Transactivation of Gut-enriched Kruppel-like factor by butyrate in human colonic cancer cells

Abstract

Pancreatic cancer has an abysmal prognosis because of late diagnosis and lack response to available therapeutics. Therefore, it is important to identify risk factors and to be able to prevent and detect this cancer in an early, non-invasive stage. Pancreanc lntraepithdial Neoplasias (PanINs) are precursor lesions which could be an ideal target for chemoprevention. COX-2 is up-regulated in PanlNs. We recently reported that 5-1ipoxygenase (5-LOX) is 0verexpressed in resected human pancreatic cancers and that the 5-LOX pathway is even more important than COX-2 in this disease. However, whether the 5-LOX pathway is activated early or only in late disease'and whether it might be a target for chemoprevention Ls not known. Therefore, we investigated the expression of 5-LOX in PanlN lesions in the human pancreas as well as two pancreatic cancer models. Immunocytochemistry for 5-LOX ,a~s undertaken in human surgical specimens from 10 pancreatic adenocarcinomas, 9 cases 0fchronic pancreatitis and I0 normal pancreatic tissues from multi-organ donors, immunoslaining was also carried out in pancreatic specimens of two models of pancreatic adenocarcinoma: carcinogen (BOP)-treated hamsters and Ek-Kras transgenic mice (Kras mutant), as wdl as normal harhster and mouse pancreatic tissues. In human and hamster tissues, 5l.OX was constitutively expressed at a modest level in the cytoplasm of acinar ceils. Intense 5-LOX staining was evident in the nuclear envelope of cancer cells and all grades of PanlNs 0/9/10 human pancreatic adenocareinoma and 7/9 chronic pancreatitis tissues. In contrast, 5-LOX expression was only detected in a small proportion of ductaI cells (0-75%) in l0 normal human pancreatic tissues. Similarly, PanlNs in BOP-treated hamsters and EL-Kras mice showed positive staining, whereas normal ductal cells were completely negative. This study demonstrates that 5-LOX ts up-regulated in human PanINs and early lesions of pancreatic cancer in two different animal models. These findings provide even more evidence that 5-LOX plays a key role in the development of pancreatic cancer. Furthermore, like COX-2, this lipoxygenase pathway is an attractive target for the prevention of this devastating disease 5-LOX and COX-2 inhibitors should eventually be used for chemoprevention in patients at risk for developing pancreatic cancer