RRC ID 52604
Author Arima K, Komohara Y, Bu L, Tsukamoto M, Itoyama R, Miyake K, Uchihara T, Ogata Y, Nakagawa S, Okabe H, Imai K, Hashimoto D, Chikamoto A, Yamashita YI, Baba H, Ishimoto T.
Title Downregulation of 15-hydroxyprostaglandin dehydrogenase by interleukin-1β from activated macrophages leads to poor prognosis in pancreatic cancer.
Journal Cancer Sci
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.
Volume 109(2)
Pages 462-470
Published 2018-2-1
DOI 10.1111/cas.13467
PMID 29224225
PMC PMC5797824
MeSH Carcinoma, Pancreatic Ductal / genetics Carcinoma, Pancreatic Ductal / metabolism Carcinoma, Pancreatic Ductal / pathology* Cell Line, Tumor Down-Regulation* Female Gene Expression Regulation, Neoplastic Humans Hydroxyprostaglandin Dehydrogenases / genetics Hydroxyprostaglandin Dehydrogenases / metabolism* Interleukin-1beta / genetics Interleukin-1beta / metabolism* Macrophages / metabolism* Macrophages / pathology Male Neoplasm Invasiveness Neoplasm Metastasis Neoplasm Staging Pancreatic Neoplasms / genetics Pancreatic Neoplasms / metabolism Pancreatic Neoplasms / pathology* Prognosis Survival Analysis
IF 4.751
Times Cited 9
Human and Animal Cells PK-8(RCB2700)