of high cell density, the Hippo pathway is activated and cytoplasmic YAP/TAZ retain TGFβ (transforming growth factor β)-activated SMAD family members 2/3-4 (SMAD 2/3-4) in the cytoplasm. At low cell density, YAP/TAZ and SMAD 2/3-4 translocate to the nucleus to cooperatively induce transcription. D YAP and TAZ are members of β-catenin destruction complex, responsible for β-catenin inactivation. Upon activation of the Wnt pathway, YAP/TAZ and β-catenin enter the nucleus and synergistically induce Wnt and TEAD (TEA Domain transcription factor) target genes. Moreover, by complexing with TBX5 (T-box transcription factor 5), they induce anti-apoptotic genes.

Fig. 3. Mechanisms of YAP/TAZ activation induced by Helicobacter pylori infection.

The H. pylori-secreted oncoprotein Cytotoxin-associated gene A (CagA) activates YAP/TAZ through different mechanisms. CagA mediates the crosslink between Hippo and Wnt pathways by inducing SHP2 (SH2 containing protein tyrosine phosphatase-2), that activates RAS-ERK signaling and promotes YAP/TAZ nuclear translocation and activation of TEAD-regulated genes. Once in the nucleus, SHP2 interacts with parafibromin/β-catenin in a transcriptionally active complex, which induces Wnt target genes. Moreover, by inhibiting Partitioning-defective 1 (PAR1), CagA induces the disruption of tight junctions, resulting in YAP/TAZ activation.

Fig. 4. miRNAs implicated in Hippo pathway dysregulation in gastric cancer.

Oncogenic miRNAs activating YAP/TAZ signaling are often upregulated (in red) in human GC. By contrast, YAP/TAZ inhibiting oncosuppressive miRNAs are reported to be downregulated (in blue) in GC. For each miRNA are indicated the Hippo target/targets, and the functional effects of its/their regulation. The stable circular RNA LARP4 (circLARP4) can reverse the oncogenic role of miR-424-5p, resuming YAP phosphorylation and retention in the cytoplasm, and is often downregulated in GC. Similarly, the long intergenic non-coding RNA linc01133 competes with miR-145-5p to promote YES1-dependent YAP1 nuclear translocation and is upregulated in GC tissues.

Fig. 5. Drugs targeting the Hippo pathway.

Hippo-targeted drugs act at different levels of the signaling cascade: some of them directly target the YAP-TEAD complex (red squares), while others inhibit YAP/TAZ nuclear localization (sky blue squares) or act at the level of upstream regulators, mainly linked to mechanical cues (green squares).