The HMGA1-COX-2 axis: A key molecular pathway and potential target in pancreatic adenocarcinoma

Joelle Hillion, Shamayra S. Smail, Francescopaolo Di Cello, Amy Belton, Sandeep N. Shah, Tait Huso, Andrew Schuldenfrei, Dwella Moton Nelson, Leslie Cope, Nathaniel Campbell, Collins Karikari, Abimbola Aderinto, Anirban Maitra, David L. Huso, Linda M.S. Resar

Research output: Contribution to journalArticlepeer-review

Abstract

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 theHMGA1-cyclooxygenase (COX-2) pathway inhumanpancreatic 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 anchorageindependent 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.

Original languageEnglish (US)
Pages (from-to)372-379
Number of pages8
JournalPancreatology
Volume12
Issue number4
DOIs
StatePublished - 2012

Keywords

  • Cyclooxygenase-2
  • High mobility group A1 (HMGA1)
  • Pancreatic adenocarcinoma
  • Tumor progression

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Hepatology
  • Gastroenterology

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