Sevoflurane inhibits the proliferation and invasion of hepatocellular carcinoma cells through regulating the PTEN/Akt/GSK‑3β/β‑catenin signaling pathway by downregulating miR‑25‑3p

Abstract

Sevoflurane (Sevo) is one of the most frequently used volatile anesthetic agents in surgical oncology and has various effects on tumors, including inhibiting tumor growth, recurrence, and metastases; however, the molecular mechanisms are unknown. This study tried to investigate the influence of Sevo on hepatocellular carcinoma (HCC) cells and its possible mechanisms of action. The present study found that Sevo suppressed both the proliferative and invasive capabilities of both HCCLM3 and Huh7 cells in a dose-dependent manner. Moreover, 53 differentially expressed microRNAs (miRNAs/miRs) in HCC cells that resulted from Sevo were screened out using miRNA microarray assay. In particular, miR-25-3p displayed a significant decrease in response to Sevo treatment. Further studies showed that Sevo's inhibitory actions on HCC cells were attenuated by overexpression of miR-25-3p but enhanced by its inhibitor. Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN (PTEN), a tumor suppressor gene, was directly targeted by miR-25-3p and its expression was upregulated by Sevo. In addition, Sevo suppressed the expression of phosphorylated-protein kinase B (p-Akt) (S473), glycogen synthase kinase (GSK) 3β (p-GSK3β) (S9), β-catenin, c-Myc and matrix metalloproteinase 9; whereas these inhibitory effects were reversed by miR-25-3p overexpression. More importantly, Sevo's tumor-suppressive effects were enhanced by LY294002 (a PI3-kinase inhibitor) but weakened by insulin growth factor-1 (an agonist of the Akt signaling pathway). These data suggest that Sevo's antitumor effects on HCC could be explained, in part, by Sevo inhibiting the miR-25-3p/PTEN/Akt/GSK-3β/β-catenin signaling pathway.

Wnt/β-Catenin Signaling as a Driver of Hepatocellular Carcinoma Progression: An Emphasis on Molecular Pathways

“…Then, PTEN inhibits Akt to enhance GSK-3β expression, leading to β-catenin signaling inhibition and a decrease in expression level of its downstream targets including c-Myc and MMP-9. 249 In addition to PTEN, MARCH1 can function as regulator of PI3K/Akt signaling in HCC. Exposing HepG2 cells to secalonic acid-F (SAF) is correlated with a significant decrease in MARCH1 expression.…”

Long-term effect of anesthesia choice on patients with hepatocellular carcinoma undergoing open liver resection

“…sevoflurane could restore the level of miR-29a and inhibit tumor progression by lowering the expression of long non-coding RNA KCNQ1 opposite strand/antisense transcript 1 (lncRNA KCNQ1OT1) (26), which led to the reduction of DNA methyltransferase 3 alpha (Dnmt3a) (25) and chromebox protein homolog 3 (CBX3) (26) in HCC cell lines. In vitro studies also suggested that sevoflurane-stimulated tumor cells exhibited higher level of phosphatase and tensin homologue (PTEN) and inactivation of phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) signaling pathway (25,27), a crucial signaling in tumorigenesis (65). Also, in both cell lines and animal models experiments, researchers observed a correlation of increased level of miR-148-3p and decreased Rho-associated protein kinase 1 (ROCK1) after sevoflurane treatment (28), which might account for its antitumor property.…”

Pancreatic Cancer and Microenvironments: Implications of Anesthesia

“…Impairment of MMP-9 expression and regulation affects various dysfunctions, including tumorigenesis, and MMP-9 suppression can be targeted in anticancer therapeutics [ 108 ]. Anesthesia may affect MMP-9 expression [ 74 , 94 , 109 , 110 , 111 , 112 , 113 , 114 , 115 ].…”

“…Sevoflurane and desflurane reduced the invasion of colorectal and neuroglioma cancer cells through downregulation of MMP-9 [ 94 , 110 ]. Moreover, sevoflurane inhibited the proliferation and invasion of HCC cells through downregulation of MMP-9 [ 111 ]. Zhang et al showed that fentanyl inhibited tumor growth and cell invasion in colorectal cancer by downregulation of miR-182 and MMP-9 expression [ 112 ].…”