微小RNA-551a参与晚期肝细胞癌患者索拉非尼应答机制研究

Involvement of microRNA-551a in the response mechanism of sorafenib in patients with advanced hepatocellular carcinoma

目的:索拉非尼是晚期肝细胞癌(hepatocellular carcinoma,HCC)患者化学药物治疗的标准一线用药之一。本研究旨在探索微小RNA(microRNA,miRNA)-551a在索拉非尼应答中的作用。方法:通过综合生物信息学方法分析HCC相关miRNAs表达谱特征,并鉴定索拉非尼应答miRNAs及其相关分子机制。选取2021年2月至2022年2月皖西卫生职业学院附属医院收治的24例晚期HCC患者。选择同期收治的18例肝硬化患者作为对照组。验证索拉非尼应答miRNAs的表达特征及预测HCC预后的价值。结果:高表达miRNA-551a的晚期HCC患者预后较差,其表达被索拉非尼抑制。miRNA-551a通过多种促癌通路和自噬途径参与HCC进展及索拉非尼应答机制。临床验证队列中,索拉非尼治疗前晚期HCC患者血清miRNA-551a表达水平高于对照组(P<0.05),治疗后其miRNA-551a表达水平降低(P<0.05)。治疗前血清高表达miRNA-551a的晚期HCC患者受益于索拉非尼治疗(P<0.05)。单因素及多因素Cox比例回归模型也证实,治疗前血清miRNA-551a水平可以独立于临床病理特征预测索拉非尼治疗晚期HCC患者的预后(P<0.05)。分子对接和动力学模型证实,索拉非尼能直接结合pre-miRNA-551a,阻止内切核糖核酸酶Dicer切割pre-miRNA-551a裂解为成熟体miRNA-551a。基于miRNA-551a表达特征与临床病理特征相结合的Nomogram模型能有效预测HCC患者1年、3年和5年总生存率,且理想状态下可以筛选索拉非尼应答患者。结论:miRNA-551a作为促癌基因能被索拉非尼抑制表达从而参与其应答机制,miRNA-551a表达特征评估和定位有助于指导HCC患者个性化治疗。

Objective:Sorafenib is one of the standard first-line therapies for patients with advanced hepatocellular carcinoma(HCC)disease.This study aimed to explore the role of microRNAs(miRNAs)in sorafenib response mechanisms.Method:HCC-related miRNAs expression profiles were analyzed,and a comprehensive bioinformatics approach identified sorafenib response miRNAs and their associated molecular mechanisms.A total of 24 patients with advanced HCC admitted to our hospital for treatment between February 2021 and February 2022 were selected.During the same period,18 patients with cirrhosis admitted for treatment were selected as the control group.To verify the expression characteristics and prognostic value of sorafenib-responsive miRNAs.Result:HCC patients with high miRNA-551a expression had a poorer prognosis,and expression was suppressed by sorafenib,which is involved in HCC progression and sorafenib response mechanisms through multiple pro-oncogenic pathways and autophagic pathways.In the clinical validation cohort,serum miRNA-551a expression was higher in advanced HCC patients before sorafenib treatment than in controls(P<0.05)and decreased after treatment(P<0.05).Patients with advanced HCC with high pre-treatment serum miRNA-551a expression benefited from sorafenib treatment(P<0.05).Univariate and multivariate Cox proportional regression models also confirmed that pre-treatment serum miRNA-551a levels could predict the prognosis of advanced HCC patients treated with sorafenib independently of clinicopathological features(P<0.05).Molecular docking and kinetic modeling confirmed that sorafenib directly binds pre-miRNA-551a and prevents cleavage of pre-miRNA-551a from maturing miRNA-551a by the endoribonuclease Dicer.The Nomogram model based on the combination of miRNA-551a expression characteristics and clinicopathological features effectively predicted the prognosis of HCC patients at survival rates at 1-,3-and 5-years and,ideally,screening of sorafenib-responsive patients.Conclusion:miRNA-551a,as a pro-oncogene,can be suppressed by sorafenib expression involved in its response mechanism.The assessment and targeting of miRNA-551a expression characteristics can help personalize the treatment of HCC patients.