Inhibition of SUMO2/3 antagonizes isoflurane‑induced cancer‑promoting effect in hepatocellular carcinoma Hep3B cells

Wang,Peng; Xue,Na; Zhang,Chunyan; Shan,Shimin; Jiang,Zhongmin; Wu,Wenhan; Liu,Xiaozhi

doi:10.3892/ol.2021.12535

Inhibition of SUMO2/3 antagonizes isoflurane‑induced cancer‑promoting effect in hepatocellular carcinoma Hep3B cells

Authors:
- Peng Wang
- Na Xue
- Chunyan Zhang
- Shimin Shan
- Zhongmin Jiang
- Wenhan Wu
- Xiaozhi Liu
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Affiliations: Department of Anesthesiology, The Fifth Central Hospital of Tianjin, Tianjin 300450, P.R. China, Tianjin Key Laboratory of Epigenetics for Organ Development in Preterm Infants, The Fifth Central Hospital of Tianjin, Tianjin 300450, P.R. China, Department of Pharmacy, Binhai New Area Hospital of Traditional Chinese Medicine, Tianjin 300450, P.R. China
Published online on: February 10, 2021 https://doi.org/10.3892/ol.2021.12535
Article Number: 274
Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Surgery for patients with complicated liver cancer often results in a long exposure to anesthesia with an increase in side effects. Continued long‑term exposure to isoflurane may promote liver cancer progression. Small ubiquitin‑like modifier (SUMO) 2 and 3, also known as SUMO2/3, conjugates to substrate proteins when cells undergo acute stress. However, whether or not SUMO2/3 is involved in isoflurane‑mediated liver cancer progression is unknown. In the present study, hepatocellular carcinoma (HCC) cells were exposed to 2% isoflurane for 12 h, followed by 36 h of drug withdrawal, and the formation of SUMO2/3 conjugates and cancer behavioral characteristics were studied. The results demonstrated that the formation of SUMO2/3 conjugates was significantly increased following HCC cells being exposed to isoflurane for 0.5 h, and continued to increase for 48 h, even after the drug had been withdrawn. Furthermore, isoflurane‑exposed HCC cells exhibited increased proliferation and invasion activity during the subsequent observation period. SUMO specific protease 3 (SENP3), which inhibits the binding of SUMO2/3 to its target proteins, was overexpressed and it was discovered that isoflurane‑induced SUMOylation was significantly inhibited, and accordingly, the proliferation and invasion abilities of HCC cells were decreased to a certain extent. These findings indicated that SUMO2/3 is involved in the progression of HCC cells, at least in the Hep3B cell line, induced by the anesthetic isoflurane, and that inhibition of SUMO2/3 may antagonize the response. These results provided a novel target for decreasing the adverse reactions occurring in patients with HCC during anesthesia, particularly those who are exposed to isoflurane for long periods of time.

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1	Chao J, Zhao S and Sun H: Dedifferentiation of hepatocellular carcinoma: Molecular mechanisms and therapeutic implications. Am J Transl Res. 12:2099–2109. 2020.PubMed/NCBI
2	Garin E, Palard X and Rolland Y: Personalised dosimetry in radioembolisation for HCC: Impact on clinical outcome and on trial design. Cancers (Basel). 12:15572020. View Article : Google Scholar
3	Tellapuri S, Sutphin PD, Beg MS, Singal AG and Kalva SP: Staging systems of hepatocellular carcinoma: A review. Indian J Gastroenterol. 37:481–491. 2018. View Article : Google Scholar : PubMed/NCBI
4	Glantzounis GK, Paliouras A, Stylianidi MC, Milionis H, Tzimas P, Roukos D, Pentheroudakis G and Felekouras E: The role of liver resection in the management of intermediate and advanced stage hepatocellular carcinoma. A systematic review. Eur J Surg Oncol. 44:195–208. 2018. View Article : Google Scholar : PubMed/NCBI
5	Lai HC, Lee MS, Lin C, Lin KT, Huang YH, Wong CS, Chan SM and Wu ZF: Propofol-based total intravenous anaesthesia is associated with better survival than desflurane anaesthesia in hepatectomy for hepatocellular carcinoma: A retrospective cohort study. Br J Anaesth. 123:151–160. 2019. View Article : Google Scholar : PubMed/NCBI
6	Huang H, Benzonana LL, Zhao H, Watts HR, Perry NJ, Bevan C, Brown R and Ma D: Prostate cancer cell malignancy via modulation of HIF-1α pathway with isoflurane and propofol alone and in combination. Br J Cancer. 111:1338–1349. 2014. View Article : Google Scholar : PubMed/NCBI
7	Zhang W and Shao X: Isoflurane promotes non-small cell lung cancer malignancy by activating the Akt-mammalian target of rapamycin (mTOR) signaling pathway. Med Sci Monit. 22:4644–4650. 2016. View Article : Google Scholar : PubMed/NCBI
8	Meier A, Gross ETE, Schilling JM, Seelige R, Jung Y, Santosa E, Searles S, Lin T, Tu XM, Patel HH and Bui JD: Isoflurane impacts murine melanoma growth in a sex-specific, immune-dependent manner: A brief report. Anesth Analg. 126:1910–1913. 2018. View Article : Google Scholar : PubMed/NCBI
9	Hu J, Hu J, Jiao H and Li Q: Anesthetic effects of isoflurane and the molecular mechanism underlying isoflurane-inhibited aggressiveness of hepatic carcinoma. Mol Med Rep. 18:184–192. 2018.PubMed/NCBI
10	Seeler JS and Dejean A: SUMO and the robustness of cancer. Nat Rev Cancer. 17:184–197. 2017. View Article : Google Scholar : PubMed/NCBI
11	Flotho A and Melchior F: Sumoylation: A regulatory protein modification in health and disease. Annu Rev Biochem. 82:357–385. 2013. View Article : Google Scholar : PubMed/NCBI
12	Geiss-Friedlander R and Melchior F: Concepts in sumoylation: A decade on. Nat Rev Mol Cell Biol. 8:947–956. 2007. View Article : Google Scholar : PubMed/NCBI
13	Henley JM, Craig TJ and Wilkinson KA: Neuronal SUMOylation: Mechanisms, physiology, and roles in neuronal dysfunction. Physiol Rev. 94:1249–1285. 2014. View Article : Google Scholar : PubMed/NCBI
14	Chang SC and Ding JL: Ubiquitination and SUMOylation in the chronic inflammatory tumor microenvironment. Biochim Biophys Acta Rev Cancer. 1870:165–175. 2018. View Article : Google Scholar : PubMed/NCBI
15	Qiu G, Jin Z, Chen X and Huang J: Interpretation of guidelines for the diagnosis and treatment of primary liver cancer (2019 edition) in China. Glob Health Med. 2:306–311. 2020. View Article : Google Scholar : PubMed/NCBI
16	Pang Y, Kartsonaki C, Turnbull I, Guo Y, Chen Y, Clarke R, Bian Z, Bragg F, Millwood IY, Yang L, et al: Adiposity in relation to risks of fatty liver, cirrhosis and liver cancer: A prospective study of 0.5 million Chinese adults. Sci Rep. 9:7852019. View Article : Google Scholar : PubMed/NCBI
17	McCarty TR, Echouffo-Tcheugui JB, Lange A, Haque L and Njei B: Impact of bariatric surgery on outcomes of patients with nonalcoholic fatty liver disease: A nationwide inpatient sample analysis, 2004–2012. Surg Obes Relat Dis. 14:74–80. 2018. View Article : Google Scholar : PubMed/NCBI
18	Pinto RZ, Maher CG, Ferreira ML, Ferreira PH, Hancock M, Oliveira VC, McLachlan AJ and Koes B: Drugs for relief of pain in patients with sciatica: Systematic review and meta-analysis. BMJ. 344:e4972012. View Article : Google Scholar : PubMed/NCBI
19	Komaki Y, Komaki F, Micic D, Ido A and Sakuraba A: Risk of colorectal cancer in chronic liver diseases: A systematic review and meta-analysis. Gastrointest Endosc. 86:93–104.e5. 2017. View Article : Google Scholar : PubMed/NCBI
20	Antipass A, Austin A, Awad S, Hughes D and Idris I: Evaluation of liver function tests and risk score assessment to screen patients for significant liver disease prior to bariatric and metabolic surgery. Obes Surg. 30:2840–2843. 2020. View Article : Google Scholar : PubMed/NCBI
21	Ikuta S, Tanimura K, Yasui C, Aihara T, Yoshie H, Iida H, Beppu N, Kurimoto A, Yanagi H, Mitsunobu M and Yamanaka N: Chronic liver disease increases the risk of linezolid-related thrombocytopenia in methicillin-resistant Staphylococcus aureus-infected patients after digestive surgery. J Infect Chemother. 17:388–391. 2011. View Article : Google Scholar : PubMed/NCBI
22	Esser T, Keilhoff G and Ebmeyer U: Anesthesia specific differences in a cardio-pulmonary resuscitation rat model; halothane versus sevoflurane. Brain Res. 1652:144–150. 2016. View Article : Google Scholar : PubMed/NCBI
23	Dugan CM, Fullerton AM, Roth RA and Ganey PE: Natural killer cells mediate severe liver injury in a murine model of halothane hepatitis. Toxicol Sci. 120:507–518. 2011. View Article : Google Scholar : PubMed/NCBI
24	Yin H, Cheng L, Langenbach R and Ju C: Prostaglandin I(2) and E(2) mediate the protective effects of cyclooxygenase-2 in a mouse model of immune-mediated liver injury. Hepatology. 45:159–169. 2007. View Article : Google Scholar : PubMed/NCBI
25	Zhu Y, Xiao X, Li G, Bu J, Zhou W and Zhou S: Isoflurane anesthesia induces liver injury by regulating the expression of insulin-like growth factor 1. Exp Ther Med. 13:1608–1613. 2017. View Article : Google Scholar : PubMed/NCBI
26	Feng D, Wang Y, Xu Y, Luo Q, Lan B and Xu L: Interleukin 10 deficiency exacerbates halothane induced liver injury by increasing interleukin 8 expression and neutrophil infiltration. Biochem Pharmacol. 77:277–284. 2009. View Article : Google Scholar : PubMed/NCBI
27	Delgado TC, Lopitz-Otsoa F and Martínez-Chantar ML: Post-translational modifiers of liver kinase B1/serine/threonine kinase 11 in hepatocellular carcinoma. J Hepatocell Carcinoma. 6:85–91. 2019. View Article : Google Scholar : PubMed/NCBI
28	Jin ZL, Pei H, Xu YH, Yu J and Deng T: The SUMO-specific protease SENP5 controls DNA damage response and promotes tumorigenesis in hepatocellular carcinoma. Eur Rev Med Pharmacol Sci. 20:3566–3573. 2016.PubMed/NCBI
29	Kim DH, Kwon S, Byun S, Xiao Z, Park S, Wu SY, Chiang CM, Kemper B and Kemper JK: Critical role of RanBP2-mediated SUMOylation of small heterodimer partner in maintaining bile acid homeostasis. Nat Commun. 7:121792016. View Article : Google Scholar : PubMed/NCBI
30	Xia W, Tian H, Cai X, Kong H, Fu W, Xing W, Wang Y, Zou M, Hu Y and Xu D: Inhibition of SUMO-specific protease 1 induces apoptosis of astroglioma cells by regulating NF-κB/Akt pathways. Gene. 595:175–179. 2016. View Article : Google Scholar : PubMed/NCBI
31	Lin CH, Liu SY and Lee EH: SUMO modification of Akt regulates global SUMOylation and substrate SUMOylation specificity through Akt phosphorylation of Ubc9 and SUMO1. Oncogene. 35:595–607. 2016. View Article : Google Scholar : PubMed/NCBI
32	Risso G, Pelisch F, Pozzi B, Mammi P, Blaustein M, Colman-Lerner A and Srebrow A: Modification of Akt by SUMO conjugation regulates alternative splicing and cell cycle. Cell Cycle. 12:3165–3174. 2013. View Article : Google Scholar : PubMed/NCBI
33	Carbia-Nagashima A, Gerez J, Perez-Castro C, Paez-Pereda M, Silberstein S, Stalla GK, Holsboer F and Arzt E: RSUME, a small RWD-containing protein, enhances SUMO conjugation and stabilizes HIF-1alpha during hypoxia. Cell. 131:309–323. 2007. View Article : Google Scholar : PubMed/NCBI
34	Wei F, Schöler HR and Atchison ML: Sumoylation of Oct4 enhances its stability, DNA binding, and transactivation. J Biol Chem. 282:21551–21560. 2007. View Article : Google Scholar : PubMed/NCBI
35	Xu Y, Li J, Zuo Y, Deng J, Wang LS and Chen GQ: SUMO-specific protease 1 regulates the in vitro and in vivo growth of colon cancer cells with the upregulated expression of CDK inhibitors. Cancer Lett. 309:78–84. 2011. View Article : Google Scholar : PubMed/NCBI
36	Ge H, Du J, Xu J, Meng X, Tian J, Yang J and Liang H: SUMOylation of HSP27 by small ubiquitin-like modifier 2/3 promotes proliferation and invasion of hepatocellular carcinoma cells. Cancer Biol Ther. 18:552–559. 2017. View Article : Google Scholar : PubMed/NCBI
37	Knowles BB, Howe CC and Aden DP: Human hepatocellular carcinoma cell lines secrete the major plasma proteins and hepatitis B surface antigen. Science. 209:497–499. 1980. View Article : Google Scholar : PubMed/NCBI
38	Knasmuller S, Parzefall W, Sanyal R, Ecker S, Schwab C, Uhl M, Mersch-Sundermann V, Williamson G, Hietsch G, Langer T, et al: Use of metabolically competent human hepatoma cells for the detection of mutagens and antimutagens. Mutat Res. 402:185–202. 1998. View Article : Google Scholar : PubMed/NCBI
39	Qiu GH, Xie X, Xu F, Shi X, Wang Y and Deng L: Distinctive pharmacological differences between liver cancer cell lines HepG2 and Hep3B. Cytotechnology. 67:1–12. 2015. View Article : Google Scholar : PubMed/NCBI