Figure 6
From: ER stress protein AGR2 precedes and is involved in the regulation of pancreatic cancer initiation
Schematic illustration of AGR2 role and induction in pancreatic cancer initiation. Different conditions and environmental factors (pancreatitis, obesity, smoking, alcohol, pathogens and reactive oxygen species) can cause ER stress in the pancreas. ER stress induces the expression of UPR proteins to restore ER homoeostasis. When UPR is not sufficient to restore homoeostasis in presence of a prolonged or chronic ER stress it can result in inflammatory diseases such as chronic pancreatitis. Paracrine transfer of ER stress between pancreatic cells might further stimulate the development of a pro-inflammatory environment. Occurrence of KRAS mutation in such environment is a key driver event for pancreatic cancer initiation. AGR2 expression is both induced by ER stress and KRAS mutation and is critical for ER homoeostasis and the early stages of pancreatic carcinogenesis. While AGR2 expression is induced through all the initiating stages of PDAC, UPR proteins appeared to be downregulated during the formation of premalignant lesions. This loss might potentially be directly caused by the occurrence of KRAS oncogenic mutation (also stimulating AGR2 expression) and result in protection of cancer-initiating cells from UPR-related apoptosis. Dependency on AGR2 at that stage may therefore reflect its important role in cellular proteostasis during neoplasia.
