Clinical application progress of circulating free nucleic acid in the diagnosis and treatment of hepatocellular carcinoma

doi:10.3969/j.issn.1673-8640.2019.07.021

Abstract

Abstract:

Hepatocellular carcinoma（HCC） is gradually formed on the basis of chronic liver disease or cirrhosis by a multi-factor and multi-step process of tumor progression. Due to the low determination rate in early diagnosis,the majority of patients with HCC are determined at the middle and advanced stages or accompanied by extrahepatic metastasis with poor prognosis. Recent advances in genomics and its clinical application have discovered a series of novel markers,such as circulating free nucleic acid（cfNA）,supported by research data,to be considered having a good clinical application prospect for clinical early diagnosis,the monitoring of therapeutic efficacy,prognosis evaluation and individualized treatment of patients with HCC. This review focuses on the clinical application of circulating tumor DNA（ctDNA）,microRNA（miRNA）,long non-coding RNA（lncRNA） and circular RNA（circRNA） in the diagnosis and treatment of HCC.

Key words: Circulating free nucleic acid, Hepatocellular carcinoma, Circulating tumor DNA, MicroRNA, Long non-coding RNA, Circular RNA

CLC Number:

R446.1

MING Xinliang, LIU Xuefang, ZHU Man, TU Jiancheng. Clinical application progress of circulating free nucleic acid in the diagnosis and treatment of hepatocellular carcinoma[J]. Laboratory Medicine, 2019, 34(7): 667-671.

Figures/Tables 1

References 37

[1]	CHEN W,ZHENG R,ZHANG S,et al.Cancer incidence and mortality in China in 2013:an analysis based on urbanization level[J]. Chin J Cancer Res,2017,29(1):1-10.
[2]	TORRE L A,BRAY F,SIEGEL R L,et al.Global cancer statistics,2012[J]. CA Cancer J Clin,2015,65(2):87-108.
[3]	ALLEMANI C,MATSUDA T,DI CARLO V,et al.Global surveillance of trends in cancer survival 2000-14 (CONCORD-3):analysis of individual records for 37 513 025 patients diagnosed with one of 18 cancers from 322 population-based registries in 71 countries[J]. Lancet,2018,391(10125):1023-1075.
[4]	NG K K C,CHOK K S H,CHAN A C Y,et al. Randomized clinical trial of hepatic resection versus radiofrequency ablation for early-stage hepatocellular carcinoma[J]. Br J Surg,2017,104(13):1775-1784.
[5]	刘永炜,吴向民. 血清AFP、CA199和CEA水平在肝癌诊断和预后中的作用[J]. 检验医学,2017,32(5):406-409.
[6]	PICIOCCHI M,CARDIN R,VITALE A,et al.Circulating free DNA in the progression of liver damage to hepatocellular carcinoma[J]. Hepatol Int,2013,7(4):1050-1057.
[7]	BETTEGOWDA C,SAUSEN M,LEARY R J,et al. Detection of circulating tumor DNA in early- and late-stage human malignancies[J]. Sci Transl Med,2014,6(224):224ra24.
[8]	ONO A,FUJIMOTO A,YAMAMOTO Y,et al.Circulating tumor DNA analysis for liver cancers and its usefulness as a liquid biopsy[J]. Cell Mol Gastroenterol Hepatol,2015,1(5):516-534.
[9]	PARK S,LEE E J,RIM C H,et al.Plasma cell-free DNA as a predictive marker after radiotherapy for hepatocellular carcinoma[J]. Yonsei Med J,2018,59(4):470-479.
[10]	HUANG A,ZHANG X,ZHOU S L,et al.Plasma circulating cell-free DNA integrity as a promising biomarker for diagnosis and surveillance in patients with hepatocellular carcinoma[J]. J Cancer,2016,7(13):1798-1803.
[11]	WEN L,LI J,GUO H,et al.Genome-scale detection of hypermethylated CpG islands in circulating cell-free DNA of hepatocellular carcinoma patients[J]. Cell Res,2015,25(11):1250-1264.
[12]	XU R H,WEI W,KRAWCZYK M,et al.Circulating tumour DNA methylation markers for diagnosis and prognosis of hepatocellular carcinoma[J]. Nat Mater,2017,16(11):1155-1161.
[13]	GOLDEN R J,CHEN B,LI T,et al.An argonaute phosphorylation cycle promotes microRNA-mediated silencing[J]. Nature,2017,542(7640):197-202.
[14]	BANDOPADHYAY M,SARKAR N,DATTA S,et al.Hepatitis B virus X protein mediated suppression of miRNA-122 expression enhances hepatoblastoma cell proliferation through cyclin G1-p53 axis[J]. Infect Agent Cancer,2016,11:40.
[15]	HOPCRAFT S E,AZARM K D,ISRAELOW B,et al.Viral determinants of miR-122-independent hepatitis C virus replication[J]. mSphere,2016,1(1):e00009-e00015.
[16]	ZHU H T,LIU R B,LIANG Y Y,et al.Serum microRNA profiles as diagnostic biomarkers for HBV-positive hepatocellular carcinoma[J]. Liver Int,2017,37(6):888-896.
[17]	ZHOU J,YU L,GAO X,et al.Plasma microRNA panel to diagnose hepatitis B virus-related hepatocellular carcinoma[J]. J Clin Oncol,2011,29(36):4781-4788.
[18]	LI L,CHEN J,CHEN X,et al.Serum miRNAs as predictive and preventive biomarker for pre-clinical hepatocellular carcinoma[J]. Cancer Letters,2016,373(2):234-240.
[19]	LIN X J,CHONG Y,GUO Z W,et al.A serum microRNA classifier for early detection of hepatocellular carcinoma:a multicentre,retrospective,longitudinal biomarker identification study with a nested case-control study[J]. Lancet Oncol,2015,16(7):804-815.
[20]	OKAJIMA W,KOMATSU S,ICHIKAWA D,et al.Circulating microRNA profiles in plasma:identification of miR-224 as a novel diagnostic biomarker in hepatocellular carcinoma independent of hepatic function[J]. Oncotarget,2016 ,7(33):53820-53836.
[21]	TOMIMARU Y,EGUCHI H,NAGANO H,et al.Circulating microRNA-21 as a novel biomarker for hepatocellular carcinoma[J]. J Hepatol,2012,56(1):167-175.
[22]	ZEKRI A N,YOUSSEF A S E,EL-DESOUKY E D,et al. Serum microRNA panels as potential biomarkers for early detection of hepatocellular carcinoma on top of HCV infection[J]. Tumor Biol,2016,37:12273-12286.
[23]	XU J,LIN H,LI G,et al.The miR-367-3p increases sorafenib chemotherapy efficacy to suppress hepatocellular carcinoma metastasis through altering the androgen receptor signals[J]. EBioMedicine,2016,12:55-67.
[24]	KONISHI H,ICHIKAWA D,YAMAMOTO Y,et al.Plasma level of metastasis-associated lung adenocarcinoma transcript 1 is associated with liver damage and predicts development of hepatocellular carcinoma[J]. Cancer Sci,2016,107(2):149-154.
[25]	ZHENG H,LI P,KWOK J G,et al.Alcohol and hepatitis virus-dysregulated lncRNAs as potential biomarkers for hepatocellular carcinoma[J]. Oncotarget,2017,9(1):224-235.
[26]	LI J,WANG X,TANG J,et al.HULC and Linc00152 act as novel biomarkers in predicting diagnosis of hepatocellular carcinoma[J]. Cell Physiol Biochem,2015,37(2):687-696.
[27]	YU J,HAN J,ZHANG J,et al.The long noncoding RNAs PVT1 and uc002mbe.2 in sera provide a new supplementary method for hepatocellular carcinoma diagnosis[J]. Medicine(Baltimore),2016,95(31):e4436.
[28]	JING W,GAO S,ZHU M,et al.Potential diagnostic value of lncRNA SPRY4-IT1 in hepatocellular carcinoma[J]. Oncol Rep,2016,36(2):1085-1092.
[29]	ZHANG J,ZHANG D,ZHAO Q,et al.A distinctively expressed long noncoding RNA,RP11-466I1.1,may serve as a prognostic biomarker in hepatocellular carcinoma[J]. Cancer Med,2018. [Epub ahead of print]
[30]	MA Y,LUO T,DONG D,et al.Characterization of long non-coding RNAs to reveal potential prognostic biomarkers in hepatocellular carcinoma[J]. Gene,2018,663:148-156.
[31]	CHEN C C,CHEN C Y,UENG S H,et al.Corylin increases the sensitivity of hepatocellular carcinoma cells to chemotherapy through long noncoding RNA RAD51-AS1-mediated inhibition of DNA repair[J]. Cell Death Dis,2018,9(5):543.
[32]	ZHANG X,ZHOU H,JING W,et al.The circular RNA hsa_circ_0001445 regulates the proliferation and migration of hepatocellular carcinoma and may serve as a diagnostic biomarker[J]. Dis Markers,2018,2018:3073467.
[33]	HAN D,LI J,WANG H,et al.Circular RNA circMTO1 acts as the sponge of microRNA-9 to suppress hepatocellular carcinoma progression[J]. Hepatology,2017,66(4):1151-1164.
[34]	JOST I,SHALAMOVA L A,GERRESHEIM G K,et al.Functional sequestration of microRNA-122 from hepatitis C virus by circular RNA sponges[J]. RNA Biol,2018,15(8):1032-1039.
[35]	YANG W,DU W W,LI X,et al.Foxo3 activity promoted by non-coding effects of circular RNA and Foxo3 pseudogene in the inhibition of tumor growth and angiogenesis[J]. Oncogene,2016,35(30):3919-3931.
[36]	樊绮诗,吴蓓颖. 第二代测序技术在肿瘤诊疗中的应用及其价值与风险[J]. 检验医学,2017,32(4):245-249.
[37]	WANG P,CAO J,LIU S,et al.Upregulated microRNA-429 inhibits the migration of HCC cells by targeting TRAF6 through the NF-κB pathway[J]. Oncol Rep,2017,37(5):2883-2890.

cfNA	类别	变化	作用	应用	评价	参考文献
ctDNA	浓度	增高	与肿瘤增大和预后不良相关	诊断、预后	无创无损、实时多次易获取、灵敏、准确、假阳性率低,但半衰期短、易降解、个体差异大、易受治疗影响、易出现新遗传变异	[1] [7] [9,36]
	甲基化	突变	与细胞过度凋亡、肿瘤发生相关	诊断、预后		[11]
	完整性	增加	与肿瘤状态相关	诊断、治疗		[10]
miRNA	miR-429	下调	促进HCC细胞的增殖和迁移	预测、预防	检测无创、稳定,早期阶段表现异常,研究方法简便,但序列较短有较高的脱靶效应,检测成本较高	[18,37]
	miR-122	下调	与预后不良和转移性增加有关	预后		[17]
	miR-367-3p	下调	促进HCC细胞转移和侵袭	治疗		[23]
	miR-224	上调	加速细胞生长、增强HCC侵袭性	诊断、监测		[20]
	miR-21	上调	增加细胞增殖并抑制凋亡	筛查、诊断、预后		[21]
lncRNA	SPRY4-IT1	上调	与分化、肿瘤大小和TNM 分期相关	诊断、预后	序列长,遗传信息丰富、多样化和特异性强,但表达量低,测定困难, 肝癌诊断分型预后方面的研究比较少,缺乏大样本、前瞻性的随机对照研究	[28]
	MALAT	上调	加速肝细胞增殖和周期进程	诊断、预测		[24]
	PVT1	上调	促进细胞增殖、调节细胞周期	筛查、诊断、预后		[27]
	HULC	上调	与肿瘤发生、生长和侵袭相关	预测、诊断、预后		[26]
	Linc00152	上调	预测肿瘤发生、肿瘤生长和肿瘤转移	预测、预后		[26]
	RP11-466I1.1	上调	促进肿瘤侵袭	预后		[29]
circRNA	hsa_circ_0001445	下调	抑制细胞凋亡和促进增殖、侵袭	诊断	稳定,不易降解,但与肿瘤特异性表达特征的形成机制尚不清楚	[32]

cfNA	类别	变化	作用	应用	评价	参考文献
ctDNA	浓度	增高	与肿瘤增大和预后不良相关	诊断、预后	无创无损、实时多次易获取、灵敏、准确、假阳性率低,但半衰期短、易降解、个体差异大、易受治疗影响、易出现新遗传变异	[1] [7] [9,36]
	甲基化	突变	与细胞过度凋亡、肿瘤发生相关	诊断、预后		[11]
	完整性	增加	与肿瘤状态相关	诊断、治疗		[10]
miRNA	miR-429	下调	促进HCC细胞的增殖和迁移	预测、预防	检测无创、稳定,早期阶段表现异常,研究方法简便,但序列较短有较高的脱靶效应,检测成本较高	[18,37]
	miR-122	下调	与预后不良和转移性增加有关	预后		[17]
	miR-367-3p	下调	促进HCC细胞转移和侵袭	治疗		[23]
	miR-224	上调	加速细胞生长、增强HCC侵袭性	诊断、监测		[20]
	miR-21	上调	增加细胞增殖并抑制凋亡	筛查、诊断、预后		[21]
lncRNA	SPRY4-IT1	上调	与分化、肿瘤大小和TNM 分期相关	诊断、预后	序列长,遗传信息丰富、多样化和特异性强,但表达量低,测定困难, 肝癌诊断分型预后方面的研究比较少,缺乏大样本、前瞻性的随机对照研究	[28]
	MALAT	上调	加速肝细胞增殖和周期进程	诊断、预测		[24]
	PVT1	上调	促进细胞增殖、调节细胞周期	筛查、诊断、预后		[27]
	HULC	上调	与肿瘤发生、生长和侵袭相关	预测、诊断、预后		[26]
	Linc00152	上调	预测肿瘤发生、肿瘤生长和肿瘤转移	预测、预后		[26]
	RP11-466I1.1	上调	促进肿瘤侵袭	预后		[29]
circRNA	hsa_circ_0001445	下调	抑制细胞凋亡和促进增殖、侵袭	诊断	稳定,不易降解,但与肿瘤特异性表达特征的形成机制尚不清楚	[32]