25-HC decreases the sensitivity of human gastric cancer cells to 5-fluorouracil and promotes cells invasion via the TLR2/NF-κB signaling pathway

Hyperlipidemia is associated with metastasis in patients with gastric cancer (GC). 25-Hydroxycholesterol (25-HC) is a type of oxysterol which is synthesized from cholesterol and is involved in a number of processes, including inflammation, immune responses and cancer development. However, the role of 25-HC in gastric cancer remains unknown. In the present study, we demonstrated that 25-HC had no effects on GC cell proliferation and apoptosis, whereas it decreased the sensitivity of GC cells to 5-fluorouracil (5-FU), as demonstrated by the increased cell proliferation and the decreased cell apoptosis. On the other hand, exposure to 2.5-10 µM of 25-HC significantly promoted GC invasion, both in vitro (using AGS and MGC-803 GC cell lines) and in vivo (in an animal model), accompanied by the upregulation of the expression levels of matrix metalloproteinases (MMPs). Further investigations revealed that the promotion of GC invasion was, at least in part due to the activation of Toll-like receptor 2 (TLR2)/nuclear factor (NF)-κB signaling. Our results demonstrated that 25-HC promoted GC cells invasion by upregulating TLR2/NF-κB-mediated MMP expression. Thus, on the whole, the findings of this study suggest a novel mechanism of hyperlipidemia-induced GC progression.