miR-9和miR-195-3p在原发性肝癌诊断中的应用及其在介入治疗前后的变化

doi:10.3760/cma.j.cn371439-20240115-00105

摘要/Abstract

摘要：

目的探讨miR-9和miR-195-3p对于原发性肝癌（PHC）的诊断效能，以及介入治疗后miR-9和miR-195-3p水平的变化。方法选取2019年5月—2020年5月于唐山市人民医院就诊的123例PHC患者和30例肝硬化患者分别作为PHC组和肝硬化组，选取同期体检健康的人群50例作为健康组。通过实时荧光定量PCR检测血清miR-9和miR-195-3p水平；分析血清miR-9和miR-195-3p水平与PHC患者临床病理特征的关系；采用受试者操作特征（ROC）曲线分析miR-9和miR-195-3p对PHC的诊断效能；比较经导管肝动脉化疗栓塞（TACE）术治疗前、后PHC患者血清miR-9和miR-195-3p水平变化。结果健康组、肝硬化组、PHC组血清miR-9（0.99±0.10、1.31±0.28、1.68±0.43）和miR-195-3p（0.97±0.10、0.83±0.22、0.63±0.18）水平差异均具有统计学意义（F=69.78，P<0.001；F=74.82，P<0.001），3组间血清miR-9水平依次升高，miR-195-3p水平依次降低（均P<0.05）。不同肿瘤最大径、临床分期及分化程度PHC患者的血清miR-9（t=7.45，P<0.001；t=5.32，P<0.001；t=4.96，P<0.001）和miR-195-3p（t=16.17，P<0.001；t=4.21，P<0.001；t=7.53，P<0.001）水平差异均有统计学意义。ROC曲线分析显示，血清miR-9和miR-195-3p检测联合鉴别诊断肝硬化和PHC的曲线下面积（AUC）为0.919，大于血清miR-9（AUC为0.712，Z=4.38，P<0.001）和miR-195-3p（AUC为0.844，Z=2.04，P=0.042）单独鉴别诊断的AUC。TACE治疗后，患者血清miR-9水平较治疗前下降（1.39±0.21比1.68±0.43，t=14.22，P<0.001），miR-195-3p水平较治疗前上升（0.78±0.22比0.63±0.18，t=14.84，P<0.001）。结论 PHC患者血清miR-9水平较肝硬化和健康者升高，miR-195-3p水平较肝硬化和健康者降低，二者联合检测对肝硬化和PHC具有较高的鉴别诊断效能。PHC患者TACE治疗后血清miR-9水平下降、miR-195-3p水平上升。

关键词: 肝肿瘤, 化学栓塞，治疗性, miR-9, miR-195-3p

Abstract:

Objective To investigate the diagnostic efficacy of miR-9 and miR-195-3p for primary hepatic carcinoma （PHC）， and the changes in miR-9 and miR-195-3p levels after interventional therapy. Methods A total of 123 cases of PHC patients and 30 cases of liver cirrhosis patients attending Tangshan People's Hospital from May 2019 to May 2020 were selected as the PHC group and the liver cirrhosis group， respectively， and 50 people who were physically healthy during the same period were selected as the healthy group. Serum miR-9 and miR-195-3p levels were detected by real-time quantitative PCR. The relationship between serum miR-9 and miR-195-3p levels and clinical-pathological characteristics of PHC patients was analyzed. Receiver operator characteristic （ROC） curve was applied to analyze the diagnostic efficacy of miR-9 and miR-195-3p for PHC. The changes in serum miR-9 and miR-195-3p levels in PHC patients before and after transcatheter arterial chemoembolization（TACE） were compared. Results There were statistically significant differences in serum miR-9 （0.99±0.10， 1.31±0.28， 1.68±0.43） and miR-195-3p （0.97±0.10， 0.83±0.22， 0.63±0.18） levels among the healthy group， liver cirrhosis group， and PHC group （F=69.78， P<0.001； F=74.82， P<0.001）， with serum miR-9 levels increased successively and miR-195-3p levels decreased successively among the three groups （all P<0.05）. There were statistically significant differences in serum miR-9 （t=7.45， P<0.001； t=5.32， P<0.001； t=4.96， P<0.001）and miR-195-3p （t=16.17， P<0.001； t=4.21， P<0.001； t=7.53， P<0.001） levels in PHC patients with different maximum diameters of tumor， clinical stages and degrees of differentiation. ROC curve analysis showed that the area under the curve （AUC） for the combined differential diagnosis of liver cirrhosis and PHC by serum miR-9 and miR-195-3p testing was 0.919， which was higher than the AUC for the differential diagnosis of serum miR-9 （AUC： 0.712， Z=4.38， P<0.001） and miR-195-3p （AUC： 0.844， Z=2.04， P=0.042） alone. After TACE treatment， serum miR-9 levels decreased （1.39±0.21 vs. 1.68±0.43， t=14.22， P<0.001） and miR-195-3p levels increased （0.78±0.22 vs. 0.63±0.18， t=14.84， P<0.001） in patients compared to pre-treatment levels. Conclusion Serum miR-9 level is increased and miR-195-3p level is decreased in patients with PHC compared with patients with liver cirrhosis and healthy subjects， and the combination of the two has high differential diagnostic efficacy for liver cirrhosis and PHC. After TACE treatment， serum miR-9 level is decreased and miR-195-3p level is increased in PHC patients.

Key words: Liver neoplasms, Chemoembolization， therapeutic, miR-9, miR-195-3p

张冬茜, 张海光, 张晓茹, 郑璇, 韩素桂, 李颖, 郝春海. miR-9和miR-195-3p在原发性肝癌诊断中的应用及其在介入治疗前后的变化[J]. 国际肿瘤学杂志, 2024, 51(10): 627-631.

Zhang Dongqian, Zhang Haiguang, Zhang Xiaoru, Zheng Xuan, Han Sugui, Li Ying, Hao Chunhai. Application of miR-9 and miR-195-3p in the diagnosis of primary hepatic carcinoma and their changes before and after interventional therapy[J]. Journal of International Oncology, 2024, 51(10): 627-631.

图/表 5

表1

表2

表3

图1

表4

参考文献 18

[1]	Konyn P, Ahmed A, Kim D. The current trends in the health burden of primary liver cancer across the globe[J]. Clin Mol Hepatol, 2023, 29(2): 358-362. DOI: 10.3350/cmh.2023.0092. pmid: 36916167
[2]	Zajkowska M, Mroczko B. Chemokines in primary liver cancer[J]. Int J Mol Sci, 2022, 23(16): 8846. DOI: 10.3390/ijms23168846.
[3]	Yao XH, Xie LS, Zeng Y. MiR-9 promotes angiogenesis via targeting on sphingosine-1-phosphate receptor 1[J]. Front Cell Dev Biol, 2020, 8: 755. DOI: 10.3389/fcell.2020.00755.
[4]	Si T, Huang LY, Liang T, et al. Ruangan lidan decoction inhibits the growth and metastasis of liver cancer by downregulating miR-9-5p and upregulating PDK4[J]. Cancer Biol Ther, 2023, 24(1): 2246198. DOI: 10.1080/15384047.2023.2246198.
[5]	Mei J, Lin WP, Li SH, et al. Long noncoding RNA TINCR facilitates hepatocellular carcinoma progression and dampens chemosensitivity to oxaliplatin by regulating the miR-195-3p/ST6GAL1/NF-κB pathway[J]. J Exp Clin Cancer Res, 2022, 41(1): 5. DOI: 10.1186/s13046-021-02197-x. pmid: 34980201
[6]	中华人民共和国卫生和计划生育委品会医政医管局. 原发性肝癌诊疗规范(2017年版)[J]. 中华肝脏病杂志, 2017, 25(12): 886-895. DOI: 10.3760/cma.j.issn.1007-3418.2017.12.002.
[7]	中华医学会肝病学分会. 肝硬化诊治指南[J]. 中华肝脏病杂志, 2019, 27(11): 846-865. DOI: 10.3760/cma.j.issn.1007-3418.2019.11.008.
[8]	Zhou HY, Song TA. Conversion therapy and maintenance therapy for primary hepatocellular carcinoma[J]. Biosci Trends, 2021, 15(3): 155-160. DOI: 10.5582/bst.2021.01091.
[9]	Chen WQ, Chiang CL, Dawson LA. Efficacy and safety of radiotherapy for primary liver cancer[J]. Chin Clin Oncol, 2021, 10(1): 9. DOI: 10.21037/cco-20-89.
[10]	Khafaei M, Rezaie E, Mohammadi A, et al. MiR-9: from function to therapeutic potential in cancer[J]. J Cell Physiol, 2019, 234(9): 14651-14665. DOI: 10.1002/jcp.28210.
[11]	Zhu WJ, Huang HH, Feng YF, et al. Hypoxia-induced miR-9 expression promotes ovarian cancer progression via activating PI3K/Akt/mTOR/GSK3β signaling pathway[J]. Neoplasma, 2023, 70(2): 216-228. DOI: 10.4149/neo_2023_221103N1079.
[12]	Geng LY, Xu JJ, Zhu YH, et al. Targeting miR-9 in glioma stem cell-derived extracellular vesicles: a novel diagnostic and therapeutic biomarker[J]. Transl Oncol, 2022, 22: 101451. DOI: 10.1016/j.tranon.2022.101451.
[13]	Wang LB, Cui MX, Cheng DM, et al. MiR-9-5p facilitates hepatocellular carcinoma cell proliferation, migration and invasion by targeting ESR1[J]. Mol Cell Biochem, 2021, 476(2): 575-583. DOI: 10.1007/s11010-020-03927-z. pmid: 33106914
[14]	Jin MF, Wang L, Zheng T, et al. MiR-195-3p inhibits cell proliferation in cervical cancer by targeting BCDIN3D[J]. J Reprod Immunol, 2021, 143: 103211. DOI: 10.1016/j.jri.2020.103211.
[15]	Lien MY, Tsai HC, Chang AC, et al. Chemokine CCL4 induces vascular endothelial growth factor C expression and lymphangioge-nesis by miR-195-3p in oral squamous cell carcinoma[J]. Front Immunol, 2018, 9: 412. DOI: 10.3389/fimmu.2018.00412.
[16]	Yang H, Gao S, Chen J, et al. UBE2I promotes metastasis and correlates with poor prognosis in hepatocellular carcinoma[J]. Cancer Cell Int, 2020, 20: 234. DOI: 10.1186/s12935-020-01311-x. pmid: 32536822
[17]	Sporn JC, Katsuta E, Yan L, et al. Expression of microRNA-9 is associated with overall survival in breast cancer patients[J]. J Surg Res, 2019, 233: 426-435. DOI: 10.1016/j.jss.2018.08.020. pmid: 30502282
[18]	Lao Y, Li TD, Xie X, et al. MiR-195-3p is a novel prognostic biomarker associated with immune infiltrates of lung adenocarcinoma[J]. Int J Gen Med, 2022, 15: 191-203. DOI: 10.2147/IJGM.S350340. pmid: 35023957

组别	miR-9	miR-195-3p
PHC组（n=123）	1.68±0.43^ab	0.63±0.18^ab
肝硬化组（n=30）	1.31±0.28^b	0.83±0.22^b
健康组（n=50）	0.99±0.10	0.97±0.10
F值	69.78	74.82
P值	<0.001	<0.001

临床资料	例数	miR-9	t值	P值	miR-195-3p	t值	P值
年龄（岁）
≥55	68	1.71±0.36	1.01	0.313	0.65±0.15	1.65	0.101
<55	55	1.65±0.28	1.01	0.313	0.61±0.11	1.65	0.101
性别
男	90	1.70±0.33	0.95	0.345	0.64±0.14	1.48	0.141
女	33	1.64±0.25	0.95	0.345	0.60±0.11	1.48	0.141
肿瘤最大径（cm）
≥5	67	1.81±0.24	7.45	<0.001	0.53±0.06	16.17	<0.001
<5	56	1.53±0.16	7.45	<0.001	0.75±0.09	16.17	<0.001
临床分期
Ⅰ~Ⅱ期	80	1.61±0.18	5.32	<0.001	0.66±0.11	4.21	<0.001
Ⅲ~Ⅳ期	43	1.81±0.23	5.32	<0.001	0.58±0.08	4.21	<0.001
分化程度
中、高分化	75	1.61±0.18	4.96	<0.001	0.68±0.09	7.53	<0.001
低分化	48	1.79±0.22	4.96	<0.001	0.56±0.08	7.53	<0.001

指标	最佳截断值	AUC	95%CI	敏感性（%）	特异性（%）	Youden指数
miR-9	1.60	0.712^a	0.634~0.783	62.60	73.43	0.359
miR-195-3p	0.69	0.844^b	0.777~0.898	66.67	86.67	0.533
二者联合		0.919	0.864~0.957	94.31	73.33	0.676