The Role of YAP-Dependent Epithelial-to-Mesenchymal Takeover in Gastric Cancer Metastasis
Introduction Cancer metastasis signifies an aggressive cell migration of a primary tumor to secondary tissues of the body. The process is correlated with poor prognosis and remains incompletely understood, despite the high mortality rates associated with this process1,2. Both tumor progression and later metastatic stages are associated with hijacking of an innate cell developmental program called epithelial-to-mesenchymal transition (EMT). It has been suggested that the induction of this program serves as a prerequisite of metastatic properties and allows the tumor to develop stem-cell like properties, mesenchymal migratory properties and even drug-resistance1,2,3. New studies indicate that EMT dysfunction is correlated with aberrant expression of the yes-associated protein (YAP), a transcriptional regulator1,4. Methods To determine the role of YAP in EMT, gastric orthotopic implantation cancer models utilized severe combined immunodeficiency (SCID) mice with lentiviral vectors integrating small-hairpin RNA (shRNA) knockdowns of the YAP gene. The experimental groups included the YAP shRNA vector-transfected cells (YAP-shRNA group), negative control vector-transfected cells (NC group) and untransfected cells (CON group). The negative control vector carries a sequence unrelated to the human genome. Experimenters stained gastric tumor cells with anti-Ki67 antibodies and quantitated the percentage of cells containing this proliferation marker. Apoptotic cells were stained with a TUNEL assay and quantitated. The same experimental groups were assayed with the endothelial marker CD31 to quantitate micro-vessel densities in the gastric tumor after YAP knockdown5. Results The aforementioned study demonstrated that there were fewer proliferation positive cells in the YAP-shRNA group compared with the other two groups. These findings demonstrate that YAP silenced through RNA interference reduced cancer cell proliferation in the mouse gastric cancer model5. This suggests YAP plays a considerable role in conferring proliferative properties that may allow malignant cells the ability to metastasize. Numerous other studies suggest this occurs via YAP-mediated activation of TEAD. Through this recognized signaling pathway, TEAD stimulates the gene transcription of mesenchymal markers like vimentin, N-cadherin and fibronectin6. Conclusion The successful epithelial-to-mesenchymal transition of a single cell in a benign tumor may induce the metastasis of gastric cancer, as apparent by recent data1-3. At the crux of this malicious EMT is a dysfunctional YAP pathway, and inhibition of proteins along the signaling pathway could have anti-metastatic therapeutic value5. The continued discovery of the nuances of this pathway hold immense clinical value in the form of increased survival for gastric cancer patients.
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