{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T17:09:47Z","timestamp":1785431387477,"version":"3.56.0"},"reference-count":28,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T00:00:00Z","timestamp":1782777600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002462","name":"Chungnam National University","doi-asserted-by":"publisher","award":["CNU-2023-0592-01"],"award-info":[{"award-number":["CNU-2023-0592-01"]}],"id":[{"id":"10.13039\/501100002462","id-type":"DOI","asserted-by":"publisher"}]},{"award":["CNU-2023-0592-01"],"award-info":[{"award-number":["CNU-2023-0592-01"]}],"id":[{"id":"https:\/\/ror.org\/0227as991","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medicina"],"abstract":"<jats:p>Background and Objectives: Sevoflurane, a widely used inhalational anesthetic, is frequently administered during hepatocellular carcinoma (HCC) surgery, including hepatic resection and orthotopic liver transplantation. Because such procedures often require prolonged anesthetic exposure, the potential influence of sevoflurane on HCC cell behavior is of clinical interest. We aimed to evaluate the effects of sevoflurane on the proliferation and migration of HepG2 cells in vitro and on tumor growth in a xenograft mouse model in vivo, and to explore whether hypoxia-inducible factor-1\u03b1 (HIF-1\u03b1) might be involved in this process. Materials and Methods: For the in vitro experiments, HepG2 cells were exposed to room air (0%), 2%, or 4% sevoflurane. A scratch wound healing assay was used to assess cell migration, and the number of viable cells was quantified by hemocytometer counting on day 4 to estimate proliferation. For the in vivo experiments, BALB\/c nude mice bearing HepG2 xenografts were exposed to room air, 2% sevoflurane, or 4% sevoflurane for 3 h, three times weekly for 5 weeks. Tumor size and tumor weight were measured at the end of the exposure period. HIF-1\u03b1 protein levels in tumor tissue were measured by enzyme-linked immunosorbent assay (ELISA) in tumor lysates and normalized to total tumor protein as an exploratory mechanistic analysis. Given the small sample available for this endpoint, the analysis had limited sensitivity to detect modest differences. Results: When wound closure was quantified and pooled across the analyzable experiments, no statistically significant difference was detected among the room air, 2% sevoflurane, and 4% sevoflurane groups (day-2 closure 19.9 \u00b1 32.1%, 22.1 \u00b1 25.8%, and 22.3 \u00b1 28.8%, respectively; repeated-measures ANOVA p = 0.82), with variability dominated by between-experiment rather than treatment differences. In the proliferation assay, the number of viable HepG2 cells on day 4 was significantly lower in the 2% sevoflurane group (62.6 \u00b1 3.3 \u00d7 105) than in the room air group (68.5 \u00b1 4.2 \u00d7 105; p &lt; 0.05); the 4% sevoflurane group (66.0 \u00b1 3.2 \u00d7 105) showed an intermediate value that did not reach statistical significance. In the xenograft model, mean tumor size in the room air, 2% sevoflurane, and 4% sevoflurane groups was 7.1 \u00b1 1.9, 2.7 \u00b1 2.0, and 2.1 \u00b1 0.9 cm3, respectively (p = 0.041 for room air vs. 2% sevoflurane; p = 0.034 for room air vs. 4% sevoflurane). Tumor weight was likewise lower in the sevoflurane groups (room air, 7.88 \u00b1 2.2 g; 2% sevoflurane, 2.95 \u00b1 2.1 g; 4% sevoflurane, 2.3 \u00b1 1.6 g; p = 0.044 for room air vs. 2% sevoflurane; p = 0.067 for room air vs. 4% sevoflurane). No statistically significant differences in tumor HIF-1\u03b1 protein levels were observed among the three groups. Conclusions: In this exploratory study, sevoflurane exposure was associated with reduced HepG2 xenograft tumor growth in vivo, whereas its in vitro effects were more limited: a reduction in viable cell number was observed only at 2% sevoflurane, and an effect on cell migration could not be confirmed when analyzed across experiments. Tumor HIF-1\u03b1 levels did not differ significantly between groups, suggesting that other molecular pathways may be involved. Further mechanistic and clinical studies are warranted before any conclusions can be drawn about the relevance of these findings to the perioperative management of patients with HCC.<\/jats:p>","DOI":"10.3390\/medicina62071267","type":"journal-article","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T10:01:17Z","timestamp":1782813677000},"page":"1267","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Effects of Sevoflurane on the Proliferation, Migration, and Xenograft Growth of HepG2 Hepatocellular Carcinoma Cells: An Exploratory In Vitro and In Vivo Study"],"prefix":"10.3390","volume":"62","author":[{"given":"Kyong Sik","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Anesthesiology and Pain Medicine, Chungnam National University College of Medicine, Daejeon 35015, Republic of Korea"},{"name":"Department of Anesthesiology and Pain Medicine, Chungnam National University Sejong Hospital, Sejong 30099, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeojung","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Pain Medicine, Chungnam National University College of Medicine, Daejeon 35015, Republic of Korea"},{"name":"Department of Anesthesiology and Pain Medicine, Chungnam National University Sejong Hospital, Sejong 30099, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keuna","family":"Shin","sequence":"additional","affiliation":[{"name":"Research Institute for Medical Sciences, Chungnam National University, Daejeon 35015, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aung Soe","family":"Paing","sequence":"additional","affiliation":[{"name":"Department of Surgery, 1000-Bedded Naypyitaw General Hospital, Naypyitaw 15011, Myanmar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sujin","family":"Baek","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Pain Medicine, Chungnam National University College of Medicine, Daejeon 35015, Republic of Korea"},{"name":"Department of Anesthesiology and Pain Medicine, Chungnam National University Hospital, Daejeon 35015, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2468-9271","authenticated-orcid":false,"given":"Boohwi","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Pain Medicine, Chungnam National University College of Medicine, Daejeon 35015, Republic of Korea"},{"name":"Department of Anesthesiology and Pain Medicine, Chungnam National University Hospital, Daejeon 35015, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2356-8999","authenticated-orcid":false,"given":"Chaeseong","family":"Lim","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Pain Medicine, Chungnam National University College of Medicine, Daejeon 35015, Republic of Korea"},{"name":"Research Institute for Medical Sciences, Chungnam National University, Daejeon 35015, Republic of Korea"},{"name":"Department of Anesthesiology and Pain Medicine, Chungnam National University Hospital, Daejeon 35015, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"431","DOI":"10.4143\/crt.2019.139","article-title":"Prediction of Cancer Incidence and Mortality in Korea, 2019","volume":"51","author":"Jung","year":"2019","journal-title":"Cancer Res. Treat."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"S228","DOI":"10.3350\/cmh.2024.0824","article-title":"Hepatocellular Carcinoma: Updates on Epidemiology, Surveillance, Diagnosis and Treatment","volume":"31","author":"Hwang","year":"2024","journal-title":"Clin. Mol. Hepatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1016\/j.transproceed.2015.02.015","article-title":"Liver Transplantation in Korea: Past, Present, and Future","volume":"47","author":"Lee","year":"2015","journal-title":"Transplant. Proc."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1007\/s00540-019-02701-w","article-title":"Differential Effects of Sevoflurane on the Growth and Apoptosis of Human Cancer Cell Lines","volume":"34","author":"Hirai","year":"2020","journal-title":"J. Anesth."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1093\/bja\/aeu402","article-title":"Sevoflurane Promotes the Expansion of Glioma Stem Cells through Activation of Hypoxia-Inducible Factors In Vitro","volume":"114","author":"Shi","year":"2015","journal-title":"Br. J. Anaesth."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1424","DOI":"10.1038\/s41401-019-0221-0","article-title":"Sevoflurane Promotes Migration, Invasion, and Colony-Forming Ability of Human Glioblastoma Cells Possibly via Increasing the Expression of Cell Surface Protein 44","volume":"40","author":"Lai","year":"2019","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1016\/j.bja.2017.11.066","article-title":"Differential Effects of Sevoflurane on the Metastatic Potential and Chemosensitivity of Non-Small-Cell Lung Adenocarcinoma and Renal Cell Carcinoma In Vitro","volume":"120","author":"Ciechanowicz","year":"2018","journal-title":"Br. J. Anaesth."},{"key":"ref_8","first-page":"14","article-title":"Sevoflurane Inhibits Malignant Progression of Colorectal Cancer via Hsa_circ_0000231-Mediated miR-622","volume":"28","author":"Wang","year":"2021","journal-title":"J. Biol. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3523","DOI":"10.1007\/s10528-023-10607-2","article-title":"Sevoflurane Confers Protection Against the Malignant Phenotypes of Lung Cancer Cells via the microRNA-153-3p\/HIF1\u03b1\/KDM2B Axis","volume":"62","author":"Xiong","year":"2023","journal-title":"Biochem. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1016\/j.jclinane.2016.08.008","article-title":"Sevoflurane Attenuates Platelets Activation of Patients Undergoing Lung Cancer Surgery and Suppresses Platelets-Induced Invasion of Lung Cancer Cells","volume":"35","author":"Liang","year":"2016","journal-title":"J. Clin. Anesth."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Yun, S.-W., Kim, K.-S., Shin, K.-A., Park, H.-M., Lee, S.-Y., Shin, Y.-S., Paing, A.-S., Choi, S.-Y., and Lim, C.-S. (2023). Effect of Sevoflurane on the Proliferation of A549 Lung Cancer Cells. Medicina, 59.","DOI":"10.3390\/medicina59030613"},{"key":"ref_12","unstructured":"Lim, C., Ahn, J., Kim, K., and Yoon, S. (2023, January 13\u201317). Sevoflurane of 2 vol% Inhibits the Proliferation of HepG2 Cancer Cells In Vitro. Proceedings of the ANESTHESIOLOGY 2023, the American Society of Anesthesiologists (ASA) Annual Meeting, San Francisco, CA, USA."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1007\/BF00300234","article-title":"Determination of Subcutaneous Tumor Size in Athymic (Nude) Mice","volume":"24","author":"Tomayko","year":"1989","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Hoffmann, B., Lange, T., Labitzky, V., Riecken, K., Wree, A., Schumacher, U., and Wedemann, G. (2020). The Initial Engraftment of Tumor Cells Is Critical for the Future Growth Pattern: A Mathematical Study Based on Simulations and Animal Experiments. BMC Cancer, 20.","DOI":"10.1186\/s12885-020-07015-9"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/s13741-024-00367-x","article-title":"Sevoflurane Preconditioning in Living Liver Donation Is Associated with Better Initial Graft Function after Pediatric Transplantation: A Retrospective Study","volume":"13","author":"Dieu","year":"2024","journal-title":"Perioper. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1002\/fft2.44","article-title":"Guidelines for Cell Viability Assays","volume":"1","author":"Kamiloglu","year":"2020","journal-title":"Food Front."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.21037\/tcr-21-2404","article-title":"Effects of Long-Term Exposure to Sevoflurane on the Proliferation, Migration, Invasion, and Cisplatin Sensitivity of Esophageal Cancer","volume":"11","author":"Hu","year":"2022","journal-title":"Transl. Cancer Res."},{"key":"ref_18","first-page":"4255","article-title":"Effects of Sevoflurane on Breast Cancer Cell Function In Vitro","volume":"33","author":"Ecimovic","year":"2013","journal-title":"Anticancer Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"9636897221104447","DOI":"10.1177\/09636897221104447","article-title":"Sevoflurane Inhibits Metastasis in Hepatocellular Carcinoma by Inhibiting MiR-665-Induced Activation of the ERK\/MMP Pathway","volume":"31","author":"Zhu","year":"2022","journal-title":"Cell Transplant."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4451","DOI":"10.2147\/DDDT.S223581","article-title":"Sevoflurane Inhibits Proliferation and Invasion of Human Ovarian Cancer Cells by Regulating JNK and p38 MAPK Signaling Pathway","volume":"13","author":"Kang","year":"2019","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2057","DOI":"10.2147\/CMAR.S265356","article-title":"Sevoflurane Limits Glioma Progression by Regulating Cell Proliferation, Apoptosis, Migration, and Invasion via miR-218-5p\/DEK\/\u03b2-Catenin Axis in Glioma","volume":"13","author":"Qi","year":"2021","journal-title":"Cancer Manag. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.etap.2005.07.002","article-title":"The Merits of In Vitro versus In Vivo Modeling in Investigation of the Immune System","volume":"21","author":"Silliman","year":"2006","journal-title":"Environ. Toxicol. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1007\/s10555-007-9055-1","article-title":"Hypoxia in Cancer: Significance and Impact on Clinical Outcome","volume":"26","author":"Vaupel","year":"2007","journal-title":"Cancer Metastasis Rev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1038\/cdd.2008.21","article-title":"The Role of Hypoxia-Inducible Factors in Tumorigenesis","volume":"15","author":"Rankin","year":"2008","journal-title":"Cell Death Differ."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Zheng, S.-S., Chen, X.-X., Yin, X., and Zhang, B.-H. (2013). Prognostic Significance of HIF-1\u03b1 Expression in Hepatocellular Carcinoma: A Meta-Analysis. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0065753"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Kawamoto, M., Yamaji, T., Saito, K., Shirasago, Y., Satomura, K., Endo, T., Fukasawa, M., and Hanada, K. (2020). Identification of Characteristic Genomic Markers in Human Hepatoma HuH-7 and HuH7.5.1-8 Cell Lines. Front. Genet., 11.","DOI":"10.3389\/fgene.2020.546106"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Arzumanian, V.A., Kiseleva, O.I., and Poverennaya, E.V. (2021). The Curious Case of the HepG2 Cell Line: 40 Years of Expertise. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222313135"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1512","DOI":"10.1016\/j.humpath.2009.07.003","article-title":"Hep G2 Is a Hepatoblastoma-Derived Cell Line","volume":"40","author":"Cheung","year":"2009","journal-title":"Hum. Pathol."}],"container-title":["Medicina"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1648-9144\/62\/7\/1267\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T12:20:43Z","timestamp":1782822043000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1648-9144\/62\/7\/1267"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,30]]},"references-count":28,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["medicina62071267"],"URL":"https:\/\/doi.org\/10.3390\/medicina62071267","relation":{},"ISSN":["1648-9144"],"issn-type":[{"value":"1648-9144","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,30]]}}}