The dual role of HMGB1 in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of exocrine pancreatic cancer with a 9% 5-year survival rate. High mobility group box 1 (HMGB1) is a nuclear protein that can act as a DNA chaperone in the sustainment of chromosome structure and function. When released into the extracellular space, HMGB1 becomes the most well characterized damage-associated molecular pattern (DAMP) to trigger immune responses. Recent evidence indicates that intracellular HMGB1 is a novel tumor suppressor in PDAC, which is connected to its role in the prevention of oxidative stress, genomic instability, and histone release. However, since extracellular HMGB1 is a DAMP and proinflammatory cytokine, cancer cells can also exploit it to survive through the receptor for advanced glycation endproducts (RAGE) in the pancreatic tumor microenvironment. Interestingly, targeting the HMGB1-RAGE pathway has become a new anti-cancer therapy strategy for PDAC.