Hippo-YAP/TAZ signaling in gastric cancer: molecular pathogenesis and emerging therapeutic horizons

Gastric cancer remains a significant global health challenge, ranking as the 5th most common cancer worldwide with high mortality rates. Despite advances in diagnostic and therapeutic approaches, the prognosis for advanced gastric cancer remains poor due to its invasive nature and the lack of effective targeted treatments. The Hippo-YAP/TAZ signaling pathway, originally discovered in the fruit fly Drosophila melanogaster, has emerged as a critical regulator of cell proliferation, apoptosis, and organ size. Dysregulation of this pathway is increasingly implicated in gastric tumorigenesis. This pathway governs the activity of transcriptional co-activators YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif), through a core kinase cascade involving MST1/2 (Mammalian Ste20-like kinase 1/2), LATS1/2 (Large tumor suppressor kinase 1/2), and scaffold proteins such as SAV1 (Salvador homolog 1). Aberrations in the Hippo pathway have led to unchecked nuclear localization and transcriptional activity of YAP/TAZ, driving oncogenic gene expression that promotes cell survival, metastasis, and resistance to apoptosis. This review focuses on the molecular mechanisms underlying the dysregulation of the Hippo-YAP/TAZ signaling pathway in gastric cancer. It explores the crosstalk between Hippo-YAP/TAZ signalling and other oncogenic pathways, including Wnt/β-catenin and PI3K/Akt, as well as the influence of tumour microenvironmental factors such as hypoxia and extracellular matrix stiffness on pathway activation. Additionally, emerging therapeutic strategies targeting YAP/TAZ-TEAD interactions and upstream regulators are discussed, offering potential avenues for improving gastric cancer outcomes in diagnosis and treatment.