Role of exosome-derived circular RNA in tumor diagnosis and treatment

doi:10.3969/j.issn.1673-8640.2020.12.003

Abstract

Abstract:

Exosomes refer to small vesicles secreted by cells,containing various molecules and playing a role in intercellular communication. Circular RNA is a class of nucleic acid molecules contained in exosomes. It forms circular structures by covalent bonds without a 5' cap and a 3' poly（A） tail,mainly functioning as miRNA sponges and playing an important regulatory role in gene expression. Exosome-derived circRNA can promote tumor proliferation,metastasis and drug resistance,which are enriched in plasma and may be served as biomarkers for diagnosis and prognosis in early tumor. This review highlights the biological functions of exosomal circRNA in the onset and development of different tumors and provides a reference for the application of exosome-derived circRNA in tumor diagnosis and treatment.

Key words: Exosome, Circular RNA, Tumor

CLC Number:

R446.1

YANG Wenjing, LÜ Lihua, YAO Jiayi, WANG Hao, ZHANG Chunyan, WANG Beili, PAN Baishen, GUO Wei. Role of exosome-derived circular RNA in tumor diagnosis and treatment[J]. Laboratory Medicine, 2020, 35(12): 1213-1219.

Figures/Tables 2

References 46

[1]	BRAICU C,TOMULEASA C,MONROIG P,et al.Exosomes as divine messengers:are they the Hermes of modern molecular oncology?[J]. Cell Death Differ,2015,22(1):34-45.
[2]	MENG X,LI X,ZHANG P,et al.Circular RNA:an emerging key player in RNA world[J]. Brief Bioinform,2017,18(4):547-557.
[3]	LI Y,ZHENG Q,BAO C,et al.Circular RNA is enriched and stable in exosomes:a promising biomarker for cancer diagnosis[J]. Cell Res,2015,25(8):981-984.
[4]	XU R,RAI A,CHEN M,et al.Extracellular vesicles in cancer - implications for future improvements in cancer care[J]. Nat Rev Clin Oncol,2018,15(10):617-638.
[5]	KALLURI R,LEBLEU V S. The biology,function,and biomedical applications of exosomes[J]. Science,2020,367(6478):eaau6977.
[6]	LI X,WANG X.The emerging roles and therapeutic potential of exosomes in epithelial ovarian cancer[J]. Mol Cancer,2017,16(1):92.
[7]	JECK W R,SORRENTINO J A,WANG K,et al.Circular RNAs are abundant,conserved,and associated with ALU repeats[J]. RNA,2013,19(2):141-157.
[8]	SU M,XIAO Y,MA J,et al.Circular RNAs in cancer:emerging functions in hallmarks,stemness,resistance and roles as potential biomarkers[J]. Mol Cancer,2019,18(1):90.
[9]	WANG Y,LIU J,MA J,et al.Exosomal circRNA:biogenesis,effect and application in human diseases[J]. Mol Cancer,2019,18(1):116.
[10]	TIAN L,CAO J,JIAO H,et al.CircRASSF2 promotes laryngeal squamous cell carcinoma progression by regulating the miRNA-302b-3p/IGF-1R axis[J]. Clin Sci(Lond),2019,133(9):1053-1066.
[11]	ZHANG H,DENG T,GE S,et al.Exosome circRNA secreted from adipocytes promotes the growth of hepatocellular carcinoma by targeting deubiquitination-related USP7[J]. Oncogene,2019,38(15):2844-2859.
[12]	FENG W,GONG H,WANG Y,et al.circIFT80 functions as a ceRNA of miRNA-1236-3p to promote colorectal cancer progression[J]. Mol Ther Nucleic Acids,2019,18:375-387.
[13]	LI Y,LI C,XU R,et al.A novel circFMN2 promotes tumor proliferation in CRC by regulating the miR-1182/hTERT signaling pathways[J]. Clin Sci(Lond),2019,133(24):2463-2479.
[14]	ZHANG X,WANG S,WANG H,et al.Circular RNA circNRIP1 acts as a microRNA-149-5p sponge to promote gastric cancer progression via the AKT1/mTOR pathway[J]. Mol Cancer,2019,18(1):20.
[15]	LI T,SUN X,CHEN L.Exosome circ_0044516 promotes prostate cancer cell proliferation and metastasis as a potential biomarker[J]. J Cell Biochem,2020,121(3):2118-2126.
[16]	WANG G,LIU W,ZOU Y,et al.Three isoforms of exosomal circPTGR1 promote hepatocellular carcinoma metastasis via the miRNA449a-MET pathway[J]. EBioMedicine,2019,40:432-445.
[17]	HUANG X Y,HUANG Z L,HUANG J,et al.Exosomal circRNA-100338 promotes hepatocellular carcinoma metastasis via enhancing invasiveness and angiogenesis[J]. J Exp Clin Cancer Res,2020,39(1):20.
[18]	SU Y,LV X,YIN W,et al.CircRNA Cdr1as functions as a competitive endogenous RNA to promote hepatocellular carcinoma progression[J]. Aging(Albany NY),2019,11(19):8182-8203.
[19]	LU J,WANG Y H,YOON C,et al.Circular RNA circ-RanGAP1 regulates VEGFA expression by targeting miR-877-3p to facilitate gastric cancer invasion and metastasis[J]. Cancer Lett,2020,471:38-48.
[20]	ZHANG H,ZHU L,BAI M,et al.Exosomal circRNA derived from gastric tumor promotes white adipose browning by targeting the miR-133/PRDM16 pathway[J]. Int J Cancer,2019,144(10):2501-2515.
[21]	LI Z,YANFANG W,LI J,et al.Tumor-released exosomal circular RNA PDE8A promotes invasive growth via the miR-338/MACC1/MET pathway in pancreatic cancer[J]. Cancer Lett,2018,432:237-250.
[22]	LI J,LI Z,JIANG P,et al.Circular RNA IARS(circ-IARS) secreted by pancreatic cancer cells and located within exosomes regulates endothelial monolayer permeability to promote tumor metastasis[J]. J Exp Clin Cancer Res,2018,37(1):177.
[23]	CHEN X,CHEN R X,WEI W S,et al.PRMT5 circular rna promotes metastasis of urothelial carcinoma of the bladder through sponging miRNA-30c to induce epithelial-mesenchymal transition[J]. Clin Cancer Res,2018,24(24):6319-6330.
[24]	GUAN X,ZONG Z H,LIU Y,et al.circPUM1 promotes tumorigenesis and progression of ovarian cancer by sponging miR-615-5p and miR-6753-5p[J]. Mol Ther Nucleic Acids,2019,18:882-892.
[25]	ZONG Z H,DU Y P,GUAN X,et al.CircWHSC1 promotes ovarian cancer progression by regulating MUC1 and hTERT through sponging miR-145 and miR-1182[J]. J Exp Clin Cancer Res,2019,38(1):437.
[26]	ZHAO H,CHEN S,FU Q.Exosomes from CD133+ cells carrying circ-ABCC1 mediate cell stemness and metastasis in colorectal cancer[J]. J Cell Biochem,2020,121(5-6):3286-3297.
[27]	WANG S,HU Y,LV X,et al.Circ-0000284 arouses malignant phenotype of cholangiocarcinoma cells and regulates the biological functions of peripheral cells through cellular communication[J]. Clin Sci(Lond),2019,133(18):1935-1953.
[28]	LI L,LI W,CHEN N,et al.FLI1 exonic circular RNAs as a novel oncogenic driver to promote tumor metastasis in small cell lung cancer[J]. Clin Cancer Res,2019,25(4):1302-1317.
[29]	ZHAO Z,JI M,WANG Q,et al.Circular RNA cdr1as upregulates scai to suppress cisplatin resistance in ovarian cancer via miR-1270 suppression[J]. Mol Ther Nucleic Acids,2019,18:24-33.
[30]	HON K W,AB-MUTALIB N S,ABDULLAH N M A,et al. Extracellular vesicle-derived circular RNAs confers chemoresistance in colorectal cancer[J]. Sci Rep,2019,9(1):16497.
[31]	WANG X,ZHANG H,YANG H,et al.Exosome-delivered circRNA promotes glycolysis to induce chemoresistance through the miR-122-PKM2 axis in colorectal cancer[J]. Mol Oncol,2020,14(3):539-555.
[32]	DAI X,CHEN C,YANG Q,et al.Exosomal circRNA_100284 from arsenite-transformed cells,via microRNA-217 regulation of EZH2,is involved in the malignant transformation of human hepatic cells by accelerating the cell cycle and promoting cell proliferation[J]. Cell Death Dis,2018,9(5):454.
[33]	QIN W,TSUKASAKI Y,DASGUPTA S,et al.Exosomes in human breast milk promote EMT[J]. Clin Cancer Res,2016,22(17):4517-4524.
[34]	ZHENG P,CHEN L,YUAN X,et al.Exosomal transfer of tumor-associated macrophage-derived miR-21 confers cisplatin resistance in gastric cancer cells[J]. J Exp Clin Cancer Res,2017,36(1):53.
[35]	DOU Y,CHA D J,FRANKLIN J L,et al.Circular RNAs are down-regulated in KRAS mutant colon cancer cells and can be transferred to exosomes[J]. Sci Rep,2016,6:37982.
[36]	PAN B,QIN J,LIU X,et al.Identification of serum exosomal hsa-circ-0004771 as a novel diagnostic biomarker of colorectal cancer[J]. Front Genet,2019,10:1096.
[37]	BARBAGALLO C,BREX D,CAPONNETTO A,et al.LncRNA UCA1,upregulated in CRC biopsies and downregulated in serum exosomes,controls mRNA expression by RNA-RNA interactions[J]. Mol Ther Nucleic Acids,2018,12:229-241.
[38]	SHAO Y,TAO X,LU R,et al.Hsa_circ_0065149 is an indicator for early gastric cancer screening and prognosis prediction[J]. Pathol Oncol Res,2020,26(3):1475-1482.
[39]	CHEN W,QUAN Y,FAN S,et al.Exosome-transmitted circular RNA hsa_circ_0051443 suppresses hepatocellular carcinoma progression[J]. Cancer Lett,2020,475:119-128.
[40]	WANG J,ZHAO X,WANG Y,et al.circRNA-002178 act as a ceRNA to promote PDL1/PD1 expression in lung adenocarcinoma[J]. Cell Death Dis,2020,11(1):32.
[41]	CHEN F,HUANG C,WU Q,et al.Circular RNAs expression profiles in plasma exosomes from early-stage lung adenocarcinoma and the potential biomarkers[J]. J Cell Biochem,2020,121(3):2525-2533.
[42]	YANG S J,WANG D D,ZHOU S Y,et al.Identification of circRNA-miRNA networks for exploring an underlying prognosis strategy for breast cancer[J]. Epigenomics,2020,12(2):101-125.
[43]	WANG J,ZHANG Q,ZHOU S,et al.Circular RNA expression in exosomes derived from breast cancer cells and patients[J]. Epigenomics,2019,11(4):411-421.
[44]	XU H,GONG Z,SHEN Y,et al.Circular RNA expression in extracellular vesicles isolated from serum of patients with endometrial cancer[J]. Epigenomics,2018,10(2):187-197.
[45]	YANG C,WEI Y,YU L,et al.Identification of altered circular RNA expression in serum exosomes from patients with papillary thyroid carcinoma by high-throughput sequencing[J]. Med Sci Monit,2019,25:2785-2791.
[46]	FAN L,CAO Q,LIU J,et al.Circular RNA profiling and its potential for esophageal squamous cell cancer diagnosis and prognosis[J]. Mol Cancer,2019,18(1):16.

生物功能	circRNA名称	肿瘤类型	变化趋势	分子机制	临床参数分析	参考文献
调控细胞增殖	circRASSF2	喉鳞状细胞癌	↑	miRNA-302b-3p/IGF-1R	T分期、淋巴结转移	[10]
	circDB	HCC	↑	miRNA-34a/USP7/Cyclin A2		[11]
	circIFT80	结直肠癌	↑	miRNA-1236-3p/HOXB7	肿瘤分期、肿瘤大小、远处转移	[12]
	circFMN2	结直肠癌	↑	miRNA-1182	肿瘤大小、肿瘤分期、远处转移、TNM分期	[13]
	circNRIP1	胃癌	↑	miRNA-149-5p/AKT1/mTOR	肿瘤大小、淋巴浸润	[14]
	circ_0044516	前列腺癌	↑	miRNA-29a-3p	肿瘤转移	[15]
调控侵袭以及转移	circPTGR1	HCC	↑	miRNA449a/MET	临床分期、预后	[16]
	circ_100338	HCC	↑	HUVEC	生存时间、TNM分期、血管侵犯、肺转移	[17]
	circCdr1as	HCC	↑	miRNA-1270/AFP		[18]
	circRanGAP1	胃癌	↑	miRNA-877-3p/VEGFA	TNM分期、淋巴结转移、低生存率	[19]
	ciRS-133	胃癌	↑	miRNA-133/PRDM16	白色脂肪组织褐变	[20]
	circPED8A	胰腺癌	↑	miRNA-338/MACC1/MET	十二指肠浸润、血管浸润、T因子、TNM分期、低生存率	[21]
	circIARS	胰腺癌	↑	miRNA-12/RhoA	肝转移、脉管侵犯、TNM分期	[22]
	circPRMT5	膀胱尿路上皮癌	↑	miRNA-30c/SNAIL1/ E-钙黏蛋白	淋巴结转移、晚期进展	[23]
	circPUM1	卵巢癌	↑	miRNA-615-5p,miRNA-6753-5p		[24]
	circWHSC1	卵巢癌	↑	miRNA-1182,miRNA-145		[25]
	circ_0000677	结直肠癌	↑	Wnt/β-catenin		[26]
	circ_0000284	胆管癌	↑	miRNA-637/LY6E	分化程度、TNM分期、淋巴结浸润	[27]
调控药物耐药	FECR1	小细胞肺癌	↑	miRNA584-ROCK1	低生存率、化疗反应	[28]
	circCdr1as	卵巢癌	↓	miRNA-1270	顺铂耐药	[29]
	circ_0000338	结直肠癌	↑	/	奥沙利铂耐药	[30]
	ciRS-122	结直肠癌	↑	miRNA-122/M2-PK	奥沙利铂耐药	[31]

生物功能	circRNA名称	肿瘤类型	变化趋势	分子机制	临床参数分析	参考文献
调控细胞增殖	circRASSF2	喉鳞状细胞癌	↑	miRNA-302b-3p/IGF-1R	T分期、淋巴结转移	[10]
	circDB	HCC	↑	miRNA-34a/USP7/Cyclin A2		[11]
	circIFT80	结直肠癌	↑	miRNA-1236-3p/HOXB7	肿瘤分期、肿瘤大小、远处转移	[12]
	circFMN2	结直肠癌	↑	miRNA-1182	肿瘤大小、肿瘤分期、远处转移、TNM分期	[13]
	circNRIP1	胃癌	↑	miRNA-149-5p/AKT1/mTOR	肿瘤大小、淋巴浸润	[14]
	circ_0044516	前列腺癌	↑	miRNA-29a-3p	肿瘤转移	[15]
调控侵袭以及转移	circPTGR1	HCC	↑	miRNA449a/MET	临床分期、预后	[16]
	circ_100338	HCC	↑	HUVEC	生存时间、TNM分期、血管侵犯、肺转移	[17]
	circCdr1as	HCC	↑	miRNA-1270/AFP		[18]
	circRanGAP1	胃癌	↑	miRNA-877-3p/VEGFA	TNM分期、淋巴结转移、低生存率	[19]
	ciRS-133	胃癌	↑	miRNA-133/PRDM16	白色脂肪组织褐变	[20]
	circPED8A	胰腺癌	↑	miRNA-338/MACC1/MET	十二指肠浸润、血管浸润、T因子、TNM分期、低生存率	[21]
	circIARS	胰腺癌	↑	miRNA-12/RhoA	肝转移、脉管侵犯、TNM分期	[22]
	circPRMT5	膀胱尿路上皮癌	↑	miRNA-30c/SNAIL1/ E-钙黏蛋白	淋巴结转移、晚期进展	[23]
	circPUM1	卵巢癌	↑	miRNA-615-5p,miRNA-6753-5p		[24]
	circWHSC1	卵巢癌	↑	miRNA-1182,miRNA-145		[25]
	circ_0000677	结直肠癌	↑	Wnt/β-catenin		[26]
	circ_0000284	胆管癌	↑	miRNA-637/LY6E	分化程度、TNM分期、淋巴结浸润	[27]
调控药物耐药	FECR1	小细胞肺癌	↑	miRNA584-ROCK1	低生存率、化疗反应	[28]
	circCdr1as	卵巢癌	↓	miRNA-1270	顺铂耐药	[29]
	circ_0000338	结直肠癌	↑	/	奥沙利铂耐药	[30]
	ciRS-122	结直肠癌	↑	miRNA-122/M2-PK	奥沙利铂耐药	[31]

名称	肿瘤类型	研究对象		标本类型	趋势	临床参数分析	AUC	敏感性/%	特异性/%	参考文献
名称	肿瘤类型	病例数	对照例数	标本类型	趋势	临床参数分析	AUC	敏感性/%	特异性/%	参考文献
circ_0004771	结直肠癌	110	35（HC）	血清	↑	TNM分期、远处转移	0.88	80.91	82.86	[36]
circHIPK3	结直肠癌	20	20（HC）	血清	↑		0.771	71	80	[37]
circ_0065149	EGC	39	41（HC）	血浆	↓	肿瘤大小、外周神经侵袭	0.64	48.7	90.2	[38]
circ_0051443	HCC	60	60（HC）	血浆	↓	肝硬化	0.808 9			[39]
FECR1	小细胞肺癌	61	55（HC）	血清	↑	低生存率、化疗反应				[31]
circ_002178	肺腺癌	120	30（HC）	血清	↑		0.996 7			[40]
circ_0001492、 circ_0001346	肺腺癌	15	15（HC）	血浆	↑					[41]
circ_00005795、 circ_0088088	乳腺癌	8	8（HC）	血清	↓ ↑					[42-43]
circ_0000284	胆管癌	25	25（HC）	血浆	↑	肿瘤分化程度、TNM分期、淋巴结浸润				[27]
名称	肿瘤类型	研究对象		标本类型	趋势	临床参数分析	AUC	敏感性/%	特异性/%	参考文献
名称	肿瘤类型	病例数	对照例数	标本类型	趋势	临床参数分析	AUC	敏感性/%	特异性/%	参考文献
circPED8A	胰腺癌	93	20（HC）	血浆	↑	十二指肠浸润、血管浸润、T因子、TNM分期、低生存率				[21]
circIARS	胰腺癌	20（伴转移）	20（不伴转移）	血浆	↑	肝转移、脉管侵犯、TNM 分期				[22]
circ_0044516	前列腺癌	6	6（HC）	血液	↑					[15]
circPRMT5	膀胱尿路上皮癌	血清：71 尿液：18	血清：35 （HC）尿液：18 （HC）	血清尿液	↑	淋巴结转移、晚期肿瘤进展				[23]
circ_0109046、 circ_0002577	子宫内膜癌	10	10（HC）	血清	↑ ↑					[44]
circ_007293、 circ_031752、 circ_020135	甲状腺乳头状癌	3	3（良性甲状腺肿）	血清	↑ ↑ ↓					[45]
circ_0001946、 circ_0043603	食管鳞状细胞癌	50	50 （HC）	血浆	↓	预后	0.928	84	89	[46]

名称	肿瘤类型	研究对象		标本类型	趋势	临床参数分析	AUC	敏感性/%	特异性/%	参考文献
名称	肿瘤类型	病例数	对照例数	标本类型	趋势	临床参数分析	AUC	敏感性/%	特异性/%	参考文献
circ_0004771	结直肠癌	110	35（HC）	血清	↑	TNM分期、远处转移	0.88	80.91	82.86	[36]
circHIPK3	结直肠癌	20	20（HC）	血清	↑		0.771	71	80	[37]
circ_0065149	EGC	39	41（HC）	血浆	↓	肿瘤大小、外周神经侵袭	0.64	48.7	90.2	[38]
circ_0051443	HCC	60	60（HC）	血浆	↓	肝硬化	0.808 9			[39]
FECR1	小细胞肺癌	61	55（HC）	血清	↑	低生存率、化疗反应				[31]
circ_002178	肺腺癌	120	30（HC）	血清	↑		0.996 7			[40]
circ_0001492、 circ_0001346	肺腺癌	15	15（HC）	血浆	↑					[41]
circ_00005795、 circ_0088088	乳腺癌	8	8（HC）	血清	↓ ↑					[42-43]
circ_0000284	胆管癌	25	25（HC）	血浆	↑	肿瘤分化程度、TNM分期、淋巴结浸润				[27]
名称	肿瘤类型	研究对象		标本类型	趋势	临床参数分析	AUC	敏感性/%	特异性/%	参考文献
名称	肿瘤类型	病例数	对照例数	标本类型	趋势	临床参数分析	AUC	敏感性/%	特异性/%	参考文献
circPED8A	胰腺癌	93	20（HC）	血浆	↑	十二指肠浸润、血管浸润、T因子、TNM分期、低生存率				[21]
circIARS	胰腺癌	20（伴转移）	20（不伴转移）	血浆	↑	肝转移、脉管侵犯、TNM 分期				[22]
circ_0044516	前列腺癌	6	6（HC）	血液	↑					[15]
circPRMT5	膀胱尿路上皮癌	血清：71 尿液：18	血清：35 （HC）尿液：18 （HC）	血清尿液	↑	淋巴结转移、晚期肿瘤进展				[23]
circ_0109046、 circ_0002577	子宫内膜癌	10	10（HC）	血清	↑ ↑					[44]
circ_007293、 circ_031752、 circ_020135	甲状腺乳头状癌	3	3（良性甲状腺肿）	血清	↑ ↑ ↓					[45]
circ_0001946、 circ_0043603	食管鳞状细胞癌	50	50 （HC）	血浆	↓	预后	0.928	84	89	[46]