Application of miR-9 and miR-195-3p in the diagnosis of primary hepatic carcinoma and their changes before and after interventional therapy

Abstract

Abstract:

ObjectiveTo 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.MethodsA 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.ResultsThere 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 （allP<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±0.21vs.1.68±0.43，t=14.22，P<0.001） and miR-195-3p levels increased （0.78±0.22vs.0.63±0.18，t=14.84，P<0.001） in patients compared to pre-treatment levels.ConclusionSerum 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

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.

Figures/Tables5

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

时间	miR-9	miR-195-3p
治疗前	1.68±0.43	0.63±0.18
治疗后	1.39±0.21	0.78±0.22
t值	14.22	14.84
P值	<0.001	<0.001

References18

[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