TheHMGA1-COX-2axis: A key molecular pathway and potential target in pancreatic adenocarcinoma

Context Although pancreatic cancer is a common, highly lethal malignancy, the molecular events that enable precursor lesions to become invasive carcinoma remain unclear. We previously reported that the high-mobility group A1 (HMGA1) protein is overexpressed in >90% of primary pancreatic cancers, with absent or low levels in early precursor lesions. Methods Here, we investigate the role of HMGA1 in reprogramming pancreatic epithelium into invasive cancer cells. We assessed oncogenic properties induced by HMGA1 in non-transformed pancreatic epithelial cells expressing activatedK-RAS. We also explored the HMGA1-cyclooxygenase (COX-2) pathway in human pancreatic cancer cells and the therapeutic effects of COX-2 inhibitors in xenograft tumorigenesis. Results HMGA1cooperates with activatedK-RASto induce migration, invasion, and anchorage-independent cell growth in a cell line derived from normal human pancreatic epithelium. Moreover,HMGA1andCOX-2expression are positively correlated in pancreatic cancer cell lines (r2 = 0.93;p < 0.001). HMGA1 binds directly to theCOX-2promoter at an AT-rich regionin vivoin three pancreatic cancer cell lines. In addition, HMGA1 inducesCOX-2expression in pancreatic epithelial cells, while knock-down ofHMGA1results in repression ofCOX-2in pancreatic cancer cells. Strikingly, we also discovered that Sulindac (a COX-1/COX-2 inhibitor) or Celecoxib (a more specific COX-2 inhibitor) block xenograft tumorigenesis from pancreatic cancer cells expressing high levels ofHMGA1. Conclusions Our studies identify for the first time an important role for the HMGA1-COX-2 pathway in pancreatic cancer and suggest that targeting this pathway could be effective to treat, or even prevent, pancreatic cancer.