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

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‐hydroxyprostagla...

Full description

Saved in:
Bibliographic Details
Published in:Cancer science 2018-02, Vol.109 (2), p.462-470
Main Authors: Arima, Kota, Komohara, Yoshihiro, Bu, Luke, Tsukamoto, Masayo, Itoyama, Rumi, Miyake, Keisuke, Uchihara, Tomoyuki, Ogata, Yoko, Nakagawa, Shigeki, Okabe, Hirohisa, Imai, Katsunori, Hashimoto, Daisuke, Chikamoto, Akira, Yamashita, Yo‐ichi, Baba, Hideo, Ishimoto, Takatsugu
Format: Article
Language:English
Subjects:
15‐Hydroxyprostaglandin dehydrogenase
Adenocarcinoma
Cancer therapies
Carcinoma, Pancreatic Ductal - genetics
Carcinoma, Pancreatic Ductal - metabolism
Carcinoma, Pancreatic Ductal - pathology
CD163 antigen
Cell Line, Tumor
Cytokines
Dehydrogenases
Down-Regulation
Enzymes
Female
Gene Expression Regulation, Neoplastic
Humans
Hydroxyprostaglandin Dehydrogenases - genetics
Hydroxyprostaglandin Dehydrogenases - metabolism
Immunoglobulins
Inflammation
Interleukin-1beta - genetics
Interleukin-1beta - metabolism
interleukin‐1β
Lymph nodes
Macrophages
Macrophages - metabolism
Macrophages - pathology
Male
Metabolites
Metastases
Molecular modelling
Neoplasm Invasiveness
Neoplasm Metastasis
Neoplasm Staging
Original
Pancreatic cancer
pancreatic ductal adenocarcinoma
Pancreatic Neoplasms - genetics
Pancreatic Neoplasms - metabolism
Pancreatic Neoplasms - pathology
Prognosis
Prostaglandin E2
Survival Analysis
tumor microenvironment
Tumor necrosis factor-TNF
Tumors
tumor‐associated macrophage
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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. IL‐1β derived from activated macrophages down‐regulates 15‐PGDH expression in PDAC cells. Down‐regulation of 15‐PGDH promotes PDAC cell growth and leads to poor prognosis in PDAC patients.
ISSN:1347-9032
1349-7006
DOI:10.1111/cas.13467