Abstract
Sevoflurane was frequently used as a volatile anesthetic in cancer surgery. However, the potential mechanism of sevoflurane on lung cancer remains largely unclear. In this study, lung cancer cell lines (H446 and H1975) were treated by various concentrations of sevoflurane. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assessment and colony formation assay were performed to detect the cell viability and proliferation, separately. Also, transwell assay or flow cytometry assay was applied as well to evaluate the invasive ability or apoptosis in lung cancer cells, respectively. Western blot assay was employed to detect the protein levels of β-catenin and Wnt5a. Moreover, quantitative real-time polymerase chain reaction (qRT-PCR) was used to examine the expression level of prostate cancer-associated transcript 6 (PCAT6) and miR-326 in lung cancer tissues and cells. The target interaction between miR-326 and PCAT6 or Wnt5a was predicted by bioinformatics analysis and verified by the dual-luciferase reporter gene assay. Sevoflurane inhibited the abilities on viability, proliferation, invasion, and activation of Wnt/β-catenin signaling, but promoted apoptosis of H446 and H1975 cells in a dose-dependent manner. The expression of PCAT6 was increased in lung cancer tissues and cells, except for that of miR-326. Besides, sevoflurane could lead to expressed limitation of PCAT6 or improvement of miR-326. This process presented a stepwise manner. Up-regulation of PCAT6 restored the suppression of sevoflurane on abilities of proliferation, invasion, rather than apoptosis, and re-activated the Wnt5a/β-catenin signaling in cells. Moreover, the putative binding sites between miR-326 and PCTA6 or Wnt5a were predicted by starBase v2.0 software online. PCAT6 suppressing effects on cells could be reversed by pre-treatment with miR-326 vector. The promotion of Wnt5a inverted effects led from miR-326 or sevoflurane. Our study indicated that sevoflurane inhibited the proliferation, and invasion, but enhanced the apoptosis in lung cancer cells by regulating the lncRNA PCAT6/miR-326/Wnt5a/β-catenin axis.
Highlights
Sevoflurane was one of the frequently-used anesthetics in tumor resection
Compared with the untreated group, the addition of sevoflurane greatly reduced the viability of H446 and H1975 cells in a dose- and time- dependent manner (Figure 1A-B, P < 0.05); Taken together, these data indicated that sevoflurane significantly suppressed the viability of lung cancer cells
The results of the apoptosis assay demonstrated that the apoptotic rate was remarkably increased in H446 and H1975 cells exposed to sevoflurane compared with that in the untreated group (Figure 1F, P < 0.05)
Summary
Sevoflurane was one of the frequently-used anesthetics in tumor resection. Related studies have shown that Sevoflurane’s inhibitory effect on cancer cells has been confirmed in a variety of tumors including lung cancer [1-3]. Studies have shown that lncRNA PCAT6 is up-regulated in lung cancer tissues and cells and is associated with tumor progression [15, 16]. Whether sevoflurane can regulate PCAT6 expression in lung cancer, and affect the malignant biological behavior of tumor cells has not been reported. Another study investigated by Wang et al, discovered downregulation of miR-326 in lung cancer cells, further research indicated that upregulation of miR-326 suppressed proliferation, invasion, migration and induced cell apoptosis, cycle arrest of lung cancer in vitro by downregulating Specificity protein 1 transcription factors and inactivation of JAK2/STAT3 and PI3K/AKT signaling pathways [21]. This study was designed to better understand the molecular mechanism of sevoflurane inhibiting lung cancer progression, and determining relationships among PCAT6, miR-326, and the Wnt/β-catenin pathway
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