MicroRNAs as non-invasive diagnostic biomarkers for gastric cancer: Current insights and future perspectives

Table 1 Differentially expressed circulating microRNAs in gastric cancer

microRNA	Changes inGC	Changes inGC tissue	Controls (n)	GC(n)	TNM reported	ROC	Validation	Source (Pl/Bl/Se)	qPCR	Normalization(qPCR)	Ref.
let-7a	↓	↓	30	69	Yes		Yes	Plasma	TaqMan	RNU6b	[56]
	↓	↓	45	80	Yes			Serum	SYBR	RNU6b	[57]
	↔		30	30	Yes			Plasma	TaqMan	RNU6b	[58]
let-7c	↔		202	214	No			Serum	SYBR	standard curve	[59]
let-7e	↑		82	82	No	0.7	Yes	Serum	TaqMan	cel-miR-39	[60]
let-7f	↔		30	30	Yes			Plasma	TaqMan	RNU6b	[58]
	↑		202	214	No			Serum	SYBR	standard curve	[59]
let-7g	↔		30	30	No			Serum	SYBR	miR-16	[61]
let-7i	↑		202	214	No			Serum	SYBR	standard curve	[59]
miR-1	↑		127	164	Yes			Serum	TaqMan	volume	[62]
	↔		30	30	No			Plasma	SYBR	cel-miR-39	[63]
miR-100	↑		47	50	Yes	0.71		Serum	TaqMan	RNU6b	[52]
miR-103	↑		14	17	No			Plasma	SYBR	Sp6	[64]
	↔		50	50	No	0.548		Plasma	SYBR	cel-miR-39	[65]
miR-106a	↑		30	69	Yes		Yes	Plasma	TaqMan	RNU6b	[56]
	↑		27	41	No	0.684		PBMC	SYBR	RNU6b	[66]
	↔		30	30	No			Plasma	SYBR	cel-miR-39	[63]
	↑	↑	22	48	NA			Serum	NA	NA	[67]
	↑	↑	20	20	Yes		Yes	Serum	TaqMan	cel-miR-39 miR-191-5p	[68]
	↑		130	130	No	0.786	Yes	Serum + Exosomes	TaqMan	cel-miR-39	[69]
miR-106b	↑	↑	30	69	Yes	0.721	Yes	Plasma	TaqMan	RNU6b	[56]
	↑		90	90	Yes	0.773	Yes	Plasma	SYBR	cel-miR-39	[63]
	↑		15	31	Yes			Serum	TaqMan	cel-miR-39	[70]
	↑	↑	20	20	Yes			Plasma	TaqMan	cel-miR-39 RNU6b	[71]
	↓		36	40	Yes	0.856		Serum	SYBR	QuantoEC	[72]
	↑		65	65	Yes	0.898		Plasma	TaqMan	RNU6b	[73]
miR-107	↑	↑	36	36	No	0.63		Serum	SYBR	5srRNA	[74]
	↑		14	14	Yes			Serum	TaqMan	RNU6b	[75]
	↔		50	50	No	0.563		Plasma	SYBR	cel-miR-39	[65]
miR-10b-5p	↑	↑	167	203	Yes	0.627	Yes	Serum + exosomes	SYBR	cel-miR-39 miR-16	[76]
miR-122	↔		36	96	Yes			Plasma	SYBR	ath-miR-159a	[77]
miR-1233	↓		3	3	No			Plasma	SYBR	RNU6b	[78]
miR-130a	↑	↑	41	41	No	0.905		Serum	SYBR	RNU6B	[79]
	↑	↑	20	20	Yes		Yes	Serum	TaqMan	cel-miR-39 miR-191-5p	[68]
miR-132-3p	↑	↑	167	203	Yes	0.652	Yes	Serum + exosomes	SYBR	cel-miR-39 miR-16	[76]
miR-139	↓	↑	18	25	No	0.940		Plasma	SYBR	RNU6b	[80]
miR-140-5p	↑		50	50	Yes			Plasma	SYBR	RNU6B	[81]
miR-141	↓		3	3	No			Plasma	SYBR	RNU6b	[78]
	↓		14	17	No			Plasma	SYBR	Sp6	[64]
miR-142-3p	↓		285	285	Yes	0.839	Yes	Plasma	TaqMan	cel-miR-39	[47]
miR-143-3p	↔		73	206	Yes		Yes	Serum	SYBR	RNU6b	[82]
miR-144	↓	↓	40	96	Yes	0.821		Serum	SYBR	RNU6b	[83]
miR-146a	↔		15	31	Yes			Serum	TaqMan	cel-miR-39	[70]
	↔		73	206	Yes		Yes	Serum	SYBR	RNU6b	[82]
	↑	↔	20	20	Yes		Yes	Serum	TaqMan	cel-miR-39 miR-191-5p	[68]
miR-146b	↑	↔	20	20	Yes		Yes	Serum	TaqMan	cel-miR-39 miR-191-5p	[68]
miR-148a	↔		15	31	Yes			Serum	TaqMan	cel-miR-39	[70]
	↓		285	285	Yes	0.842	Yes	Plasma	TaqMan	cel-miR-39	[47]
	↓	↓	39	38	Yes	0.349		Plasma	TaqMan	miR-16-5p	[26]
miR-151-5p	↑		130	230	Yes	0.625	Yes	Plasma	TaqMan	RNU6b	[58]
miR-155	↑		20	30	No		Yes	Plasma	TaqMan	RNU6b	[84]
	↔		15	15	No			Plasma	TaqMan	RNU6b	[85]
miR-15b-5p	↑	↑	100	100	No			Plasma	SYBR	RNU6b	[86]
miR-16	↑		106	160	Yes	0.768-0.925	Yes	Plasma	TaqMan	cel-miR-39	[51]
	↑		47	50	Yes	0.90		Serum	TaqMan	RNU6b	[52]
	↓		129	189	Yes	0.772	Yes	Plasma	TaqMan	cel-miR-39 miR-16-5p	[53]
miR-17	↑		27	41	No	0.743		PBMC	SYBR	RNU6b	[66]
	↓		36	40	Yes	0.879		Serum	SYBR	QuantoEC	[72]
	↑		30	69	Yes		Yes	Plasma	TaqMan	RNU6b	[56]
	↔		30	30	No			Plasma	SYBR	cel-miR-39	[63]
	↔		20	20	No			Serum + exosomes	TaqMan	cel-miR-39	[69]
miR-181a	↑	↑	18	25	No	0.882		Plasma	SYBR	RNU6b	[80]
miR-181b	↓		89	92	Yes		Yes	Serum	SYBR	miR-16	[61]
miR-181c	↑	↑	60	30	No			Plasma	SYBR	RNU6b	[87]
miR-185	↑	↑	109	133	Yes	0.65	Yes	Plasma	SYBR	cel-miR-39 RNU6b	[88]
	↑	↔	167	203	Yes	0.637	Yes	Serum + exosomes	SYBR	cel-miR-39 miR-16	[76]
miR-187-3p	↑		61	61	Yes		Yes	Serum	SYBR	RNU6b	[89]
miR-18a	↑		50	50	Yes			Plasma	SYBR	RNU6B	[81]
	↑	↑	65	104	Yes	0.805		Plasma	TaqMan	RNU6b	[90]
miR-191	↑		82	82	No	0.63	Yes	Serum	TaqMan	cel-miR-39	[60]
	↑		58	57	Yes	0.849		Serum	TaqMan	miR-16	[49]
miR-192	↔		36	96	Yes			Plasma	SYBR	ath-miR-159a	[77]
miR-194	↑		3	3	No			Plasma	SYBR	RNU6b	[78]
	↔		50	50	No	0.512		Plasma	SYBR	cel-miR-39	[65]
miR-195	↓		285	285	Yes	0.765	Yes	Plasma	TaqMan	cel-miR-39	[47]
	↓	↓	36	62	Yes		Yes	Serum	SYBR	RNU6b	[91]
	↓		190	20	No			Plasma	(TaqMan)	global mean	[92]
	↑	↔	167	203	Yes	0.683	Yes	Serum + exosomes	SYBR	cel-miR-39 miR-16	[76]
mir-196a	↓	↑	14	17	No			Plasma	SYBR	Sp6	[64]
	↑	↑	126	98	Yes	0.864		Plasma	SYBR	miR-16	[93]
miR-196b	↑	↑	126	98	Yes	0.811		Plasma	SYBR	miR-16	[93]
miR-198	↔		30	30	Yes			Plasma	TaqMan	RNU6b	[58]
miR-199a-3p	↑		70	80	Yes	0.818	Yes	Plasma	TaqMan	RNU6b	[94]
	↑		130	230	Yes	0.837	Yes	Plasma	TaqMan	RNU6b	[58]
	↑		50	50	Yes			Plasma	SYBR	RNU6B	[81]
miR-19a	↑	↑	20	20	Yes		Yes	Serum	TaqMan	cel-miR-39 miR-191-5p	[68]
miR-19b	↑	↔	20	20	Yes		Yes	Serum	TaqMan	cel-miR-39 miR-191-5p	[68]
	↑		3	3	No			Plasma	SYBR	RNU6b	[78]
	↓		129	189	Yes	0.749	Yes	Plasma	TaqMan	cel-miR-39, miR-16-5p	[53]
	↑		130	130	No	0.769	Yes	Serum + exosomes	TaqMan	cel-miR-39	[69]
miR-200b	↓		14	17	No			Plasma	SYBR	Sp6	[64]
miR-200c	↑		15	52	Yes	0.715		blood	SYBR	RNU6b 5SrRNA	[95]
	↑		100	98	Yes			Serum	SYBR	RNU6b	[96]
miR-203	↓		89	92	Yes		Yes	Serum	SYBR	miR-16	[61]
	↓		22	130	Yes	0.707	Yes	Serum	TaqMan	cel-miR-39	[97]
miR-204	↓		40	115	Yes		Yes	Serum	SYBR	RNU6b	[98]
miR-206	↓		150	150	Yes	0.89		Serum	TaqMan	cel-miR-39	[99]
miR-20a	↑		127	164	Yes			Serum	TaqMan	volume	[62]
	↑		90	90	Yes	0.859	Yes	Plasma	SYBR	cel-miR-39	[63]
	↑	↑	30	30	No			Plasma	SYBR	RNU6b	[100]
	↑	↑	109	133	Yes	0.67	Yes	Plasma	SYBR	cel-miR-39 RNU6b	[88]
	↑	↑	28	28	No			Plasma	SYBR	RNU6b	[101]
	↑	↔	167	203	Yes	0.637	Yes	Serum + exosomes	SYBR	cel-miR-39 miR-16	[76]
	↑		12	12	No			Serum	SYBR	cel-miR-39	[102]
miR-21	↑		30	69	Yes		Yes	Plasma	TaqMan	RNU6b	[56]
	↑		20	53	Yes	0.853		Blood	SYBR	RNU6b	[103]
	↑		70	70	Yes	0.794	Yes	Plasma	TaqMan	cel-miR-39	[104]
	↑		39	30	Yes	0.81		Serum	SYBR	miR-16	[105]
	↑		20	40	Yes			Serum	All-in-one	Volume miR-16, miR-93	[48]
	↔		90	90	Yes			Plasma	SYBR	cel-miR-39	[63]
	↔		15	31	Yes			Serum	TaqMan	cel-miR-39	[70]
	↔		15	15	No			Plasma	TaqMan	RNU6b	[85]
	↑		50	50	Yes	0.912		Serum	SYBR	RNU6b	[106]
	↑		50	50	Yes	0.898		PBMC	SYBR	RNU6b	[106]
	↑	↑	14	17	No			Plasma	SYBR	Sp6	[64]
	↑		89	92	Yes		Yes	Serum	SYBR	miR-16	[61]
	↑	↑	20	20	Yes		Yes	Serum	TaqMan	cel-miR-39 miR-191-5p	[68]
miR-210	↑	↑	109	133	Yes	0.75	Yes	Plasma	SYBR	cel-miR-39 RNU6b	[88]
miR-212	↑	↔	20	20	Yes		Yes	Serum	TaqMan	cel-miR-39 miR-191-5p	[68]
miR-218	↓		70	70	Yes	0.743	Yes	Plasma	TaqMan	cel-miR-39	[104]
	↓		56	68	Yes			Serum	SYBR	cel-miR-39	[107]
miR-220	↑	↔	20	20	Yes		Yes	Serum	TaqMan	cel-miR-39 miR-191-5p	[68]
miR-221	↑		82	82	No	0.7	Yes	Serum	TaqMan	cel-miR-39	[60]
	↑		90	90	Yes	0.796	Yes	Plasma	SYBR	cel-miR-39	[63]
	↑		14	17	No			Plasma	SYBR	Sp6	[64]
miR-222	↑		82	82	No	0.65	Yes	Serum	TaqMan	cel-miR-39	[60]
	↑		56	114	Yes	0.85		Plasma	TaqMan	RNU6b	[108]
miR-223	↑		70	70	Yes	0.91	Yes	Plasma	TaqMan	cel-miR-39	[104]
	↑		15	31	Yes			Serum	TaqMan	cel-miR-39	[70]
	↑		47	50	Yes	0.85		Serum	TaqMan	RNU6b	[52]
	↑	↑	50	50	Yes	0.81		Plasma	SYBR	RNU6b	[109]
	↑		3	3	No			Plasma	SYBR	RNU6b	[78]
	↑	↑	20	20	Yes		Yes	Serum	TaqMan	cel-miR-39 miR-191-5p	[68]
	↑	↑	20	15	Yes			Plasma	NCode	cel-miR-39/-54/-238; miR-16	[110]
	↑	↑	39	38	Yes	0.671		Plasma	TaqMan	miR-16-5p	[26]
miR-23a	↑		14	17	No			Plasma	SYBR	Sp6	[64]
miR-23b	↑		50	138	Yes	0.80		Plasma	SYBR	RNU6b	[111]
miR-25	↔		10	10	No			Plasma	TaqMan	cel-miR-39	[104]
	↑		106	160	Yes	0.694-0.925	Yes	Plasma	TaqMan	cel-miR-39	[51]
	↑	↑	20	20	Yes			Plasma	TaqMan	cel-miR-39; RNU6b	[71]
	↑	↑	109	133	Yes	0.65	Yes	Plasma	SYBR	cel-miR-39; RNU6b	[88]
	↔	↑	70	70	Yes			Plasma	TaqMan	RNU6B	[112]
	↑		14	14	Yes			Serum	TaqMan	RNU6b	[75]
	↑		65	65	Yes	0.817		Plasma	TaqMan	RNU6b	[73]
miR-26a	↓		285	285	Yes	0.882	Yes	Plasma	TaqMan	cel-miR-39	[47]
miR-26b	↔		30	30	Yes			Plasma	TaqMan	RNU6b	[58]
miR-27a	↑		127	164	Yes			Serum	TaqMan	volume	[62]
	↑		82	82	No	0.67	Yes	Serum	TaqMan	cel-miR-39	[60]
	↔		30	30	No			Plasma	SYBR	cel-miR-39	[63]
	↔		15	31	Yes			Serum	TaqMan	cel-miR-39	[70]
	↑	↑	35	35	Yes	0.70	Yes	Plasma	TaqMan	RNU6b	[85]
miR-27b	↑		82	82	No	0.66	Yes	Serum	TaqMan	cel-miR-39	[60]
miR-296	↑	↔	20	20	Yes		Yes	Serum	TaqMan	cel-miR-39; miR-191-5p	[68]
	↑	↑	167	203	Yes	0.652	Yes	Serum + exosomes	SYBR	cel-miR-39 miR-16	[76]
miR-30a-5p	↔		20	20	No			Serum + exosomes	TaqMan	cel-miR-39	[69]
miR-30c	↑	↔	20	20	Yes		Yes	Serum	TaqMan	cel-miR-39; miR-191-5p	[68]
miR-31	↓		89	92	Yes		Yes	Serum	SYBR	miR-16	[61]
miR-32	↑	↑	40	40	No			Plasma	SYBR	RNU6b	[113]
miR-323-3p	↑	↔	20	20	Yes		Yes	Serum	TaqMan	cel-miR-39; miR-191-5p	[68]
miR-331	↑	↑	20	20	Yes		Yes	Serum	TaqMan	cel-miR-39; miR-191-5p	[68]
miR-335	↓	↓	7	4	No			Plasma	TaqMan	RNU6b	[114]
miR-34	↔		30	30	No			Plasma	SYBR	cel-miR-39	[63]
miR-346	↓		14	17	No			Plasma	SYBR	Sp6	[64]
miR-34a	↑		127	164	Yes			Serum	TaqMan	volume	[62]
miR-365	↑	↔	20	20	Yes		Yes	Serum	TaqMan	cel-miR-39; miR-191-5p	[68]
miR-370	↑	↑	12	40	Yes	0.79		Plasma	TaqMan	miR-16	[115]
miR-371-5p	↑		61	61	Yes		Yes	Serum	SYBR	RNU6b	[89]
miR-374	↑	↑	20	20	Yes		Yes	Serum	TaqMan	cel-miR-39; miR-191-5p	[68]
miR-375	↓	↓	20	20	No	0.835		Serum	TaqMan	RNU6b	[116]
	↓	↓	39	38	Yes	0.32		Plasma	TaqMan	miR-16-5p	[26]
miR-376a	↔	↑	108	65	Yes			Plasma	TaqMan	RNU6B	[117]
miR-376c	↑		82	82	No	0.71	Yes	Serum	TaqMan	cel-miR-39	[60]
	↔		30	30	No			Plasma	SYBR	cel-miR-39	[63]
	↑	↑	108	65	Yes	0.77		Plasma	TaqMan	RNU6B	[117]
miR-378	↑	↓	61	61	Yes	0.861	Yes	Serum	SYBR	RNU6b	[89]
	↔		30	30	No			Plasma	SYBR	cel-miR-39	[63]
	↓		14	17	No			Plasma	SYBR	Sp6	[64]
miR-421	↑		17	40	Yes	0.773		PBMC	SYBR	RNU6b	[118]
	↑		50	50	No		Yes	Serum (?)	SYBR	RNU6b	[119]
	↑		90	90	No	0.779		Serum	SYBR	RNU6b	[120]
	↑		90	90	No	0.821		PBMC	SYBR	RNU6b	[120]
miR-423-5p	↑		127	164	Yes			Serum	TaqMan	volume	[62]
	↔		30	30	No			Plasma	SYBR	cel-miR-39	[63]
miR-425	↔		58	57	Yes			Serum	TaqMan	miR-16	[49]
miR-433	↔		15	31	Yes			Serum	TaqMan	cel-miR-39	[70]
	↑	↔	20	20	Yes		Yes	Serum	TaqMan	cel-miR-39; miR-191-5p	[68]
miR-451	↑	↓	30	56	Yes	0.96	Yes	Plasma	TaqMan	RNU6b	[54]
	↔		90	90	Yes			Plasma	SYBR	cel-miR-39	[63]
	↑	↔	20	20	Yes		Yes	Serum	TaqMan	cel-miR-39; miR-191-5p	[68]
	↑		106	160	Yes	0.790-0.850	Yes	Plasma	TaqMan	cel-miR-39	[51]
	↔		73	206	Yes		Yes	Serum	SYBR	RNU6b	[82]
miR-484	↓	↓	14	17	No			Plasma	SYBR	Sp6	[64]
miR-486	↑	↓	30	56	Yes	0.92	Yes	Plasma	TaqMan	RNU6b	[54]
	↔		30	30	No			Plasma	SYBR	cel-miR-39	[63]
	↑		106	160	Yes	0.779-0.863	Yes	Plasma	TaqMan	cel-miR-39	[51]
	↓		14	17	No			Plasma	SYBR	Sp6	[64]
miR-501-3p	↔		73	206	Yes		Yes	Serum	SYBR	RNU6b	[82]
miR-518d	↑	↔	20	20	Yes		Yes	Serum	TaqMan	cel-miR-39; miR-191-5p	[68]
miR-518f	↑	↔	20	20	Yes		Yes	Serum	TaqMan	cel-miR-39; miR-191-5p	[68]
miR-627	↑	↑	111	123	Yes	0.937	Yes	Plasma	SYBR	RNU6B	[81]
miR-629	↑	↑	111	123	Yes	0.912	Yes	Plasma	SYBR	RNU6B	[81]
miR-652	↑	↑	111	123	Yes	0.918	Yes	Plasma	SYBR	RNU6B	[81]
miR-720	↔		30	30	Yes			Plasma	TaqMan	RNU6b	[58]
miR-744	↑		82	82	No	0.74	Yes	Serum	TaqMan	cel-miR-39	[60]
	↔		30	30	No			Plasma	SYBR	cel-miR-39	[63]
miR-92a	↑		106	160	Yes	0.732-0.913	Yes	Plasma	TaqMan	cel-miR-39	[51]
	↓		89	92	Yes		Yes	Serum	SYBR	miR-16	[61]
miR-92b	↑	↑	109	133	Yes	0.69	Yes	Plasma	SYBR	cel-miR-39; RNU6b	[88]
miR-93	↑	↑	20	20	Yes			Plasma	TaqMan	cel-miR-39; RNU6b	[71]
	↑		65	65	Yes	0.756		Plasma	TaqMan	RNU6b	[73]
miR-940	↓	↓	105	115	Yes	0.96	Yes	Plasma	SYBR	miR-16	[55]

GC: Gastric cancer; phen/chlor: Phenol-chloroform method; SYBR: SYBR Green; NA: Non available.

Table 2 Profiling of circulating microRNAs in gastric cancer

Ref.	Year	Source	Extraction Kit	Platform	Sample Origin	GC(number of technical runs)	Controls (number of technical runs)	pooled samples	GC(number ofpooled samples)	Controls (number ofpooled samples)
Liu et al[62]	2011	Serum	phen/chlor	Solexa	China	1	1	Yes	20	20
Song et al[60]	2012	Serum	miRNeasy	qPCR-array	China	1	1	Yes	14	14
Liu et al[89]	2012	Serum	mirVana	Agilent	China	7	10	No
Konishi et al[54]	2012	Plasma	mirVana	microarray	Japan	3	3	No
Gorur et al[92]	2013	Plasma	high-pure miRNA Isolation	TaqMan Array	Turkey	1	1	Yes	20	190
Shah et al[121]	2013	Blood	miRNeasy	Geniom Biochip	Poland	1	1	Yes	8	19
Li et al[58]	2013	Plasma	mirVana	Agilent	China	20	20	No
Zhu et al[51]	2014	Plasma	miRNeasy	TaqMan Array	China	1	1	Yes	40	40
Zhang et al[53]	2015	Plasma	mirVana	Agilent	China	16	18	No
Zhou et al[88]	2015	Plasma	mirVana	Exiqon	China	3	1	Yes	30	10
Shin et al[81]	2015	Plasma	Trizol miRNeasy	miRCURY LNA	China	5	5	No
Zhang et al[78]	2015	Plasma	mirVana	Agilent	China	3	3	No
Liu et al[55]	2016	Plasma	miRNeasy	miRCURY LNA	Hong-Kong	5	5	No
Qiu et al[47]	2016	Plasma	miRNeasy	Agilent	China	1	1	Yes	5	5
Treece et al[64]	2016	Plasma	miRCURY	GastroGenus miR Panel	United States	17	14	No
Jiang et al[82]	2017	Serum	unknown	miSeq	China	2	1	Yes	20	10
Huang et al[76]	2017	Serum	mirVana	Exiqon	China	3	1	Yes	30	10
Sierzega et al[68]	2017	Serum	miRNA ABC Purification	TaqMan Array	Poland	20	20	No

GC: Gastric cancer; phen/chlor: Phenol-chloroform method.