肝细胞癌患者术中使用右美托咪定：对预后影响及机制分析

摘要/Abstract

摘要： 目的：探讨术中使用右美托咪定（DEX）对肝细胞癌（HCC）患者预后的影响,并研究其潜在机制。
方法：回顾性分析安徽医科大学附属六安医院2019年1月至2023年1月期间144例行肝切除术的HCC患者临床资料。通过Cox回归模型单因素和多因素分析确定DEX与HCC患者预后关联。通过生物信息学、蛋白质印迹试验、免疫组织化学（IHC）及多种在线数据库解析DEX促癌机制。
结果：144例患者平均随访时间32.9个月（范围6~48个月）,其中复发63例,死亡57例。术中使用DEX患者的无复发生存率（P<0.05）和总生存率（P<0.05）低于不使用DEX患者,多因素分析发现术中使用DEX是HCC患者复发和死亡的独立危险因素（P<0.05）。基于GSE188867数据集和TCGA-HCC队列鉴定出6个DEX调控基因,分别为CCDC34、E2F8、CENPH、CTHRC1、CENPW和E2F1。蛋白质印迹试验及IHC结果显示E2F8和E2F1在HCC组织中表达增高（P<0.05）且能被DEX快速上调（P<0.05）。计算机分子对接模型显示:DEX能稳定与E2F8中ARC-267和LYS-264残基形成氢键,结合能为-6.7 kcal/mol;能与E2F1中TYR-746残基形成氢键,结合能为-5.0 kcal/mol。基因集富集分析结果强调DEX能快速激活细胞周期信号（P<0.05）。
结论：术中DEX全身给药介导HCC患者更差预后,这过程涉及DEX能快速激活细胞周期信号,包括可能直接与E2F8和E2F1结合,应谨慎对HCC患者使用DEX。

关键词: 肝细胞癌, 右美托咪定, 预后, 蛋白质印迹试验, 免疫组织化学, 分子对接

Abstract: Objective: The aim is to investigate the impact of intraoperative dexmedetomidine (DEX) on the prognosis of patients with hepatocellular carcinoma (HCC) and to investigate the underlying mechanisms.
Methods: Retrospective analysis of clinical data of 144 HCC patients undergoing hepatectomy in Lu’an Hospital of Anhui Medical University from January 2019 to January 2023. The association between DEX and the prognosis of HCC patients was determined by univariate and multifactorial Cox risk regression. To resolve DEX cancer-promoting mechanisms by bioinformatics, western blotting, immunohistochemistry and various online databases.
Results: 144 patients were followed up for 6-48 months with a mean follow-up time of 32.9 months, including 63 recurred and 57 patients died. Patients with intraoperative DEX had lower recurrence-free survival (P<0.05) and overall survival (P<0.05) than those without DEX. Univariate combined with multifactorial Cox risk regression analysis identified intraoperative DEX use as an independent risk factor for recurrence and death in HCC patients (P<0.05). Six DEX-regulated genes were identified based on the GSE188867 dataset and the TCGA-HCC cohort: CCDC34, E2F8, CENPH, CTHRC1, CENPW, and E2F1. Western blotting and IHC results showed that E2F8 and E2F1 expression was increased in HCC tissues (P<0.05) and was rapidly upregulated by DEX (P<0.05). Computerized molecular docking models showed that DEX stably formed hydrogen bonds with ARC-267 and LYS-264 residues in E2F8 at a binding energy of -6.7 kcal/mol and with TYR-746 residues in E2F1 at an energy of -5.0 kcal/mol. The results of gene set enrichment analysis (GSEA) highlighted that DEX could rapidly activate cell cycle signaling (P<0.05).
Conclusion: Intraoperative systemic administration of DEX mediates a worse prognosis in patients with HCC, a process that involves DEX's rapid activation of cell cycle signaling, including possible direct binding to E2F8 and E2F1. DEX should be used with caution in patients with HCC.

Key words: Hepatocellular carcinoma, Dexmedetomidine, Prognosis, Western blotting, Immunohistochemistry, Molecular docking

邵超彦, 马中林, 吴伟, 吴松, 郑立东. 肝细胞癌患者术中使用右美托咪定：对预后影响及机制分析[J]. 肝癌电子杂志, 2024, 11(3): 42-53.

Shao Chaoyan, Ma Zhonglin, Wu Wei, Wu Song, Zheng Lidong. Intraoperative use of dexmedetomidine in patients with hepatocellular carcinoma: prognostic impact and mechanism analysis[J]. Electronic Journal of Liver Tumor, 2024, 11(3): 42-53.

参考文献

[1] SUNG H, FERLAY J, SIEGEL R L, et al.Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2021, 71(3): 209-249.
[2] YANG C, WANG H, LIU J, et al.Pre- to postoperative alpha-fetoprotein ratio-based nomogram to predict tumor recurrence in patients with hepatocellular carcinoma[J]. Front Oncol, 2023, 13: 1134933.
[3] Cata JP.Research in perioperative care of the cancer patient: opportunities and challenges[J]. Curr Oncol, 2023, 30(1): 1186-1195.
[4] TAVARE A N, PERRY N J, BENZONANA L L, et al.Cancer recurrence after surgery: direct and indirect effects of anesthetic agents[J]. Int J Cancer, 2012, 130(6): 1237-1250.
[5] BRUZZONE A, PIÑERO C P, ROJAS P, et al. α(2)-Adrenoceptors enhance cell proliferation and mammary tumor growth acting through both the stroma and the tumor cells[J]. Curr Cancer Drug Targets, 2011, 1(6): 763-774.
[6] LIU Y, TENG X, YAN Y, et al.Dexmedetomidine promotes necroptosis by upregulating PARP1 in non-small cell lung cancer[J]. Biotechnol Genet Eng Rev, 2023, 17: 1-21.
[7] CHI M, SHI X, HUO X, et al.Dexmedetomidine promotes breast cancer cell migration through Rab11-mediated secretion of exosomal TMPRSS2[J]. Ann Transl Med, 2020, 8(8): 531.
[8] CHEN H Y, LI G H, TAN G C, et al.Dexmedetomidine enhances hypoxia-induced cancer cell progression[J]. Exp Ther Med, 2019, 18(6): 4820-4828.
[9] LAVON H, MATZNER P, BENBENISHTY A, et al.Dexmedetomidine promotes metastasis in rodent models of breast, lung, and colon cancers[J]. Br J Anaesth, 2018, 120(1): 188-196.
[10] WANG C, DATOO T, ZHAO H, et al.Midazolam and Dexmedetomidine affect neuroglioma and lung carcinoma cell biology in vitro and in vivo[J]. Anesthesiology, 2018, 129(5): 1000-1014.
[11] SU X, FAN Y, YANG L, et al.Dexmedetomidine expands monocytic myeloid-derived suppressor cells and promotes tumour metastasis after lung cancer surgery[J]. J Transl Med, 2018, 16(1): 347.
[12] CATA J P, SINGH V, LEE B M, et al.Intraoperative use of dexmedetomidine is associated with decreased overall survival after lung cancer surgery[J]. J Anaesthesiol Clin Pharmacol, 2017, 33(3): 317-323.
[13] CHEN P, LUO X, DAI G, et al.Dexmedetomidine promotes the progression of hepatocellular carcinoma through hepatic stellate cell activation[J]. Exp Mol Med, 2020, 52(7): 1062-1074.
[14] WANG X, LI Y R, SHI Y, et al.Dexmedetomidine ameliorates liver injury and maintains liver function in patients with hepatocellular carcinoma after hepatectomy: a retrospective cohort study with propensity score matching[J]. Front Oncol, 2023, 13: 1108559.
[15] 冯鑫,刘畅,钟殿胜,等.免疫组化染色评分对EGFR突变检测的影响[J].中国肺癌杂志, 2015, 18(12): 740-744
[16] 袁临天,马利沙,刘润园,等.计算机模拟亚甲基蓝与牙龈卟啉单胞菌部分蛋白的分子对接[J].北京大学学报(医学版), 2022, 54(1): 23-30.
[17] 李志鹏,王飞,李玉娟,等.右美托咪啶对脑神经保护机制的研究进展[J].医学综述, 2014(21): 3947-3949.
[18] 王灿灿,孙倩倩,余健.右美托咪定对老年肝癌病人术后炎症及认知功能的影响[J]. 蚌埠医学院学报, 2021, 46(10): 1396-1399.
[19] PENG L, LI B, DU T, et al.Astrocytic transactivation by alpha2A-adrenergic and 5-HT2B serotonergic signaling[J]. Neurochem Int. 2010, 57(4): 421-431.
[20] LIN Z, QU S, PENG W, et al.Up-Regulated CCDC34 Contributes to the Proliferation and Metastasis of Hepatocellular Carcinoma[J]. Onco Targets Ther, 2020, 13: 51-60.
[21] ZHOU M, CHEN X, BAI H, et al.RABL2A-CCDC34 axis promotes sorafenib resistance in hepatocellular carcinoma[J]. DNA Cell Biol, 2021, 40(11): 1418-1427.
[22] LÜ Y, ZHANG J, LI L, et al. Carcinogenesis effects of E2F transcription factor 8 (E2F8) in hepatocellular carcinoma outcomes: an integrated bioinformatic report[J]. Biosci Rep, 2020, 40(2): BSR20193212.
[23] LU G, HOU H, LU X, et al.CENP-H regulates the cell growth of human hepatocellular carcinoma cells through the mitochondrial apoptotic pathway[J]. Oncol Rep, 2017, 37(6): 3484-3492.
[24] WANG Y, LEE M, YU G, et al.CTHRC1 activates pro-tumorigenic signaling pathways in hepatocellular carcinoma[J]. Oncotarget, 2017, 8(62): 105238-105250.
[25] ZHOU Y, CHAI H, GUO L, et al.Knockdown of CENPW inhibits hepatocellular carcinoma progression by inactivating E2F signaling[J]. Technol Cancer Res Treat, 2021, 20: 15330338211007253.
[26] DONG R, ZHANG D, HAN B, et al.DTL is a Novel downstream gene of E2F1 that promotes the progression of hepatocellular carcinoma[J]. Curr Cancer Drug Targets, 2023, 23(10): 817-828.
[27] ZHAO Y, KONG G Y, PEI W M, et al.Dexmedetomidine alleviates hepatic injury via the inhibition of oxidative stress and activation of the Nrf2/HO-1 signaling pathway[J]. Eur Cytokine Netw, 2019, 30(3): 88-97.
[28] GARCÍA-PRAS E, FERNÁNDEZ-IGLESIAS A, GRACIA-SANCHO J, et al. Cell death in hepatocellular carcinoma: pathogenesis and therapeutic opportunities[J]. Cancers (Basel), 2021, 14(1): 48.
[29] CAI Q, LIU G, HUANG L, et al.The role of dexmedetomidine in tumor-progressive factors in the perioperative period and cancer recurrence: a narrative review[J]. Drug Des Devel Ther, 2022, 16: 2161-2175.
[30] HU J, GONG C, XIAO X, et al.Association between intraoperative dexmedetomidine and all-cause mortality and recurrence after laparoscopic resection of colorectal cancer: Follow-up analysis of a previous randomized controlled trial[J]. Front Oncol, 2023, 13: 906514.
[31] ZHANG P, HE H, BAI Y, et al.Dexmedetomidine suppresses the progression of esophageal cancer via miR-143-3p/epidermal growth factor receptor pathway substrate 8 axis[J]. Anticancer Drugs, 2020, 31(7): 693-701.
[32] COFFEY J C, WANG J H, SMITH M J, et al.Excisional surgery for cancer cure: therapy at a cost[J]. Lancet Oncol, 2003, 4(12): 760-768.
[33] KASSAB A, GUPTA I, AL MOUSTAFA AE.Role of E2F transcription factor in oral cancer: recent insight and advancements[J]. Semin Cancer Biol, 2023, 92: 28-41.