The HMGA1-COX-2 axis: A key molecular pathway and potential target in pancreatic adenocarcinoma
| Autor: | Leslie Cope, Tait Huso, Andrew Schuldenfrei, Linda M.S. Resar, Nathaniel R. Campbell, Collins Karikari, David L. Huso, Francescopaolo Di Cello, Dwella M. Nelson, Amy Belton, Anirban Maitra, Abimbola Aderinto, Shamayra S. Smail, Sandeep N. Shah, Joelle Hillion |
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| Rok vydání: | 2012 |
| Předmět: |
Pathology
medicine.medical_specialty Endocrinology Diabetes and Metabolism Transplantation Heterologous Gene Expression Mice Nude Context (language use) Adenocarcinoma Malignancy Article Mice Sulindac Cell Movement Cell Line Tumor Pancreatic cancer medicine Animals Humans Cyclooxygenase Inhibitors Neoplasm Invasiveness HMGA1a Protein Neoplasm Metastasis Sulfonamides Hepatology biology business.industry Gastroenterology medicine.disease HMGA1 Pancreatic Neoplasms Transplantation Celecoxib Cyclooxygenase 2 Tumor progression ras Proteins biology.protein Cancer research Pyrazoles CA19-9 business Cell Division Neoplasm Transplantation |
| Zdroj: | Pancreatology. 12:372-379 |
| ISSN: | 1424-3903 |
| Popis: | 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 in90% of primary pancreatic cancers, with absent or low levels in early precursor lesions.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.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 (r(2) = 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.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. |
| Databáze: | OpenAIRE |
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