AGR2 is a SMAD4-suppressible gene that modulates MUC1 levels and promotes the initiation and progression of pancreatic intraepithelial neoplasia

Abstract

The mechanisms controlling expression of the putative oncogene AGR2 in pancreatic ductal adenocarcinoma (PDAC) are not well understood. We now show that AGR2 is a TGF-β-responsive gene in human pancreatic cancer cells, whose down-regulation is SMAD4-dependent. We also provide evidence supporting a role for AGR2 as an ER-chaperone for the cancer-associated mucin, MUC1. AGR2 is both sufficient and required for MUC1 expression in pancreatic cancer cells. Furthermore, AGR2 is co-expressed with MUC1 in mouse pancreatic intraepithelial neoplasia (mPanIN)-like lesions and in the cancer cells of four distinct genetically engineered mouse models of PDAC. We also show that Pdx1-Cre/LSL-KrasG12D/Smad4lox/lox mice heterozygous for Agr2 exhibit a delay in mPanIN initiation and progression to PDAC. It is proposed that loss of Smad4 may convert TGF-β from a tumor suppressor to a tumor promoter by causing the up-regulation of AGR2, which then leads to increased MUC1 expression, at which point both AGR2 and MUC1 facilitate mPanIN initiation and progression to PDAC.

Mechanisms of anterior gradient-2 regulation and function in cancer

“…In pancreatic cell models, SMAD4 can suppress AGR2 expression highlighting a TGF-␤ dependence in agr2 responsiveness [74]. In addition, K-ras(G12D)/Smad4(lox/lox) mice that are heterozygous for agr2 are attenuated in initiation and progression to pancreatic ductal cell carcinoma [74]. Consistent with this study, secretion of TGF-␤ from pancreatic stellate cells might reduce agr2 expression in pancreatic ductal adenocarcinoma [75].…”

“…TGF-␤ can function as a tumour suppressor or oncogenic signal depending upon context including tissue type and stage in the carcinogenesis sequence. In pancreatic cell models, SMAD4 can suppress AGR2 expression highlighting a TGF-␤ dependence in agr2 responsiveness [74]. In addition, K-ras(G12D)/Smad4(lox/lox) mice that are heterozygous for agr2 are attenuated in initiation and progression to pancreatic ductal cell carcinoma [74].…”

“…AGR2 has been localised in the endoplasmic reticulum of airway epithelial cells and in submucosal glands where it participates in production of mucins such as MUC5B, MUC5AC, and IL13 leading to enhanced symptoms of asthma [13] [88]. In addition to MUC2, MUC5AC and MUC5B, AGR2 participates also in mucin 1 (MUC1) production in pancreatic ductal adenocarcinoma [74]. Mice null for AGR2 have elevated MUC5AC accumulating in the endoplasmic reticulum with signatures of endoplasmic reticulum stress, as well as reduced asthma incidence [13].…”

New Blocking Antibodies against Novel AGR2–C4.4A Pathway Reduce Growth and Metastasis of Pancreatic Tumors and Increase Survival in Mice

“…AGR2 has been reported to be involved in protein maturation and folding (14-16,31), to regulate cathepsins (32) and to modulate MUC-1 levels (14,33). However these roles of AGR2 do not explain its ability to act as an oncogene (34), or its ability to increase the aggressiveness of several types of cancer.…”

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). Among them, gastric SRCC cells express MUC1, which is a membrane-bound mucin that stimulates dysregulated cell proliferation by increasing receptor-mediated signal transduction (14)(15)(16).…”