March 12 2018
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*
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).
- 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
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.