Reduced Angiotensin II Type 2 Receptor Expression Is Associated with Gastric Cancer Progression and Enhanced Gastric Cancer Cell Migration/Invasion

Gastric cancer (GC) is one of the leading causes of death due to cancer worldwide. Most cases have a poor prognosis due to non-curable surgical resection and the limited efficacy of chemotherapy. Angiotensin II Type 2 Receptor (AT2R), an effector protein of the renin angiotensin system (RAS), is reportedly deregulated in some human cancers and implicated in the regulation of several cancer-related cellular processes. However, our current understanding of the role of this protein in GC is very limited. The objective of this study was to evaluate the expression of AT2R during GC progression and determine the effect of receptor activation and overexpression on GC cell migration and invasion.AT2R acts as a tumor suppressor in GC by reducing cell migration and invasion.We used the data published in the The Cancer Genome Atlas (TCGA) to evaluate in GC the expression of AGTR2, the gene that encodes AT2R. In addition, we determined the expression of AT2R in precancerous gastric lesions, advanced GC and non-tumor adjacent tissue samples by immunohistochemistry. Association analysis of the expression of AGTR2 and AT2R with clinicopathological features and survival curves was also performed. Besides, the effects of AT2R on cell migration, transmigration, invasion and colony formation were evaluated using human GC cells. Finally, we determined the effect of AT2R activation in an intraperitoneal carcinomatosis xenograft mouse model.We observed that AGTR2 and AT2R expression was downregulated in GC patients (Fig. 1A), and this decreased expression correlated with depth of tumor invasion, metastasis and poor overall survival (Fig 1B). Moreover, loss of AT2R expression was associated with disease progression from pre-neoplasic lesions to GC (Fig, 1C). On the other hand, AT2R activation and overexpression reduced migration (Fig. 2A, B), transendothelial migration, invasion and colony formation of AGS and Hs 746T GC cells. Finally, AT2R activation increased mouse survival and decreased tumor formation in an in vivo model (not shown).AT2R was downregulated to a significant extent in GC patients and shown to prevent GC cell migration and invasion, suggesting a role in preventing the progression of GC lesions.