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PLOD2 as a potential regulator of peritoneal dissemination in gastric cancer
Author(s) -
Kiyozumi Yuki,
Iwatsuki Masaaki,
Kurashige Junji,
Ogata Yoko,
Yamashita Kohei,
Koga Yuki,
Toihata Tasuku,
Hiyoshi Yukiharu,
Ishimoto Takatsugu,
Baba Yoshifumi,
Miyamoto Yuji,
Yoshida Naoya,
Yanagihara Kazuyoshi,
Mimori Koshi,
Baba Hideo
Publication year - 2018
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.31410
Subject(s) - downregulation and upregulation , cancer research , biology , transfection , hypoxia (environmental) , cell migration , cell culture , chemistry , gene , biochemistry , genetics , organic chemistry , oxygen
Peritoneal dissemination is the most common metastatic pattern in advanced gastric cancer (GC) and has a very poor prognosis. However, its molecular mechanism has not been elucidated. Our study investigated genes associated with peritoneal dissemination of GC. We performed combined expression analysis of metastatic GC cell lines and identified Procollagen‐lysine, 2‐oxoglutarate 5‐dioxygenase2 (PLOD2) as a potential regulator of peritoneal dissemination. PLOD2 is regulated by hypoxia‐inducible factor‐1 (HIF‐1) and mediates extracellular matrix remodeling, alignment, and mechanical properties. We analyzed PLOD2 expression immunohistochemically in 179 clinical samples, and found high PLOD2 expression to be significantly associated with peritoneal dissemination, leading to poor prognosis. In an in vivo‐collected metastatic cell line, downregulation of PLOD2 by siRNA reduced invasiveness and migration. Hypoxia upregulated PLOD2 mediated by HIF‐1, and promoted invasiveness and migration. After exposure to hypoxia, a cell line transfected with siPLOD2 exhibited significantly suppressed invasiveness and migration, despite high HIF‐1 expression. These findings indicate that PLOD2 is a regulator of, and candidate therapeutic target for peritoneal dissemination of GC. Although peritoneal dissemination of GC has a very poor prognosis, its molecular mechanism has not been elucidated. We identified PLOD2 regulated by HIF‐1 as a potential regulator of peritoneal dissemination of GC. Finally, we showed that PLOD2 promotes cell invasiveness and migration in GC under hypoxia and lead to peritoneal dissemination of GC.