Emerging roles for the pro-oncogenic anterior gradient-2 in cancer development

Abstract

Clinical studies have defined the core 'genetic blueprint' of a cancer cell, but this information does not necessarily predict the cancer phenotype. Signalling hubs that mediate such phenotype have been identified largely using OMICS platforms that measure dynamic molecular changes within the cancer cell landscape. The pro-oncogenic protein anterior gradient 2 (AGR2) is a case in point; AGR2 has been shown using a range of expression platforms to be involved in asthma, inflammatory bowel disease, cell transformation, cancer drug resistance and metastatic growth. AGR2 protein is also highly overexpressed in a diverse range of human cancers and can be secreted and detected in extracellular fluids, thus representing a compelling pro-oncogenic signalling intermediate in human cancer. AGR2 belongs to the protein disulphide isomerase family with all the key features of an endoplasmic reticulum-resident protein-this gives clues into how it might function as an oncoprotein through the regulation of protein folding, maturation and secretion that can drive metastatic cell growth. In this review, we will describe the known aspects of AGR2 molecular biology, including gene structure and regulation, emerging protein interaction networks and how its subcellular localization mediates its biological functions. We will finally review the cases of AGR2 expression in human cancers, the pathophysiological consequences of AGR2 overexpression, its potential role as a tumour biomarker that predicts the response to therapy and how the AGR2 pathway might form the basis for drug discovery programmes aimed at targeting protein folding/maturation pathways that mediate secretion and metastasis.

Expression of Anterior Gradient 2 Is Decreased with the Progression of Human Biliary Tract Cancer

“…AGR2 is highly expressed in numerous human cancers and is associated with the development of various tumor characteristics, including increased proliferation, survival, metastasis, and drug resistance (Brychtova et al 2011;Chevet et al 2013). Increased AGR2 expression has previously been shown to be associated with metastasis and a poor prognosis in breast cancer patients (Barraclough et al 2009), and to correlate with high-grade serous carcinoma and shortened overall survival of ovarian cancer patients (Innes et al 2006).…”

“…Since AGR2 is reportedly up-regulated in various types of cancers, its utility as a cancer biomarker and therapeutic target has been investigated by numerous researchers (Brychtova et al 2011;Chevet et al 2013;Salmans et al 2013). Lepreux et al (2011) reported that AGR2 expression was high in normal columnar cholangiocytes and that its expression pattern appeared to be conserved during cholangiocarcinoma development.…”

“…Subsequent studies have demonstrated that AGR2 is highly expressed in several human cancers, including adenocarcinomas of the esophagus (Pohler et al 2004), lung (Fritzsche et al 2007), pancreas (Iacobuzio-Donahue et al 2003;Ramachandran et al 2008), ovary , and prostate (Kristiansen et al 2005). The tumor-promoting potential of AGR2 is apparent in the augmentation of various tumor phenotypes, including proliferation, survival, metastasis, and drug resistance (Brychtova et al 2011;Chevet et al 2013). …”

Hydrogen peroxide mediated mitochondrial UNG1-PRDX3 interaction and UNG1 degradation

“…As a member of the protein disulfide isomerase family, AGR2 has a thioredoxin-like domain to aid protein folding and assembly [33,34] and its expression is elevated in the preneoplastic tissue in Barrett's oesophagus and other human cancer cells, where it functions as a proto-oncogene [35][36][37]. AGR2 interacts with multiple proteins including DNA binding proteins and AAA þ ATPase [37][38][39]. The interaction of UNG1 and AGR2 has not been reported before and we propose that the interaction may stabilize UNG1 and enhances its enzymatic activity in DNA repair.…”

Agr2 Mediates Paracrine Effects on Stromal Fibroblasts That Promote Invasion by Gastric Signet-Ring Carcinoma Cells

“…Agr2 is physiologically localized in endoplasmic reticulum (ER), and it regulates the expression of components of the ER-associated degradation signaling and plays a pivotal role in resistance to ER stress (9)(10)(11). In addition, Agr2 acts as an ER chaperone for the intestinal mucins MUC2, MUC1, and MUC5 (10,12,13).…”