Discovery of a Novel Connecting Link between Renin-Angiotensin System and Cancer in Barrett's Esophagus by Proteomic Screening

Abstract

The renin-angiotensin system (RAS) plays a central role in the regulation of homeostasis and blood pressure. This involves an important enzyme called angiotensin-converting enzyme that leads to the conversion of angiotensin I into angiotensin II. RAS has been reported to show association with inflammation, and in sporadic studies, with cancer. In particular, angiotensin II has been reported to be prevalent in the hypoxic microenvironment and associated with cancer signaling pathways. In a recent study, Bratlie et al. (Proteomics Clin. Appl. 2019, 4, 1800102) is shown to exploit 2D gel electrophoresis, and mass spectrometry (MS) to identify differentially expressed proteins by comparing low-grade dysplasia in Barrett's Esophagus (BE) following administration of agents that interfere with RAS, that is, enalapril and candesartan, and identified specific modulation of HSP60, PDIA3, and PPA1. Though 2D gel coupled with MS is a commonly-used tool for studying proteomes, it still has limitations in terms of a comprehensive analysis due to lack of absolute quantitation in a high-throughput manner. Despite technical limitations and the small size of the study, preliminary data emerging from the investigation show interference caused by clinically approved RAS inhibitors resulting in alteration of molecular markers associated with tumorigenicity. The authors propose potential factors that may influence the progression of the disease. However, these are conspicuous changes in high-abundance proteins only. Therefore, there is a need to carry out detailed experimental studies either using an in vitro labeling technique (isobaric labeling for relative and absolute quantitation) for tissues or an in vivo labeling technique (stable isotope labeling in animal cell culture) coupled with LC-MS/MS to identify differentially-regulated proteins to delineate the role of RAS in BE.

Keywords: Barrett's esophagus; Esophageal squamous cell carcinoma; dysplasia; isobaric labeling; mass spectrometry; quantitative proteomics; stable isotope labeling.