Esophageal cancer is an important lethal cause for male cancer patients in Taiwan and its incidence is still rising in recent years. The development and progression of esophageal cancer is closely related to inflammation. Our previous study had shown that EP2, the type 2 receptor of PGE2, plays an important role in esophageal squamous cell carcinoma. Overexpression of EP2 was associated significantly with a worse survival (p=0.047) and correlated positively with T status (p=0.016). Moreover, when focusing on patients with T1-3N0M0 status, EP2 expression was an independent factor of overall survival (p=0.048). Epithelial-mesenchymal transition (EMT), an important mechanism for reorganizing germ layers and tissues during embryonic development, is now generally accepted as the key process to allow stationary epithelial cells to achieve motility. The zinc-finger transcriptional repressor Snail mediates invasiveness and metastasis of several human epithelial tumors. Our recent study showed that among 153 resected ESCC specimens, Snail overexpression rate was 26.1% (40/153). Meanwhile, Snail overexpression was associated with worse overall survival (p=0.036) and correlated positively with lymphovascular invasion (p=0.034). We used four ESCC cell lines to conduct Transwell and Matrigel studies and showed that EP2 activation increased cell migration and invasion in all ESCC cells. Knocking down EP2 expression reduced cell migration and invasion irrespective of treatments. We also discovered that activation of EP2 could induce increased expression of Snail, Slug and decreased expression of E-cadherinin in CE48T cells. Moreover, we found that application of PI3K inhibitor LY294002 could significantly decrease cell migration and invasion of CE48T cells. Therefore, we want to explore the regulatory mechanisms of EP2-mediated EMT in ESCC cells, with special concern on the PI3K/Akt pathway. In the first year of this project, we will confirm the EP2-mediated EMT including protein expression in different ESCC cell lines. More EMT phenomena will be evaluated by different approaches. In the second year of this project, we will examine the influences of the cAMP downstream pathway and the PI3K/Akt pathway on EP2-mediated EMT. The transcription factor β-catenin will be investigated by reporter constructs. Whether these pathways act dependently or independently will be well studied. In the third year of this project, we will investigate the substances directly mediated by the PI3K/Akt pathway. We will also try different types of PI3K/Akt inhibitors on ESCC cells and check their response to tumor invasion of ESCC cells. Hopefully, we can identify some novel treatment strategies for esophageal cancer from this project.
|Effective start/end date||8/1/12 → 7/31/13|