PLOD2 as a potential regulator of peritoneal dissemination in gastric cancer. Issue 5 (20th April 2018)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: International journal of cancer. Volume 143:Issue 5(2018)
• Page Start: 1202
• Page End: 1211
• Publication Date: 2018-04-20
• Subjects: gastric cancer -- HIF‐1 -- hypoxia -- peritoneal dissemination -- PLOD2; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.31410
• Languages: English
• ISSNs: 0020-7136

Abstract

Abstract : 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. Abstract : What's new? The invasion and spread of tumor cells in the peritoneal cavity is a leading cause of death in advanced gastric cancer (GC). Despite clear associations with poor prognosis, however, little is understood about the molecular mechanisms driving peritoneal invasion and metastasis in GC. In the present study elevated levels of procollagen‐lysine 2‐oxoglutarate 5‐dioxygenase 2 (PLOD2) in GC patients were associated with peritoneal dissemination and poor survival. Experiments in GC cells revealed that PLOD2 is regulated by HIF‐1α, with PLOD2 induction in hypoxia associated with cell invasiveness and migration. Invasiveness and metastatic potential were suppressed after PLOD2 silencing, independent of HIF‐1α.