The Role of CCN1 in Esophageal Adenocarcinoma: What We Have Learned From the Lab

Background: Esophageal cancer is one of the most common and deadliest cancers in the world, particularly esophageal adenocarcinoma. There has never been a special drug to treat it. Purpose: This article summarizes the work that we have done in our laboratory about the role of CCN1 in esophageal cancer and gives a new perspective of CCN1 biology. Research Design: This is a review article. Study Sample: The work was done using validated cell lines and fixed human tissue slides. Data Collection and Analysis: This is a review article, therefore, no data collection or analysis was involved. Results: CCN1 is a matricellular protein supporting adhesion, migration, and survival in normal cells, but in the esophageal cancer cells, it induces TRAIL-mediated apoptosis. CCN1 promotes TRAIL and its death receptor expression but downregulates the decoy receptors and survivin in a p53-dependant manner. It was thought that CCN1 relies on TNF to induce apoptosis, but our study found that these two molecules antagonize each other. CCN1 promotes TNFR1 cleavage and uses the soluble product to block TNF signaling, while TNF upregulates PGLYRP1 to overcome this obstacle because PGLYRP1 is a secreted protein that competes with TNF for TNFR1 binding. As a result, when CCN1 and TNF are present together in the vicinity of esophageal tumors, they cancel each other out. Conclusions: Based on our laboratory study, CCN1 has much potential to be a candidate for the treatment of esophageal cancer.