MicroRNAs as prognostic biomarkers for survival outcome in osteosarcoma: A meta-analysis

Table 1 Characteristics of eligible studies in this meta-analysis

Ref.	Country	MicroRNA	MicroRNA expression1	Sample size			Specimen	Cut off value	Follow-up (mo)	Outcome	Detection method	Survival analysis	Source of HR	NOS score
				Total	Low	High
Yuan et al[20], 2012	China	miR-21	High	65	NR	NR	Serum	Median	46	OS	RT-PCR	U/M	Reported	6
Ji et al[21], 2013	China	miR-133a	Low	92	46	46	Tissue	Median	60	OS	RT-PCR	U	K-M curve	6
Cai et al[22], 2013	China	miR-210	High	92	44	48	Tissue	Median	100	OS/PFS	RT-PCR	U	K-M curve	6
Yang et al[23], 2013	China	miR-132	Low	166	90	76	Tissue	Median	100	OS/DFS	RT-PCR	U/M	K-M curve	6
Li et al[24], 2014	China	miR-17-92	High	117	45	72	Tissue	Median	60	OS/RFS	RT-PCR	U/M	Reported	6
Xu et al[25], 2014	China	miR-9	High	79	39	40	Tissue	Median	60	OS	RT-PCR	M	Reported	6
Zhang et al[26], 2014	China	miR-133b/ 206	Low	100	NR	NR	Serum	2.7/2.8	40	OS/DFS	RT-PCR	M	K-M curve	8
Cai et al[27], 2014	China	miR-340	Low	92	NR	NR	Tissue	Median	100	OS/PFS	RT-PCR	M	K-M curve	7
Fei et al[28], 2014	China	miR-9	High	118	NR	NR	Serum	Median	80	OS	RT-PCR	U	K-M curve	6
Zhang et al[13], 2014	China	miR-196a/b	High	100	NR	NR	Serum	4.9/5.5	40	OS/DFS	RT-PCR	M	K-M curve	8
Ma et al[29], 2014	China	miR-148a	High	148	NR	NR	Plasma	Median	100	OS/DFS	RT-PCR	U/M	K-M curve	7
Lin et al[30], 2014	China	miR-17-92	High	63	25	38	Tissue	Median	60	OS	RT-PCR	U	K-M curve	6
Song et al[31], 2014	China	miR-26a	Low	144	63	81	Tissue	Median	150	OS/DFS	RT-PCR	M	K-M curve	7
Wang et al[32], 2014	China	miR-214	High	82	33	49	Tissue	Median	60	OS/FFS	RT-PCR	U	K-M curve	7
Cai et al[33], 2015	China	miR-195	Low	166	88	78	Serum	1.44	100	OS/DFS	RT-PCR	M	K-M curve	8
Liu et al[34], 2015	China	miR-126	Low	122	60	62	Tissue	Median	60	OS	RT-PCR	M	Reported	7
Sun et al[35], 2015	China	miR-217	Low	168	84	84	Tissue	Median	80	OS	RT-PCR	U/M	Reported	6
Wang, et al[36], 2015	China	miR-152	Low	80	42	38	Serum	Median	60	OS	RT-PCR	M	Reported	6
Yang et al[37], 2015	China	miR-221	High	108	55	53	Serum	Median	60	OS/RFS	RT-PCR	M	Reported	7
Tang et al[38], 2015	China	miR-27a	High	166	80	86	Serum	Median	100	OS/DFS	RT-PCR	U/M	K-M curve	8
Wang et al[39], 2015	China	miR-191	High	100	42	58	Serum	3.56	60	OS/DFS	RT-PCR	M	K-M curve	8
Cao et al[40], 2016	China	miR-326	Low	60	25	35	Serum	Median	60	OS	RT-PCR	M	Reported	6
Dong et al[41], 2016	China	miR-223	Low	112	53	59	Serum	Median	60	OS	RT-PCR	M	Reported	6
Liu et al[42], 2016	China	miR-300	High	114	46	68	Serum	Median	60	OS/DFS	RT-PCR	U/M	Reported	6
Luo et al[14], 2016	China	miR-125b	Low	56	NR	NR	Plasma	Median	30	OS	RT-PCR	U/M	Reported	7
Niu et al[43], 2016	China	miR-95-3p	Low	133	97	36	Serum	Median	60	OS	RT-PCR	M	Reported	7
Pang et al[44], 2016	China	miR-497	Low	185	91	94	Serum	Median	70	OS	RT-PCR	U/M	Reported	7
Li et al[45], 2016	China	miR-145	low	39	19	20	Tissue	Median	60	OS	RT-PCR	U	K-M curve	7
Zhang and Wang[46], 2016	China	miR-222	High	57	28	29	Serum	Median	80	OS/DFS	RT-PCR	U/M	K-M curve	7
Ren et al[47], 2016	China	miR-21	High	84	33	51	Tissue	Median	100	OS/DFS	RT-PCR	U/M	K-M curve	6
Wang et al[48], 2017	China	miR-34a	low	120	NR	NR	Serum	4.16	60	OS	RT-PCR	M	Reported	7
Yang et al[49], 2017	China	miR-203	Low	103	52	51	Tissue	Median	60	OS/DFS	RT-PCR	U/M	Reported	7
Zhu et al[11], 2017	China	miR-17-5p	High	62	NR	NR	Plasma	Median	70	OS/PFS	RT-PCR	U/M	Reported	6
Nakka et al[50], 2017	United States	miR-221	Low	32	NR	NR	Plasma	Median	150	OS	RT-PCR	M	K-M curve	6
Zou et al[51], 2017	China	miR-19a	High	166	80	86	Tissue	Median	100	OS/DFS	RT-PCR	U/M	Reported	7
Hu et al[52], 2017	China	miR-19a	High	32	NR	NR	Tissue	Median	50	OS	RT-PCR	U/M	Reported	6
Wang et al[53], 2017	China	miR-491	Low	102	58	44	Serum	Median	60	OS	RT-PCR	U/M	Reported	7
Wang et al[54], 2017	China	miR-491-5p	Low	72	36	36	Tissue/ Serum	Median	60	OS/DFS	RT-PCR	M	Reported	6
Tang et al[55], 2017	China	miR-490-3p	Low	148	76	72	Tissue	Median	70	OS	RT-PCR	M	K-M curve	6
Gao et al[56], 2018	China	miR-564	Low	217	107	110	Tissue	Median	60	OS/DFS	RT-PCR	M	K-M curve	7
Yao et al[57], 2018	China	miR-101	Low	152	82	70	Serum	Median	60	OS/RFS	RT-PCR	U/M	K-M curve	6
Cong et al[58], 2018	China	miR-124	Low	114	NR	NR	Serum	Median	60	OS/DFS	RT-PCR	M	Reported	6
Liu et al[59], 2018	China	miR-375	Low	95	47	48	Serum	Median	60	OS	RT-PCR	M	Reported	6
Zhong et al[60], 2018	China	miR-1270	High	143	69	74	Tissue	Median	70	OS	RT-PCR	U/M	Reported	7
Li et al[61], 2018	China	miR-542-3p	High	76	NR	NR	Serum	0.87	70	OS/DFS	RT-PCR	U/M	Reported	8
Zhou et al[62], 2018	China	miR-139-5p	Low	98	53	45	Serum	Median	60	OS	RT-PCR	U/M	Reported	7
Heishima et al[63], 2019	Japan	miR-214	High	106	NR	NR	Plasma	Median	72	OS/DFS	RT-PCR	U/M	Reported	7
Liang et al[12], 2019	China	miR-765	Low	33	NR	NR	Tissue	Median	72	OS	RT-PCR	U/M	Reported	6
Xu, et al[64], 2019	China	miR-106b	High	134	64	70	Tissue	Median	60	OS	RT-PCR	M	Reported	7
Diao et al[65], 2020	China	miR-22	Low	120	60	60	Plasma	Median	60	OS	RT-PCR	U/M	Reported	6
Li et al[66], 2020	China	miR-1826	Low	122	69	53	Tissue	Median	60	OS	RT-PCR	U/M	Reported	7
Li et al[67], 2020	China	miR-629	High	110	45	65	Tissue	Median	60	OS	RT-PCR	M	Reported	7
Yang et al[68], 2020	China	miR-21/ 214	High	63	NR	NR	Tissue	Median	60	OS	RT-PCR	M	Reported	7
Shi et al[69], 2020	China	miR-194	Low	124	69	55	Serum	Median	60	OS/DFS	RT-PCR	M	Reported	7

¹MicroRNA expression with poor prognosis.

High: High expression; Low: Low expression; OS: Overall survival; PFS: Progression-free survival; DFS: Disease-free survival; RFS: Recurrence-free survival; NR: Not reported; M: Multivariate analysis; U: Univariate analysis; NOS: Newcastle-Ottawa scale; RT-PCR: Real-time reverse transcription-PCR.

Table 2 Hazard ratios and 95% confidence intervals of survival outcome extracted from included studies

Ref.	MicroRNA	OS		PFS		DFS		RFS	P
		HR (95%CI)	P	HR (95%CI)	P	HR (95%CI)	P	HR (95%CI)
Yuan et al[20], 2012	miR-21	2.33 (1.11-4.89)	0.026
Ji et al[21], 2013	miR-133a	1.87 (1.12–3.31)	0.015	2.6 (0.8–7.2)	0.02
Cai et al[22], 2013	miR-210	3.3 (1.0–8.1)	0.01
Yang et al[23], 2013	miR-132	4.9 (1.0–10.2)	0.001			4.1 (0.8–9.7)	0.006
Li et al[24], 2014	miR-17-92	2.94 (1.51-5.75)	0.002					2.50 (1.77-6.92)	0.001
Xu et al[25], 2014	miR-9	4.77 (2.86–5.91)	0.002
Zhang et al[26], 2014	miR-133b	5.36 (1.26-11.03)	0.02			5.69 (1.33-11.26)	0.02
Zhang et al[26], 2014	miR-206	5.42 (1.31-11.28)	0.02			5.88 (1.56-12.08)	0.02
Zhang et al[26], 2014	miR-133b/206	9.28 (2.69-20.79)	0.001			9.69 (2.80-21.82)	0.001
Cai et al[27], 2014	miR-340	6.2 (1.4–13.9)	0.006	4.5 (1.0–9.2)	0.01
Fei et al[28], 2014	miR-9	3.18 (1.35-4.42)	0.002
Zhang et al[13], 2014	miR-196a	6.28 (1.62–13.39)	0.01			6.95 (1.63–14.61)	0.01
Zhang et al[13], 2014	miR-196b	6.33 (1.61–13.48)	0.01			6.98 (1.65–14.82)	0.01
Zhang et al[13], 2014	miR-196a/196b	9.89 (2.66–20.98)	0.001			10.09 (2.82–21.99)	0.001
Ma et al[29], 2014	miR-148a	2.70 (1.41-5.17)	0.003			2.53 (1.28-5.01)	0.008
Lin et al[30], 2014	miR-17-92	2.93 (1.25-6.88)	0.007
Song et al[31], 2014	miR-26a	5.72 (1.01-10.94)	0.007			3.97 (1.19-9.87)	0.014
Wang et al[32], 2014	miR-214	5.6 (1.2–12.9)	0.008	3.5 (1.0–8.2)	0.01
Cai et al[33], 2015	miR-195	5.16 (1.92-11.88)	0.002			3.62 (1.83-9.09)	0.01
Liu et al[34], 2015	miR-126	3.10 (1.11–9.02)	0.018
Sun et al[35], 2015	miR-217	2.83 (1.13–7.05)	0.026
Wang et al[36], 2015	miR-152	0.13 (0.02–0.70)	0.004
Yang et al[37], 2015	miR-221	7.66 (1.83–15.92)	0. 01					6.82 (1.33–13.69)	0.01
Tang et al[38], 2015	miR-27a	2.17 (1.30-3.62)	0. 01			1.39 (0.46-4.22)	0. 01
Wang, et al[39], 2015	miR-191	3.56 (1.62–7.88)	0.01			2.63 (1.28–6.06)	0.02
Cao et al[40], 2016	miR-326	3.90 (1.13-12.53)	0.001
Dong et al[41], 2016	miR-223	4.59 (1.84–11.45)	0.001
Liu et al[41], 2016	miR-300	5.96 (2.35-10.70)	0.009			5.11 (2.14-9.48)	0.019
Luo et al[14], 2016	miR-125b	0.49 (0.24-0.10)	0.049
Niu et al[43], 2016	miR-95-3p	4.22 (2.31–8.07)	0.014
Pang et al[44], 2016	miR-497	3.79 (1.99-8.57)	0.004
Li et al[45], 2016	miR-145	2.07 (1.17-3.66)	0.0124
Zhang and Wang[46], 2016	miR-222	1.19 (1.05-1.36)	0.008			1.23 (1.07-1.40)	0.003
Ren et al[47], 2016	miR-21	6.3 (1.8–12.4)	0.001			5.8 (1.7–13.5)	0.001
Wang et al[48], 2017	miR-34a	3.18 (2.87-9.56)	0.001
Yang et al[49], 2017	miR-203	2.73 (1.69-8.91)	0.01			4.19 (2.91-10.12)	0.005
Zhu et al[11], 2017	miR-17-5p	10.47 (2.29-47.87)	0.002	5.53 (2.02-15.16)	0.001
Nakka et al[50], 2017	miR-221	0.73 (0.49-1.11)	0.139
Zou et al[51], 2017	miR-19a	5.06 (1.12–11.62)	0.001			4.66 (0.88–10.97)	0.006
Hu et al[52], 2017	miR-19a	2.62 (2.12-6.15)	0.037
Wang et al[53], 2017	miR-491	2.96 (1.09-8.07)	0.03
Wang et al[54], 2017	miR-491-5p	2.55 (1.28-4.64)	0.039			2.44 (1.21-4.51)	0.03
Wang et al[54], 2017	miR-491-5p	2.72 (1.30-4.92)	0.028			2.64 (1.27-5.02)	0.022
Tang et al[55], 2017	miR-490-3p	2.13 (1.33-7.76)	0.001
Gao et al[56], 2018	miR-564	4.25 (1.66-8.63)	0.001			4.63 (1.88-9.38)	0.001
Yao et al[57], 2018	miR-101	3.82 (1.34-6.52)	0.014			4.23 (1.45-7.22)	0.008
Cong et al[58], 2018	miR-124	3.54 (1.38–5.64)	0.019			3.92 (1.57–6.39)	0.012
Liu et al[59], 2018	miR-375	3.27 (1.36-7.85)	0.008
Zhong et al[60], 2018	miR-1270	4.34 (4.08–4.79)	0.018
Li et al[61], 2018	miR-542-3p	5.98 (3.26–18.44)	0.01			6.89 (2.83–9.67)	0.018
Zhou et al[62], 2018	miR-139-5p	3.24 (1.81–4.76)	0.007
Heishima et al[63], 2019	miR-214	2.95 (1.35-7.77)	0.005			3.51 (1.68-8.55)	0.0004
Liang et al[12], 2019	miR-765	0.39 (0.20-0.77)	0.007
Xu, et al[64], 2019	miR-106b	2.77 (1.37-5.60)	0.005
Diao et al[65], 2020	miR-22	3.31 (1.41-7.77)	0.006
Li et al[66], 2020	miR-1826	2.45 (1.25-4.37)	0.014
Li et al[67], 2020	miR-629	2.89 (1.13-7.42)	0.027
Yang et al[68], 2020	miR-21	3.46 (2.17-11.52)	0.013
Yang et al[68], 2020	miR-214	3.14 (2.01-10.26)	0.017
Shi et al[69], 2020	miR-194	3.65 (1.58-5.89)	0.014			4.39 (1.90-6.91)	0.005

HR: Hazard ratio; CI: Confidence interval; OS: Overall survival; PFS: Progression-free survival; DFS: Disease-free survival; RFS: Recurrence-free survival.

Table 3 Subgroup analyses of the relationship between microRNA expression and overall survival.

years

Subgroup	Number of datasets	Heterogeneity		Pooled HR (95%CI)	P value
		I2 (%)	P value
Overall	60	89.0%	0.000	2.92 (2.43–3.41)	0.000
Expression
High	27	91.4%	0.000	3.56 (2. 59–4.54)	0.000
Low	33	74.5%	0.000	2.23 (1. 74–2.72)	0.000
Specimen
Tissue	26	92.1%	0.000	3.20 (2.16–4.23)	0.000
Serum	28	77.1%	0.000	3.04 (2.37–3.71)	0.000
Plasma	6	53.7%	0.055	0.94 (0.36–1.51)	0.001
Survival analysis
U	6	0.0%	0.569	2.36 (1.67–3.04)	0.000
M	30	76.9%	0.000	3.29 (2.52–4.07)	0.000
U/M	24	93.9%	0.000	2.73 (1.95–3.50)	0.000
Source of HR
Reported	35	92.6%	0.000	3.00 (2.21–3.79)	0.000
K-M curve	25	65.6%	0.000	2.48 (1.92–3.04)	0.000
Follow-up
≤ 5 years	40	76.2%	0.000	3.08 (2.44–3.71)	0.000
	> 5	20	94.8%	0.000	2.75 (1.88–3.63)	0.000
Country
China	58	89.0%	0.000	3.05 (2.52–3.57)	0.000
Non-China	2	44.9%	0.178	1.24 (0.59–3.07)	0.183

OS: Overall survival; M: Multivariate analysis; U: Univariate analysis; HR: Hazard ratio; CI: Confidence interval.