原发性肝癌患者血清circIPO11水平与其临床病理特征及预后关系研究

摘要/Abstract

摘要： 目的：分析原发性肝癌（primary liver cancer,PLC）患者血清IPO11基因编码的环状RNA（circIPO11）水平与其临床病理特征及预后的关系。
方法：前瞻性选择2020年2月至2022年1月就诊于天水市第一人民医院的120例PLC患者为病例组,120例健康体检者为对照组,采用实时荧光定量聚合酶链反应法测定所有样本血清circIPO11相对表达量。对比病例组血清circIPO11相对表达量,绘制受试者操作特征曲线（receiver operator characteristic curve,ROC 曲线）曲线分析circIPO11表达预测PLC发生的价值。对比不同病理特征患者的血清circIPO11相对表达量差异,分析circIPO11表达与临床病理特征、预后的相关性。Kaplan-Meier法生存分析,多因素Cox 回归模型预后分析。
结果：病例组血清circIPO11相对表达量高于对照组（P<0.05）。ROC曲线分析显示血清circIPO11相对表达量预测PLC发生的曲线下面积（95%CI）为0.883（0.842~0.925）。不同肿瘤分期、分化程度、是否合并门静脉癌栓、是否合并淋巴结转移、术前甲胎蛋白水平的PLC患者血清circIPO11相对表达量对比,差异均有统计学意义（均P<0.05）。点二列相关性发现,血清circIPO11相对表达量与PLC患者合并门静脉癌栓、合并淋巴结转移、术前甲胎蛋白水平呈正相关（r=0.403、0.298、0.397,P<0.05）;Spearman相关性发现,血清circIPO11相对表达量与PLC患者肿瘤分期呈正相关（r=0.328,P<0.05）,与分化程度呈负相关（r=-0.304,P<0.05）。120例PLC患者随访3年总生存率为46.7%（56/120）,中位生存时间为27.5个月（95%CI为25.8~29.3个月）;circIPO11低表达组、circIPO11高表达组患者中位生存时间分别为29.7个月（95%CI为27.3~32.2个月）、25.3个月（95%CI为22.9~27.7个月）,circIPO11低表达组3年生存率高于circIPO11高表达组（P<0.05）。多因素Cox回归模型分析发现肿瘤分期、分化程度、门静脉癌栓、淋巴结转移、术前甲胎蛋白水平、术前ircIPO11表达是PLC患者术后3年死亡率的独立危险因素（均P<0.05）。
结论：PLC患者血清circIPO11呈高表达,其表达与患者肿瘤分期、分化程度、淋巴结转移状态、术前甲胎蛋白水平等病理特征有关,且circIPO11高表达是PLC患者术后3年生存状况的危险因素。

关键词: 原发性肝癌, IPO11基因编码的环状 RNA, 病理特征, 预后

Abstract: Objective: To analyze the relationship between serum circIPO11 level and its clinicopathological features and prognosis in patients with primary liver cancer (PLC).
Methods: From February 2020 to January 2022, 120 PLC patients (case group) and 120 healthy people (control group) were prospective selected by Tianshui First People's Hospital, and the relative expression of circIPO11 in serum of all subjects was determined by real-time fluorescence quantitative PCR.Compare the relative expression of circIPO11 in serum between the control group and the case group, and draw ROC curve to analyze the value of circIPO11 expression in predicting PLC occurrence. The relative expression of circIPO11 in serum of patients with different pathological features in the case group was compared, and the correlation between the expression of circIPO11 and clinicopathological features and prognosis was analyzed. Kaplan-Meier survival analysis and Cox regression model for multivariate prognostic analysis.
Results: The relative expression of serum circIPO11 in case group was higher than that in control group (P< 0.05). The ROC curve showed that the relative expression of serum circIPO11 predicted the AUC(95%CI) of PLC to be 0.883 (0.842-0.925). Compared with PLC patients with different tumor stages, degrees of differentiation, portal vein tumor thrombus, lymph node metastasis and preoperative alpha-fetoprotein level, the difference was statistically significant (all P< 0.05). Point-column correlation showed that the relative expression of serum circIPO11 was positively correlated with portal vein tumor thrombus, lymph node metastasis and preoperative alpha-fetoprotein level in PLC patients (r=0.403,0.298,0.397, P< 0.05). Spearman correlation showed that the relative expression of serum circIPO11 was positively correlated with the tumor stage of PLC patients (r=0.328, P< 0.05) and negatively correlated with the differentiation degree (r=-0.304, P< 0.05).The overall survival rate of 120 patients with PLC was 46.7%(56/120) and the median survival time was 27.5 months (95%CI: 25.8-29.3 months). Kaplan-Meier survival analysis revealed that the median survival times were 29.7 months (95%CI: 27.3-32.2 months) in the low circIPO11 expression group and 25.3 months (95%CI: 22.9-27.7 months) in the high circIPO11 expression group. The 3-year survival rate was significantly higher in the low-expression group compared to the high-expression group (P< 0.05). Multivariate regression analysis showed that tumor stage, differentiation degree, portal vein tumor thrombus, lymph node metastasis, preoperative alpha-fetoprotein level and preoperative circIPO11 expression were independent risk factors for postoperative mortality of PLC patients (all P< 0.05).
Conclusions: circIPO11 is highly expressed in serum of PLC patients, and its expression is related to pathological features such as tumor stage, degree of differentiation, lymph node metastasis and preoperative alpha-fetoprotein level, and the high expression of circIPO11 is a risk factor affecting the survival status of PLC patients after 3 years.

Key words: Primary liver cancer, CircIPO11, Pathological features, Prognosis

尹亚刚, 赵建文, 田宏伟, 王定新. 原发性肝癌患者血清circIPO11水平与其临床病理特征及预后关系研究[J]. 肝癌电子杂志, 2025, 12(4): 30-36.

Yin Yagang, Zhao Jianwen, Tian Hongwei, Wang Dingxin. Study on the relationship between serum circIPO11 level and its clinicopathological characteristics and prognosis in patients with primary liver cancer[J]. Electronic Journal of Liver Tumor, 2025, 12(4): 30-36.

参考文献

[1] 曹晓强,高颢瑾,杨大干.基于常规检验数据的原发性肝癌风险预测模型的建立与评价[J].临床检验杂志,2023,41(8):575-580.
[2] MIYATA T, HAYASHI H, YAMASHITA Y I, et al.The impact of histologic liver inflammation on oncology and the prognosis of patients undergoing hepatectomy for hepatocellular carcinoma[J]. Ann Surg Oncol, 2022, 29(2): 893-902.
[3] 王雅晳,于杰,程志刚,等.经皮微波消融早期原发性肝癌预后因素分析[J].中华超声影像学杂志,2022, 31(3):252-259.
[4] 黄澜,朱宗国,冯涛.血清甲胎蛋白,PIVKA-Ⅱ,GGT,GGT/ALT检测对早期原发性肝癌的诊断价值[J].临床和实验医学杂志,2024,23(7):749-752.
[5] CHEN S, LI K, GUO J, et al.circNEIL3 inhibits tumor metastasis through recruiting the E3 ubiquitin ligase Nedd4L to degrade YBX1[J]. Proc Natl Acad Sci U S A, 2023, 120(13): e2215132120.
[6] MIS M, O'BRIEN S, STEINHART Z, et al. IPO11 mediates βcatenin nuclear import in a subset of colorectal cancers[J]. J Cell Biol, 2020, 219(2): e201903017.
[7] ALJAHDALI M O, MOLLA M H R. Multi-omics prognostic signatures of IPO11 mRNA expression and clinical outcomes in colorectal cancer using bioinformatics approaches[J]. Health Inf Sci Syst, 2023, 11(1): 57.
[8] RADANOVA M, MIHAYLOVA G, TASINOV O, et al.New circulating circular RNAs with diagnostic and prognostic potential in advanced colorectal cancer[J]. Int J Mol Sci, 2021, 22(24): 13283.
[9] 赵俊杰. IPO11高表达在膀胱尿路上皮癌进展中的作用及其机制研究[D]. 广州:第二军医大学,2015.
[10] 中华预防医学会肝胆胰疾病预防与控制专业委员会,中国研究型医院学会肝病专业委员会,中华医学会肝病学分会,等.原发性肝癌的分层筛查与监测指南(2020版)[J].临床肝胆病杂志,2021,37(2):286-295.
[11] AMIN M B, GREENE F L, EDGE S B, et al.The eighth edition AJCC cancer staging manual: continuing to build a bridge from a population-based to a more "personalized" approach to cancer staging[J]. CA Cancer J Clin, 2017, 67(2): 93-99.
[12] 徐子云,范玉纯,韦万硕,等.DNAJC2对肝细胞癌细胞生物学功能影响的初步研究[J].现代肿瘤医学,2024,32(8):1375-1381.
[13] ZHANG Y, OU G, ZHOU Z, et al.Protocol for IPO11 deletion and re-expression in H460 lung cancer cells using CRISPR-Cas9 and plasmid transfection[J]. STAR Protoc, 2023, 4(2): 102317.
[14] NI H, JI D, LI J, et al.The nuclear transporter importin-11 regulates the Wnt/β-catenin pathway and acts as a tumor promoter in glioma[J]. Int J Biol Macromol, 2021, 176: 145-156.
[15] ZHAO J, SHI L, ZENG S, et al. Importin-11 overexpression promotes the migration, invasion,progression of bladder cancer associated with the deregulation of CDKN1A and THBS1[J]. Urol Oncol, 2018, 36(6): 311.e1-311.e13.
[16] LIU W, ZHENG L, ZHANG R, et al.Circ-ZEB1 promotes PIK3CA expression by silencing miR-199a-3p and affects the proliferation and apoptosis of hepatocellular carcinoma[J]. Mol Cancer, 2022, 21(1): 72.
[17] ZHANG X Y, LI S S, GU Y R, et al.CircPIAS1 promotes hepatocellular carcinoma progression by inhibiting ferroptosis via the miR-455-3p/NUPR1/FTH1 axis[J]. Mol Cancer, 2024, 23(1): 113.
[18] REN S, XIN Z, XU Y, et al.Construction and analysis of circular RNA molecular regulatory networks in liver cancer[J]. Cell Cycle, 2017, 16(22): 2204-2211.
[19] GU Y, WANG Y, H E, et al. Circular RNA circIPO11 drives self-renewal of liver cancer initiating cells via Hedgehog signaling[J]. Mol Cancer, 2021, 20(1): 132.
[20] 王曼,李燕楚.磷酸酶与张力蛋白同源物和骨形态发生蛋白4表达与老年原发性肝癌患者临床病理参数及预后相关性分析[J].哈尔滨医科大学学报,2022,56(5):473-477.
[21] CHEN M, NOWAK D G, NARULA N, et al.The nuclear transport receptor Importin-11 is a tumor suppressor that maintains PTEN protein[J]. J Cell Biol, 2017, 216(3): 641-656.
[22] 石磊,安梓铭,冯琴.联合检测血清AFP,AFP-L3%和PIVKA-Ⅱ水平早期诊断和判断原发性肝癌患者预后临床价值探讨[J].实用肝脏病杂志,2023,26(3):404-407.
[23] 马平川,陈子祥,赵义军,等.AFP阴性肝癌患者手术疗效和预后影响因素分析[J].肝胆外科杂志,2024,32(1):16-20.
[24] 刘立友,吴东洋,蔡青山,等.原发性肝癌组织中层粘连蛋白3,黏着斑激酶蛋白表达及其与患者临床病理特征和预后关系研究[J].陕西医学杂志,2023,52(9):1259-1263.