Downregulation of 15-hydroxyprostaglandin dehydrogenase by interleukin-1β from activated macrophages leads to poor prognosis in pancreatic cancer

Abstract

Chronic inflammation has a crucial role in cancer development and the progression of various tumors, including pancreatic ductal adenocarcinoma (PDAC). The arachidonate cascade is a major inflammatory pathway that produces several metabolites, such as prostaglandin E2. The enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) degrades prostaglandin and is frequently decreased in several types of cancer; however, the molecular mechanisms of 15-PGDH suppression are unclear. The current study was carried out to elucidate the molecular mechanisms and clinical significance of 15-PGDH suppression in PDAC. Here, we showed that interleukin-1β (IL-1β), a pro-inflammatory cytokine, downregulates 15-PGDH expression in PDAC cells, and that IL-1β expression was inversely correlated with 15-PGDH levels in frozen PDAC tissues. We also found that activated macrophages produced IL-1β and reduced 15-PGDH expression in PDAC cells. Furthermore, the number of CD163-positive tumor-associated macrophages was shown to be inversely correlated with 15-PGDH levels in PDAC cells by immunohistochemical staining of 107 PDAC samples. Finally, we found that low 15-PGDH expression was significantly associated with advanced tumors, presence of lymph node metastasis and nerve invasion, and poor prognosis in PDAC patients. Our results indicate that IL-1β derived from TAMs suppresses 15-PGDH expression in PDAC cells, resulting in poor prognosis of PDAC patients.