The identification and characterization of PDE7A upregulation in gastric cancer metastasis

Abstract

Abstract Abstract of the thesis entitled “The identification and characterization of PDE7A upregulation in gastric cancer metastasis” Submitted by Krista Roberta Verhoeft For the Degree of Doctor of Philosophy At the University of Hong Kong In October 2019

Gastric cancer (GC) is one of the most common cancers and a leading cause of cancer death worldwide. Poor diet, increased age, low socioeconomic status, several hereditary syndromes and infection with Helicobacter Pylori (H. pylori) can increase the risk of developing GC. Although the worldwide incidence of GC has decreased dramatically in the last half a decade due to increased sanitation, access to fresh fruit and vegetables and reductions in H. pylori infection, incidence rates still remain high in areas such as Eastern Asia where the prognosis for patients diagnosed with GC is poor. Most cases of GC are diagnosed in the advanced stages when the primary tumor has already metastasized to neighboring lymph nodes and/or distant organs. Identifying the genes and signaling pathways involved in promoting GC metastasis is crucial for improving our understanding of this disease and identifying biomarkers to ultimately improve the survival rate of patients diagnosed with GC. Here we report the identification and characterization of a novel gene involved in promoting GC metastasis. Phosphodiesterase 7A (PDE7A) was found to be upregulated in the primary tumor and lymph node metastasis tissue of GC patients. We found that PDE7A overexpressed GC cells displayed advantages in growth, invasion and migration in vitro and in vivo. Furthermore, PDE7A inhibition with PDE7 specific inhibitor BRL-50481 decreased the tumorigenic potential of PDE7A overexpressed GC cells. Interestingly, we discovered that PDE7A is the most upregulated PDE in GC and its overexpression decreased cellular cAMP levels and could promote NF-κB signaling and activity. These findings suggest that PDE7A inhibition may reduce GC tumor growth and metastasis and therefore PDE7A can be considered as a novel therapeutic target in GC. (Word count = 276)