The HMGA1-COX-2 axis: a key molecular pathway and potential target in pancreatic adenocarcinoma.
BACKGROUND
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 (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.


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.
Hematology Division, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States.
Joelle
J
Hillion
Shamayra S
SS
Smail
Francescopaolo
F
Di Cello
Amy
A
Belton
Sandeep N
SN
Shah
Tait
T
Huso
Andrew
A
Schuldenfrei
Dwella Moton
DM
Nelson
Leslie
L
Cope
Nathaniel
N
Campbell
Collins
C
Karikari
Abimbola
A
Aderinto
Anirban
A
Maitra
David L
DL
Huso
Linda M S
LM
Resar
D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000517:prevention & control; D000818:Animals; D000068579:Celecoxib; D002455:Cell Division / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D051546:Cyclooxygenase 2 / Q000235:genetics* / Q000502:physiology; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage; D015870:Gene Expression; D025741:HMGA1a Protein / Q000235:genetics* / Q000502:physiology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000235:genetics; D009362:Neoplasm Metastasis / Q000235:genetics; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000517:prevention & control; D011720:Pyrazoles / Q000008:administration & dosage; D013449:Sulfonamides / Q000008:administration & dosage; D013467:Sulindac / Q000008:administration & dosage; D014183:Transplantation, Heterologous; D018631:ras Proteins / Q000502:physiology
D016861:Cyclooxygenase Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D025741:HMGA1a Protein; D013467:Sulindac; D051546:Cyclooxygenase 2; D018631:ras Proteins; D000068579:Celecoxib