The correlation between microRNA-221/222 cluster overexpression and malignancy: an updated meta-analysis including 2693 patients

Figures & data

Table 1 The main characteristics and survival data of included 32 studies

First author	Year	Country	Test method	Cancer type	miRNA	Sample source	Outcome	HR (95% CI)	Sample size	Cutoff value
Gramantieri L^Citation4	2009	Italy	qRT-PCR	HCC	miR-221	Tissue	OS/DFS	(U)1.12 (0.81–1.56)/(U)1.56 (1.20–2.03)	51	Median
Greither T^Citation5	2010	Germany	qRT-PCR	PC	miR-222	Tissue	OS	(M)2.05 (1.05–4.00)	56	Median
Schaefer A^Citation8	2010	Germany	qRT-PCR	PCa	miR-221/miR-222	Tissue	DFS	(U)0.93 (0.30–2.89)/(U)0.69 (0.22–2.17)	76	Median
Wong QW^Citation16	2010	China	qRT-PCR	HCC	miR-222	Tissue	OS/DFS	(U)2.73 (1.41–5.30)/(U)2.18 (1.20–3.98)	76	Median
Wang Y^Citation17	2010	China	qRT-PCR	ALL	miR-221	Tissue	OS	(U)0.54 (0.30–0.97)	32	Median
Spahn M^Citation18	2010	Germany	qRT-PCR	PCa	miR-221	FFPE	DFS	(M) 0.53 (0.29–0.95)	92	Median
Pu XX^Citation19	2010	China	qRT-PCR	CRC	miR-221	Blood	OS	(M) 3.48 (1.04–11.65)	103	Youden index
Guo HQ^Citation20	2010	China	qRT-PCR	N/T L	miR-221	Blood	OS	(U) 0.40 (0.17–0.95)/(M) 0.18 (0.06–0.56)	79	Youden index
Wang RM^Citation21	2011	China	qRT-PCR	GC	miR-221	Tissue	OS	(U) 5.85 (2.32–14.72)	96	Median
Li JP^Citation9	2011	China	qRT-PCR	HCC	miR-221	Blood	OS	(M) 1.90 (1.24–2.98)	46	Average fold change
Yoon SO^Citation22	2011	Korea	qRT-PCR	HCC	miR-221	FFPE	DFS	(M) 3.07 (1.56–6.07)	115	Fold change =1
Karakatsanis A^Citation23	2011	Greece	qRT-PCR	HCC	miR-221	FFPE	OS	(M) 1.79 (1.24–2.58)	60	Average fold change
Liu K^Citation24	2012	China	qRT-PCR	GC	miR-221	Tissue	OS	(M) 2.32 (1.11–4.85)	92	Mean
Zhang C^Citation25	2012	China	ISH	GM	miR-221/miR-222	Tissue	OS	(U) 2.03 (1.18–3.50)/(U) 2.56 (1.16–5.65)	50	Final score =3
Rong M^Citation26	2013	China	qRT-PCR	HCC	miR-221	FFPE	DFS	(U) 1.40 (0.91–2.15)	48	Median
Amankwah EK^Citation27	2013	USA	qRT-PCR	PCa	miR-221	FFPE	DFS	(U) 1.79 (0.67–4.77)	65	Median
Kim BH^Citation28	2013	Korea	qRT-PCR	GC	miR-221	FFPE	OS	(M) 1.50 (0.70–2.90)	91	Fold change =3
Gyöngyösi B^Citation29	2014	Italy	qRT-PCR	HCC	miR-221	FFPE	OS/PFS	(U) 1.92 (0.61–6.10)/(U) 1.32 (0.47–3.66)	20	Median
					miR-222	OS/PFS	(U) 2.04 (0.64–6.46)/(U) 1.43 (0.51–3.99)
Tao K^Citation30	2014	China	qRT-PCR	CRC	miR-221	FFPE	OS	(U) 2.42 (1.31–4.45)/(M) 2.04 (1.10–3.81)	90	Median
Fu ZC^Citation31	2014	China	qRT-PCR	GC	miR-222	Blood	DFS	(U) 4.49 (2.68–7.49)/(M) 3.41 (1.84–6.16)	114	2.23
Li P^Citation32	2014	China	qRT-PCR	CMM	miR-221	Blood	OS/DFS	(M) 3.19 (1.78–6.78)/(M) 2.12 (1.96–8.55)	72	2.95
Mao KP^Citation33	2014	China	qRT-PCR	NSCLC	miR-222	Tissue	OS	(M) 3.31 (1.97–5.58)	100	Median
Cai K^Citation34	2015	China	qRT-PCR	CC	miR-221	Tissue	OS	(U) 2.19 (1.11–4.43)/(M) 2.39 (1.21–4.91)	182	Median
Zhang YH^Citation35	2015	China	qRT-PCR	NSCLC	miR-221	Tissue	OS	(U) 1.87 (1.27–2.76)/(M) 1.87 (1.27–2.77)	104	Mean
Yang Z^Citation36	2015	China	qRT-PCR	OSM	miR-221	Blood	OS/RFS	(M) 7.66 (1.83–15.92)/(M) 6.82 (1.33–13.69)	108	Median
Goto Y^Citation37	2015	Japan	qRT-PCR	PCa	miR-222	Tissue	PFS	(U) 0.35 (0.14–0.92)/(M) 0.21 (0.07–0.64)	92	NM
Eissa S^Citation6	2015	Egypt	qRT-PCR	BC	miR-221	Tissue	RFS	(M) 14.84 (1.80–9.50)	76	1.03
Liao L^Citation38	2016	China	qRT-PCR	NSCLC	miR-221/miR-222	Tissue	PFS	(U) 2.52 (1.07–5.92)/(U) 3.15 (1.30–7.65)	55	Median
Xie DF^Citation39	2017	China	qRT-PCR	HCC	miR-221	Tissue	OS	(M) 1.74 (1.00–3.77)	70	≥1.795
Liu Y^Citation40	2017	China	qRT-PCR	NSCLC	miR-221	Tissue	OS	(M) 2.58 (1.41–4.85)	151	Median
Deng L^Citation10	2017	China	qRT-PCR	TNBC	miR-221	Tissue	DFS	(U) 0.49 (0.27–0.88)/(M) 0.48 (0.26–0.88)	125	NM
Zhao H^Citation41	2017	USA	qRT-PCR	GBM	miR-222	Blood	DFS	(U) 1.71 (1.07–3.63)	106	Median

Abbreviations: TNBC, triple-negative breast cancer; BC, breast cancer; NSCLC, non-small cell lung cancer; HCC, hepatocellular carcinoma; GC, gastric cancer; CRC, colorectal cancer; ALL, acute lymphoblastic leukemia; CMM, cutaneous malignant melanoma; CC, colon cancer; N/T L, NK/T-cell lymphoma; GBM, glioblastoma; GM, glioma; OSM, osteosarcoma; PC, pancreatic cancer; PCa, prostate cancer; NM, not mentioned; qRT-PCR, quantitative reverse transcription-polymerase chain reaction; OS, overall survival; DFS, disease-free survival; ISH, in situ hybridization; PFS, progression-free survival; RFS, relapse-free survival.

Figure 1 Flow diagram of the study selection process in the meta-analysis.

Abbreviations: CBM, Chinese Biomedical Literature Database; CNKI, Chinese National Knowledge Infrastructure.

Table 2 Stratified analysis of the high expression of miR-221/222 family and overall survival

Categories	Subgroups	Univariate analyses					multivariate analyses
		No of dataset	HR (95% CI)	P-value	I^2	Ph	No of dataset	HR (95% CI)	P-value	I^2	Ph
All		12	1.26 (1.07–1.47)	0.004	75%	0.000	15	2.10 (1.63–2.69)	0.000	56%	0.004
Country	China	9	1.28 (1.05–1.56)	0.02	79%	0.000	12	2.19 (1.60–3.01)	0.000	64%	0.001
	Others	3	1.09 (0.95–1.24)	0.21	0%	0.45	3	1.28 (1.12–1.48)	0.000	0%	0.82
Test method	qRT-PCR	10	1.23 (1.02–1.48)	0.03	78%	0.000	15	2.10 (1.63–2.69)	0.000	56%	0.004
	ISH	2	1.40 (1.16–1.71)	0.000	0%	0.64	/	/	/	/	/
Sample source	FFPE	3	1.42 (1.15–1.76)	0.001	0%	0.93	3	1.29 (1.12–1.48)	0.000	0%	0.82
	Tissue	8	1.30 (1.08–1.58)	0.005	78%	0.000	7	1.37 (1.24–1.52)	0.000	0%	0.94
	Blood	1	0.67 (0.46–0.98)	0.04	/	/	5	1.35 (0.90–2.03)	0.15	85%	0.000
miR221/222	miR221	9	1.20 (1.00–1.45)	0.05	79%	0.000	13	2.01 (1.52–2.65)	0.000	58%	0.004
Component	miR222	3	1.50 (1.23–1.84)	0.000	0%	0.91	2	2.73 (1.72–4.33)	0.000	19%	0.27
Sample size	≥100	2	1.33 (1.15–1.55)	0.000	0%	0.70	6	2.72 (1.96–3.79)	0.000	35%	0.18
	<100	10	1.24 (1.02–1.51)	0.03	78%	0.000	9	1.27 (1.10–1.47)	0.001	60%	0.01
Cancer type	NSCLC	1	1.87 (1.27–2.76)	0.002	/	/	3	2.42 (1.69–3.45)	0.000	35%	0.22
	HCC	4	1.71 (1.00–2.90)	0.05	53%	0.09	3	1.83 (1.38–2.42)	0.000	0%	0.97
	others	7	1.64 (0.87–3.10)	0.13	83%	0.000	9	2.05 (1.26–3.33)	0.004	71%	0.000

Note: The bold font indicated P-value of the HR was <0.05.

Abbreviations: NSCLC, non-small cell lung cancer; HCC, hepatocellular carcinoma; qRT-PCR, quantitative reverse transcription-polymerase chain reaction; ISH, in situ hybridization; FFPE, formalin-fixed and paraffin-embedded; HR, hazard ratio; CI, confidence interval; P^h, P-value of heterogeneity test.

Figure 2 Forest plot of the association between high expression of miR-221/222 family in various tumors and OS under different types of analysis.

Note: (A) univariate analysis; (B) multivariate analysis.

Abbreviations: HR, hazard ratio; OS, overall survival; SE, standard error.

Figure 3 Forest plot of the association between high expression of miR-221/222 family in various tumors and DFS under different types of analysis.

Note: (A) univariate analysis; (B) multivariate analysis.

Abbreviations: DFS, disease-free survival; HR, hazard ratio; SE, standard error.

Figure 4 One-way sensitivity analysis of high expression of miR-221/222 family in various tumors with OS under different types of analysis.

Note: (A) univariate analysis; (B) multivariate analysis.

Abbreviation: OS, overall survival.

Figure 5 Funnel plot analysis of publication bias of high expression of miR-221/222 family in various tumors with OS under different types of analysis.

Notes: (A) univariate analysis; (B) multivariate analysis.

Abbreviations: HR, hazard ratio; OS, overall survival.

Figure S1 Forest plot of the association between high expression of miR-221/222 family in various tumors and PFS under different types of analysis. (A: univariate analysis; B: multivariate analysis).

Abbreviations: HR, hazard ratio; PFS, progression-free survival; SE, standard error.

Figure S2 Forest plot of the association between high expression of miR-221/222 family in various tumors and RFS under multivariate analysis.

Abbreviations: HR, hazard ratio; RFS, relapse free survival; SE, standard error.

Figure S3 One-way sensitivity analysis of high expression of miR-221/222 family in various tumors with DFS under different types of analysis.

Note: (A) univariate analysis; (B) multivariate analysis.

Abbreviation: DFS, disease-free survival.

Figure S4 Forest plot of the association between high expression of miR-221/222 family in prostate cancer and DFS/RFS.

Abbreviations: HR, hazard ratio; DFS, disease-free survival; RFS, relapse free survival; SE, standard error.

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