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

March 12 2018

Takatsugu Ishimoto

Paper information

Kota Arima, Yoshihiro Komohara, Luke Bu, Masayo Tsukamoto, Rumi Itoyama, Keisuke Miyake, Tomoyuki Uchihara, Yoko Ogata, Shigeki Nakagawa, Hirohisa Okabe, Katsunori Imai, Daisuke Hashimoto, Akira Chikamoto, Yo-ichi Yamashita, Hideo Baba* and Takatsugu Ishimoto*
(*corresponding authors)

Downregulation of 15-hydroxyprostaglandin dehydrogenase by interleukin-1β from activated macrophages leads to poor prognosis in pancreatic cancer.
Cancer Sci. 2018 Feb;109(2): 462-470. doi: 10.1111/cas.13467.


Cover of this issue:
Expression of 15-PGDH (brown) in pancreatic cancer is reduced by co-culture of activated macrophages (Green).

Highlights

- Low 15-PGDH expression is implicated in poor prognosis on PDAC patients
- Downregulation of 15-PGDH by IL-1β promotes PDAC cell growth
- Activated macrophages produce IL-1β and decrease 15-PGDH expression in PDAC cells
- Number of infiltrating TAMs is inversely correlated with 15-PGDH expression in PDAC cells

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 (PGE₂). 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 conducted to elucidate the molecular mechanisms and clinical significance of 15-PGDH suppression in PDAC. Here, we showed that interleukin-1 beta (IL-1β), a pro-inflammatory cytokine, down-regulates 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 (TAMs) was shown to be inversely correlated with 15-PGDH levels in PDAC cells by immunohistochemical staining of 107 PDAC samples. Finally, we demonstrated 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.