PLOD2 as a potential regulator of peritoneal dissemination in gastric cancer

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.

Tumor-secreted PAI-1 promotes breast cancer metastasis via the induction of adipocyte-derived collagen remodeling

“…Several studies have suggested that PLOD2 is correlated with poor prognosis of multiple cancers, including sarcoma, lung cancer, renal cell carcinoma, breast cancer, cervical cancer and bladder cancer [19,[27][28][29][30][31]. PLOD2 reinforces the migration capacity of cancer cells, and also promotes cancer cells migration along the "highway" linear collagen [19,28,32]. Previous studies showed silencing of PLOD2 led to the inhibition of migration and invasiveness of multiple cancer cells themselves, which might mediate by abrogating the epithelialmesenchymal transition (EMT) of those cancer cells [33,34].…”

“…4). Mechanistic studies have revealed that PLOD2 can be regulated by numerous factors, including HIF-1α, TGF-β, EGF, miR 26a/b, IL-6 and leptin [9,19,27,28,32] . The paracrine signals derived from adipocytes or CAFs were reported to regulate PLOD2 expression in multiple cancers, suggesting the signals in microenvironment might involve in regulating PLOD2 expression.…”

PLOD2 increases resistance of gastric cancer cells to 5-fluorouracil by upregulating BCRP and inhibiting apoptosis

“…Data have shown that TAFs play significant roles in the therapeutic sensitivity of tumors and that therapeutic targeting of TAFs results in increased chemotherapeutic sensitivity in colorectal cancer [29]. PLOD2 is overexpressed in multiple cancers, including GC [17]. However, no study has shown its role in GC chemotherapy.…”

“…Among the GC patients, the PLOD2 high group had large amounts of collagen in their cancer tissues. PLOD2 knockdown through siRNA in several GC cell lines suppresses invasion and migration in vitro [17].…”

“…Although PLOD2 expression is reportedly associated with poor prognosis in several types of cancer [14][15][16][17], its role in chemoresistance remains unknown. In the following study, we investigated the effect of PLOD2 on the sensitivity of GC cells to 5-FU.…”