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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 activated K-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 HMGA1 cooperates with activated K-RAS to induce migration, invasion, and anchorage-independent cell growth in a cell line derived from normal human pancreatic epithelium. Moreover, HMGA1 and COX-2 expression are positively correlated in pancreatic cancer cell lines (r2=0.93; p<0.001). HMGA1 binds directly to the COX-2 promoter at an AT-rich region in vivo in three pancreatic cancer cell lines. In addition, HMGA1 induces COX-2 expression in pancreatic epithelial cells, while knock-down of HMGA1 results in repression of COX-2 in 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 of HMGA1. 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.

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In this study, five U2 small nuclear (sn)RNA variants were detected in the posterior silk gland of the Bombyx mori Nistari strain, one of which represents a novel U2 isoform not previously identified in other strains of this species. Following glycerol gradient ultracentrifugation of B. mori silk gland whole cell lysate, the newly isolated variant, U2α, was detected at a greater frequency in total cell lysate than in a high density glycerol gradient fraction rich in spliceosomal complexes. Conversely, previously identified isoforms U2A, U2B, U2D and U2N are abundant in the fraction containing high molecular weight spliceosomal complexes, possibly indicating their greater involvement in splicing. As expected, western blot and semi‐quantitative reverse transcription‐polymerase chain reaction experiments indicate high levels of specific serine and arginine rich (SR) proteins and total U2 snRNA (all variants included) in the fraction enriched in spliceosomes. Free energy values for each U2 isoform, as well as their individual stem‐loops, were estimated to determine their structural stability. Due to the essential role of U2 in the transesterification reactions, it is possible that these isoforms may modulate splicing through differential incorporation into the spliceosome.