Survival advantage and clinicopathological significance of microRNA-22 in cancers: a meta-analysis

Figures & data

Table 1 Main characteristics of 26 studies after screening

Study ID	Origin of population	Tissue type	Disease	Specimen	Number	Stage	miR-22 assay	Cutoff	Survival analysis	HR (95% CI)	p-value	Follow-up time (months)
Wan 2014^Citation21	China	Fresh	EOC	Tissue	109	I-IV	qRT-PCR	Median value	OS/PFS	Reported	0.007/0.005	60
Delfino 2013^Citation23	TCGA	–	EOC	Tissue	418/249	I-IV	qRT-PCR	NR	OS/RFS	Reported	<0.0001	160
Li 2013^Citation42	China	FTT	EOC	Tissue	45	I-IV	qRT-PCR	Mean values	OS/PFS	SC	0.550/0.175	80/160
Zhou 2013^Citation25	China	FTT	HCC	Tissue	192	I-IV	qRT-PCR	Median value	OS	SC	0.046	80
Zhang 2010^Citation43	China	–	HCC	Tissue	160	I-IV	qRT-PCR	Median value	DFS	SC	0.025	48
Chen 2016^Citation24	TCGA	FTT	HCC	Tissue	372	I-IV	qRT-PCR	Mean value	OS	Reported	0.0109	120
Zhang 2012^Citation44	China	FFPE	CRC	Tissue	86	I-IV	qRT-PCR	Median value	OS	Reported	0.042	68
Slattery 2015^Citation29	American	FTT	CRC	Tissue	1141	I-IV	qRT-PCR	Mean value	OS (Co/Re)	Reported	>0.05	120
Xia 2017^Citation45	China	–	CRC	Tissue	110	I-IV	qRT-PCR	log2 (miR-22)>0	RFS	Reported	0.0018	82
Zuo 2015^Citation31	China	Fresh	GC	Tissue	61	I-IV	qRT-PCR	Mean value	OS	SC	0.038	40
Tang 2015^Citation46	China	FFPE	GC	Tissue	89	I-IV	ISH	Expression score	–	–	–	–
Wang.2013^Citation47	China	FTT	GC	Tissue	98	I-IV	qRT-PCR	Median value	OS	Reported	0.04	60
Patel 2011^Citation27	GEO	Fresh	BC	Tissue	1809	NR	qRT-PCR	Mean value	OS/RFS/MFS	Reported	0.82/0.0047/0.06	170
Chen 2015^Citation26	China	FTT	BC	Tissue	122	I-IV	qRT-PCR	Median value	OS/DFS	Reported/SC	0.006/0.003	120
Yoshimoto 2011^Citation28	Japan	–	BC	Tissue	171	I-IV	qRT-PCR	Mean value	OS	Reported	0.67	150
Song 2013^Citation30	American	FTT	BC	Tissue	108	I-IV	qRT-PCR	NR	RFS	Reported	0.022	84
Fan 2016^Citation48	China	FTT	RCC	Tissue	68	I-IV	qRT-PCR	Mean value	–	–	–	–
Zhang 2016^Citation49	China	FTT	RCC	Tissue	50	I-IV	qRT-PCR	Median value	–	–	–	–
Wang 2015^Citation50	China	-	OST	Tissue	52	I-IV	qRT-PCR	Median value	OS/DFS	Reported	0.004/0.002	60
Song 2013^Citation51	American	FTT	MDS	Tissue	107	I-IV	ISH	Expression score	OS	SC	<0.0005	75
Wang X C 2013^Citation52	China	–	ESCC	Tissue	100	I-IV	qRT-PCR	Mean value	OS	SC	0.237	80
Liu 2014^Citation32	China	–	NPC	Serum	512	I-IV	qRT-PCR	Median risk score	OS/DMFS(T,V)	Reported	<0.01	132
Li 2014^Citation53	China	FTT	glioma	Tissue	72	I-IV	qRT-PCR	Mean value	OS	SC	<0.05	42
Lionetti 2013^Citation54	American	–	pPCL	Tissue	18	I-IV	qRT-PCR	NR	PFS	SC	0.001	32
Du 2017^Citation55	China	FTT	Bla Ca	Urine	240	I-IV	qRT-PCR	Median value	RFS	Reported	0.024	80
Zou 2017^Citation56	China	FTT	BC	Tissue	72	I-IV	qRT-PCR	Mean	–	–	–	–

Abbreviations: miR-22, microRNA-22; T, training set; V, validation set; NR, not reported; Co, colon set; Re, rectal set; “-”, not mentioned; q-RCR, quantitative real-time polymerase chain reaction; ISH, in situ hybridization; SC, survival curve; OS, overall survival; PFS, progression-free survival; DFS, disease-free survival; RFS, recurrence free survival; MFS, metastasis-free survival; DMFS, distant metastasis-free survival; TCGA, The Cancer Genome Atlas; GEO, gene expression omnibus; BC, breast cancer; EOC, epithelial ovarian cancer; CRC colorectal carcinoma; HCC, hepatocellular carcinoma; NPC, nasopharyngeal carcinoma; GC, gastric cancer; OST, osteosarcoma; MDS, myelodysplastic syndrome; ESCC, esophageal squamous cell carcinoma; pPCL, primary plasma cell leukemia; Bla Ca, bladder cancer; RCC, renal cell carcinoma.

Figure 1 Flowchart of the study selection process.

Figure 2 Forest plot of miR-22 expression and overall survival in various cancers.

Table 2 Meta-analysis of overall and subgroup analysis for miR-22 expression and OS in cancers

Categories	Studies	HR (95% CI)	Model	Heterogeneity
				I^2%	Pheterogeneity
OS (overall)	19	0.76 (0.62–0.92)	Random	78.4	0.000
OS (Subgroup analysis)
Cancer type
HCC	2	0.40 (0.26–0.62)	Fixed	0	0.511
CRC	3	0.92 (0.83–1.03)	Fixed	49.6	0.137
NPC	2	1.90 (1.37–2.63)	Fixed	0	0.776
EOC	3	0.42 (0.20–0.86)	Random	64.7	0.059
GC	2	0.90 (0.24–3.39)	Random	68.5	0.075
BC	3	0.81 (0.54–1.22)	Random	66	0.053
Sample type
Tissue	17	0.67 (0.55–0.81)	Random	75.5	0.000
Serum	2	1.90 (1.37–2.63)	Random	0	0.776
The system of cancer
Digestive system	8	0.74 (0.58–0.95)	Random	65.9	0.005
Reproduction system	6	0.55 (0.33–0.93)	Random	84.5	0.000
The main pathological type
Adenocarcinoma	11	0.75 (0.61–0.92)	Random	74.9	0.000
Squamous cell carcinoma	3	1.52 (0.97–2.37)	Random	62.3	0.022
Tumor of mesenchymal tissue	2	0.70 (0.10–4.99)	Random	80.8	0.071
Ethnic background
Asian	13	0.73 (0.52–1.01)	Random	77.6	0.000
Caucasian	3	0.94 (0.84–1.05)	Fixed	0	0.414
Assay method
q-PCR	18	0.74 (0.61–0.91)	Random	79.3	0.000
ISH	1	2.01 (0.51–7.95)	Random	–	–
Preservation method
Fresh tissue	4	1.31 (0.68–2.52)	Random	76.7	0.005
Unclear method (-)	4	0.58 (0.28–1.16)	Random	79.5	0.002
FTT	9	0.88 (0.76–1.01)	Random	53.7	0.027
FFPE	2	0.32 (0.18–0.56)	Fixed	0	0.634

Abbreviations: miR-22, microRNA-22; “-”, not mentioned; ISH, in situ hybridization; OS, overall survival; BC, breast cancer; EOC, epithelial ovarian cancer; CRC colorectal carcinoma; HCC, hepatocellular carcinoma; NPC, nasopharyngeal carcinoma; GC, gastric cancer.

Figure 3 Forest plot of subgroup analysis for OS: (A) subgroup analysis for the anatomy system of cancer (digestive system and reproduction system); (B) subgroup analysis for the main pathological type of cancer; (C) subgroup analysis for different sample type (tissue or serum); (D) subgroup analysis for different assay method for miR-22 expression (q-PCR and ISH).

Table 3 Meta-analysis of overall and subgroup analysis for miR-22 expression and disease progress in cancers

Categories	Studies	HR (95% CI)	Model	Heterogeneity
				I^2%	Pheter
PFS/DFS/RFS (overall)	11	0.57 (0.37–0.87)	Random	79.1	0
MFS/DMFS (overall)	3	1.57 (0.67–3.68)	Random	90.3	0
PFS/DFS/RFS (subgroup)
Indicator type
PFS	3	0.45 (0.19–1.08)	Random	62	0.072
RFS	5	0.86 (0.39–1.88)	Random	86	0.000
DFS	3	0.40 (0.21–0.76)	Random	54.8	0.11
Cancer type (all)
NPC	2	2.35 (1.59–3.47)	Fixed	0	0.749
BC	3	0.86 (0.30–2.47)	Random	82.6	0.003
EOC	3	0.28 (0.17–0.44)	Fixed	0	0.016
Ethnic background
Asian	9	0.69 (0.36–1.31)	Random	87.0	0.000
Caucasian	2	2.09 (0.46–9.48)	Random	63.8	0.097

Abbreviations: miR-22, microRNA-22; OS, overall survival; PFS, progression-free survival; DFS, disease-free survival; RFS, recurrence-free survival; MFS, metastasis-free survival; EOC, epithelial ovarian cancer; NPC, nasopharyngeal carcinoma; DMFS, distant metastasis-free survival.

Figure 4 Forest plot of miR-22 expression and disease progress: (A) subgroup analysis for PFS/DFS/RFS and MFS/DMFS; (B) subgroup analysis for different indicator type (PFS, DFS, RFS); (C) subgroup analysis for PFS/DFS/RFS in EOC subgroup.

Figure 5 Forest plot of miR-22 expression and clinicopathological features. (A) subgroup analysis for miR-22 expression and TNM stage; (B) subgroup analysis for miR-22 high expression and lymph node metastasis; (C) subgroup analysis for miR-22 high expression and distant metastasis; (D) subgroup analysis for miR-22 high expression and recurrence.

Table 4 Meta-analysis of miR-22 high expression and clinicopathological features

Categories	Studies	RR (95% CI)	Model	Heterogeneity
				I^2%	Pheter
TNM stage	9	0.48 (0.34–0.67)	Random	72.9	0.000
Lymph node metastasis	9	0.55 (0.40–0.77)	Random	72.1	0.000
T stage	5	0.87 (0.70–1.07)	Fixed	37.2	0.173
Distant metastasis	6	0.28 (0.18–0.43)	Fixed	0	0.960
Tumor differentiation	5	0.99 (0.85–1.15)	Fixed	49.0	0.0970
Recurrence	3	0.51 (0.32–0.80)	Fixed	44	0.167
Lymphatic invasion	3	0.86 (0.70–1.05)	Fixed	33.5	0.222

Figure 6 Sensitivity analysis and publication bias analysis under a specific model. (A), sensitivity analysis for overall survival; (B) sensitivity analysis for disease progress (PFS/RFS/DFS); (C) funnel plot of publication bias for OS; (D) funnel plot of publication bias for disease progress (PFS/RFS/DFS).

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