Sevoflurane Inhibits Metastasis in Hepatocellular Carcinoma by Inhibiting MiR-665-Induced Activation of the ERK/MMP Pathway

Abstract

Recent evidence has indicated that inhalational anesthetics may affect the growth and malignant potential of tumor cells and ultimately influence tumor recurrence after surgery. Sevoflurane, a volatile anesthetic, is used extensively in hepatectomy. However, the effect of sevoflurane on the growth of hepatocellular carcinoma (HCC) cells remains unknown. The aim of this study was to explore the effects of sevoflurane on HCC metastasis and its potential mechanisms in the human HCC cell lines, HepG2 and SMMC7721. HepG2 and SMMC7721 cells were treated with 1.7%, 3.4%, and 5.1 % sevoflurane for 6 h. Cell migration was analyzed using invasion, migration, and scratch assays. Based on previous literature, several microRNAs (miRNAs) were screened to determine regulatory miRNA targets of sevoflurane in HepG2 and SMMC7721 cells; miR-665 was detected as a potential target and overexpressed or inhibited in HepG2 and SMMC7721 cells by a lentiviral system. The p-ERK/MMP pathway was also measured by western blotting. Sevoflurane inhibited the migration and invasion of HCC cells in a dose-dependent manner. It also inhibited miR-665 expression in HCC cells. We further observed that sevoflurane inhibited HCC metastasis via miR-665. Sevoflurane-induced downregulation of miRNA-665 led to phosphorylation of ERK and matrix metalloproteinase (MMP-9) via suppression of SPRED1. These results demonstrated that sevoflurane may inhibit invasion and migration via the p-ERK/MMP-9 signaling pathway in HCC cells.