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Sevoflurane and Desflurane Exposure Enhanced Cell Proliferation

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Sevoflurane and Desflurane Exposure Enhanced Cell Proliferation International Journal of Molecular Sciences Article Sevoflurane and Desflurane Exposure Enhanced Cell Proliferation and Migration in Ovarian Cancer Cells via miR-210 and miR-138 Downregulation Masashi Ishikawa 1,2 , Masae Iwasaki 1,2, Hailin Zhao 2, Junichi Saito 2,3, Cong Hu 2 , Qizhe Sun 2, Atsuhiro Sakamoto 1 and Daqing Ma 2,* 1 Department of Anesthesiology and Pain Medicine, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8603, Japan; [email protected] (M.I.); [email protected] (M.I.); [email protected] (A.S.) 2 Division of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea & Westminster Hospital, London SW10 9NH, UK; [email protected] (H.Z.); [email protected] (J.S.); [email protected] (C.H.); [email protected] (Q.S.) 3 Department of Anesthesiology, Graduate School of Medicine, Hirosaki University, Hirosaki, Aomori 036-8562, Japan * Correspondence: [email protected] Abstract: Inhalational anaesthetics were previously reported to promote ovarian cancer malignancy, but underlying mechanisms remain unclear. The present study aims to investigate the role of sevoflurane- or desflurane-induced microRNA (miRNA) changes on ovarian cancer cell behaviour. The cultured SKOV3 cells were exposed to 3.6% sevoflurane or 10.3% desflurane for 2 h. Expression of miR-138, -210 and -335 was determined with qRT-PCR. Cell proliferation and migration were assessed Citation: Ishikawa, M.; Iwasaki, M.; with wound healing assay, Ki67 staining and Cell Counting Kit-8 (CCK8) assay with or without Zhao, H.; Saito, J.; Hu, C.; Sun, Q.; mimic miR-138/-210 transfections. The miRNA downstream effector, hypoxia inducible factor-1α Sakamoto, A.; Ma, D. Sevoflurane α and Desflurane Exposure Enhanced (HIF-1 ), was also analysed with immunofluorescent staining. Sevoflurane or desflurane exposure to Cell Proliferation and Migration in cancer cells enhanced their proliferation and migration. miR-138 expression was suppressed by both Ovarian Cancer Cells via miR-210 sevoflurane and desflurane, while miR-210 expression was suppressed only by sevoflurane. miR-335 and miR-138 Downregulation. Int. J. expression was not changed by either sevoflurane or desflurane exposure. The administration of Mol. Sci. 2021, 22, 1826. https:// mimic miR-138 or -210 reduced the promoting effects of sevoflurane and desflurane on cancer cell doi.org/10.3390/ijms22041826 proliferation and migration, in line with the HIF-1α expression changes. These data indicated that inhalational agents sevoflurane and desflurane enhanced ovarian cancer cell malignancy via miRNA Academic Editor: Luba Hunáková deactivation and HIF-1α. The translational value of this work needs further study. Received: 22 January 2021 Keywords: microRNA; sevoflurane; desflurane; hypoxia inducible factor-1α; ovarian cancer Accepted: 8 February 2021 Published: 12 February 2021 Publisher’s Note: MDPI stays neutral 1. Introduction with regard to jurisdictional claims in published maps and institutional affil- Ovarian cancer is the eighth most common cancer among women patients with poor iations. prognosis [1,2]. The 10 year progression-free survival of ovarian cancer remains at 15%, although surgery and related treatment have improved [3]. Epithelial ovarian cancer consists of 90% of ovarian cancer cases [4]. Surgical removal of cancer mass is the first- line therapy for the solid primary cancer including ovarian cancer. Postoperative cancer reoccurrence is one of the key factors leading to poor survival [5], which has been reported Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. to be related to many risk factors including surgical trauma/stress [6] and anaesthetic This article is an open access article use [7]. Clinical data suggested that inhalational anaesthetics may affect cancer progression distributed under the terms and and worsen long-term outcomes in patients with cancer surgery [8–11]. Our previous study conditions of the Creative Commons showed that sevoflurane and desflurane exposure increased cell proliferation and migration Attribution (CC BY) license (https:// via metastasis-related gene changes in vitro in an ovarian cancer cell line [12]. In contrast, creativecommons.org/licenses/by/ intravenous anaesthetics including propofol and midazolam were reported to inhibit 4.0/). cancer cell growth [13,14]. Isoflurane enhanced cell proliferation and migration via hypoxia Int. J. Mol. Sci. 2021, 22, 1826. https://doi.org/10.3390/ijms22041826 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 15 Int. J. Mol. Sci. 2021, 22, 1826 migration via metastasis-related gene changes in vitro in an ovarian cancer cell line2 of [12]. 15 In contrast, intravenous anaesthetics including propofol and midazolam were reported to inhibit cancer cell growth [13,14]. Isoflurane enhanced cell proliferation and migration via induciblehypoxia factor-1inducibleα (HIF-1 factor-1α)α and (HIF-1 matrixα) and metalloproteinase matrix metalloproteinase 9 (MMP9) in9 (MMP9) prostate in [13 prostate] and ovarian[13] and cancer ovarian cells cancer [12]. cells It is well[12]. knownIt is well that known HIF-1 thatα has HIF-1 an essentialα has an roleessential in cancer role in cellcancer proliferation cell proliferation and invasion and invasion [15,16] whilst [15,16] MMP9 whilst isMMP9 crucial is incrucial tumour in tumour migration migration and progressionand progression [17]. [17]. MicroRNAsMicroRNAs (miRNAs) (miRNAs) are are noncoding noncoding short short nucleotides nucleotides that that affect affect cancer cancer cell cell biology biology viavia protein protein post-transcription. post-transcription. miRNAs miRNAs control contro thel normalthe normal cell and cellcancer and cancer cell biology cell biology [18]. Interestingly,[18]. Interestingly, miR-138 miR-138 [19] and [19] -210 and [20 -210] regulate [20] regulate HIF genes, HIF while genes, miR-335 while miR-335 was reported was re- toported control to MMP9 control in MMP9 glioma in [21 glioma] and has[21] beenand has suggested been suggested to play a to role play in breasta role in cancer breast progressioncancer progression [22,23]. [22,23]. However, However, the potential the pote rolential of role these of these miRNAs miRNAs on ovarian on ovarian cancer can- developmentcer development and progressionand progression is limited is limited and, and, furthermore, furthermore, it remains it remains largely largely unknown unknown whetherwhether inhalational inhalational anaesthetics anaesthetics can can affect affect ovarian ovarian cancer cancer cell cell malignancy malignancy via via miRNA miRNA expressionexpression changes. changes. The The present present study, study, therefore, therefore, aims aims to to investigate investigate the the potential potential role role of of thethe miRNAs miRNAs miR-138, miR-138, -210 -210 and and -335 -335 and and their their downstream downstream effector, effector, HIF-1 HIF-1α andα MMP9,and MMP9, as wellas well as changes as changes induced induced by sevoflurane by sevoflurane or desflurane, or desflurane, which which are commonly are commonly used clinically used clin- onically ovarian on ovarian cancer cell cancer biology cell biology and malignancy. and malignancy. 2.2. Results Results 2.1. Sevoflurane and Desflurane Increased SKOV3 Cell Proliferation and Migration 2.1. Sevoflurane and Desflurane Increased SKOV3 Cell Proliferation and Migration 2.1.1. Cell Migration 2.1.1. Cell Migration First, the changes in cell proliferation and migration after anaesthetic exposure were evaluatedFirst, with the achanges wound in healing cell proliferation assay, Cell and Counting migration Kit-8 after (CCK8) anaesthetic assay andexposure Ki67 im-were munofluorescentevaluated with staining.a wound Sevoflurane healing assay, or desflurane Cell Counting exposure Kit-8 exhibited (CCK8) assay procancer and Ki67 effects im- inmunofluorescent SKOV3 cells. In staining. the wound Sevoflurane healing assay,or desf sevofluranelurane exposure and exhibited desflurane procancer significantly effects increasedin SKOV3 the cells. “wound” In the gap wound closure healing ratio assay, at 4 h (sevofluranesevoflurane 16.82and desflurane± 1.01, p < significantly 0.001; desflu- in- ranecreased 14.68 the± 1.61,“wound”p = 0.036 gap closure vs. control ratio 12.34 at 4 h± (sevoflurane1.68) and at 16.82 8 h (sevoflurane ± 1.01, p < 0.001;43.59 desflurane± 2.09, p <14.68 0.001 ±; 1.61, desflurane p = 0.036 43.01 vs. ±control1.30, p 12.34< 0.001 ± 1.68) vs. control and at 34.368 h (sevoflurane± 1.86) after 43.59 gas exposure± 2.09, p < com- 0.001; pareddesflurane to the control 43.01 ± group. 1.30, p There< 0.001 were vs. control no differences 34.36 ±between 1.86) after sevoflurane gas exposure and compared desflurane to (nthe= 6) control (Figure group.1a,b). There were no differences between sevoflurane and desflurane (n = 6) (Figure 1a,b). (a) (b) Figure 1. Cont. Int. J. Mol. Sci. 2021, 22, 1826 3 of 15 Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 3 of 15 (c) (d) (e) (f) (g) (h) Figure 1. The changes of cell viability and miRNAs after inhalational anaesthesia. (a) SKOV3 cell migration analysis with Figure 1. The changes of cell viability and miRNAs after inhalational anaesthesia. (a) SKOV3 cell migration analysis with wound healing assay after 2 h of inhalational anaesthesia: control (left), 3.6% sevoflurane (middle) and 10.4% desflurane wound healing assay after 2 h of inhalational anaesthesia: control (left), 3.6% sevoflurane (middle) and 10.4% desflurane (right), at 0 h later (upper), 24 h later (middle) and 48 h later (bottom). The microscopic images at 0, 24 and 48 h after general(right), anaesthesia. at 0 h later ( (upper),b) The comparison 24 h later (middle) between and anaesthetics 48 h later (bottom). in percenta Thege microscopic of gap closure images by wound at 0, 24 andhealing 48 h assay. after general (c) Int. J. Mol. Sci. 2021, 22, 1826 4 of 15 anaesthesia. (b) The comparison between anaesthetics in percentage of gap closure by wound healing assay.
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