INHBA upregulation correlates with poorer prognosis in patients with esophageal squamous cell carcinoma

Figures & data

Figure 1 Flow chart of meta-analysis literature search.

Table 1 The characteristics of the included studies

Study	Year	Country	Study type (R or P)	Study Period	Cancer site	Stage	N	Sex (male)	U/M	HRs	Outcome 1	In (HR)	SE
Lee et al^Citation11	2014	Taiwan	R	1996–2004	Urinary bladder urothelial carcinoma	1–4	340	0.465	U	2.825	DSS	1.039	0.328
Lee et al^Citation11	2014	Taiwan	R	1996–2004	Upper urinary tract carcinoma	1–4	295	0.732	U	2.803	DSS	1.031	0.368
Wang et al^Citation16	2016	People’s Republic of China	R	2001–2012	Breast cancer	1–3	126		U	3.311	OS	1.197	0.386
Okano et al^Citation8	2013	Japan	R	1990–2002	Colorectal cancer	1–4	126	0.595	M	1.160	OS	0.148	0.247
Oshima et al^Citation14	2014	Japan	R	2002–2007	Gastric cancer	1–3	168	0.673	U	3.048	OS	1.114	0.396
Wang et al^Citation9	2012	People’s Republic of China	R	2004–2006	Gastric cancer		132	0.621	U	2.380	OS	0.867	0.349
Katayama et al^Citation15	2017	Japan	R	2002–2010	Gastric cancer	2–3	134	0.687	U	3.926	OS	1.368	0.379

Abbreviations: OS, overall survival; DSS, disease-specific survival; R, research; P, prospective cohort study; U, univariate analysis; M, multivariate analysis; HR, hazard ration.

Figure 2 Meta-analysis plots.

Notes: Forest plot of HR for the association of high plasma INHBA level and survival (A). Begg’s funnel plots of publication bias (B).

Abbreviation: UTC, upper tract urothelial carcinoma.

Table 2 INHBA expression and other important clinicopathological parameters in esophageal squamous cell carcinoma

Variables	Cases (n=239)	INHBA expression		P-valuea
		Low (n=66, %)	High (n=173, %)
Age, yearsb				0.504
≤58	127	39 (30.7)	88 (69.3)
>58	112	30 (26.8)	82 (73.2)
Sex				0.634
Female	64	17 (26.6)	47 (73.4)
Male	175	52 (28.0)	123 (72.0)
Tumor location				0.171
Upper	12	4 (33.3)	8 (66.7)
Middle	163	41 (25.2)	122 (74.8)
Lower	64	24 (37.5)	40 (62.5)
Histological gradec				0.1
Grade 1	58	23 (39.7)	37 (60.3)
Grade 2	154	38 (24.7)	116 (75.3)
Grade 3	27	8 (29.6)	19 (70.4)
pT statusc				0.458
pT 1	6	3 (50.0)	3 (50.0)
pT 2	55	15 (27.3)	40 (72.7)
pT 3	175	51 (29.1)	124 (70.9)
pT 4	3	0 (0.00)	2 (100.0)
N categories				0.026
Negative	129	45 (34.9)	84 (65.1)
Positive	110	24 (21.8)	86 (78.2)
TNM stage				0.172
Stage 1	9	3 (33.3)	6 (66.7)
Stage 2	138	46 (33.3)	92 (66.7)
Stage 3	91	20 (22.0)	71 (78.0)

Notes:

a Probability value of <0.05 indicates statistical significance shown in bold. Probability values were calculated by Pearson’s χ² test.

b Age was divided according to the median age of 58 years.

c The grading and histopathology staging of ESCC specimens was based on the World Health Organization classification published in 2009.²⁵

Abbreviation: ESCC, esophageal squamous cell carcinoma.

Figure 3 INHBA expression determined by IHC.

Notes: Normal esophageal tissue demonstrated no expression of INHBA protein in the cytoplasm of esophageal squamous cells (magnification: A, ×40; B, ×200). Low expression level of INHBA in ESCC tissues (magnification: C, ×40; D, ×200). Median expression of INHBA in ESCC tissues (magnification: E, ×40; F, ×200). High expression levels of INHBA were detected in ESCC tissues (magnification: G, ×40; H, ×200).

Abbreviations: ESCC, esophageal squamous cell carcinoma; IHC, immunohistochemistry.

Figure 4 Disease-free survival (DFS) and overall survival (OS) curves according to patients’ INHBA expression.

Notes: DFS curve in all patients with different levels of INHBA expression (A, P=0.001). OS curve in all patients with different levels of INHBA expression (B, P=0.001). DFS and OS curves in patients in TNM stage 1 and 2 with low and high INHBA expression (C, D, P=0.009 and P=0.008, respectively). DFS and OS curves in patients in N0 stage with low and high INHBA expression (E, F, P=0.022 and P=0.023, respectively).

Table 3 Univariate Cox regression analysis in ESCC patients for disease-free survival and overall survival

Variables	Disease-free survival		Overall survival
	HR (95% CI)	P-value	HR (95% CI)	P-value
Age, yearsa		0.704		0.691
≤58	Reference		Reference
>58	0.935 (0.658–1.328)		0.932 (0.656–1.324)
Sex		0.293		0.218
Male	Reference		Reference
Female	1.241 (0.827–1.863)		1.288 (0.858–1.933)
Tumor location		0.323		0.288
Upper	1.586 (0.758–3.317)		1.551 (0.742–3.243)
Middle	0.945 (0.631–1.415)		0.905 (0.604–1.356)
Lower	Reference		Reference
Histological gradeb		0.131		0.181
Grade 1	Reference		Reference
Grade 2	1.028 (0.674–1.568)		1.016 (0.666–1.550)
Grade 2	1.688 (0.940–3.031)		1.609 (0.896–2.891)
pT statusb		<0.001		<0.001
pT 1	Reference		Reference
pT 2	1.496 (0.354–6.318)		1.660 (0.393–7.013)
pT 3	1.960 (0.483–7.958)		2.251 (0.554–9.146)
pT 4	35.323 (5.438–229.431)		63.931 (9.762–418.677)
pT1-2		0.005		0.005
Low expression	Reference		Reference
High expression	4.709 (1.413–15.690)		4.745 (1.425–15.804)
pT3-4		0.034		0.030
Low expression	Reference		Reference
High expression	1.657 (1.030–2.666)		1.673 (1.040–2.692)
pN statusb		<0.001		<0.001
0	Reference		Reference
1–3	3.257 (2.243–4.730)		3.410 (2.347–4.954)
pN0		0.022		0.023
Low expression	Reference		Reference
High expression	2.216 (1.097–4.479)		2.200 (1.089–4.445)
pN1-3		0.230		0.134
Low expression	Reference		Reference
High expression	1.403 (0.798–2.466)		1.527 (0.867–2.689)
pStageb		<0.001		<0.001
Stage 1	Reference		Reference
Stage 2	1.095 (0.342–3.509)		1.073 (0.335–3.440)
Stage 3	3.852 (1.209–12.275)		4.070 (1.276–12.986)
pStage 1/2		0.009		0.008
Low expression	Reference		Reference
High expression	2.352 (1.212–4.565)		2.365 (1.219–4.590)
pStage 3		0.277		0.223
Low expression	Reference		Reference
High expression	1.379 (0.763–2.492)		1.436 (0.792–2.603)
CEP55 expression		0.001		0.001
Low	Reference		Reference
High	2.023 (1.304–3.139)		2.053 (1.323–3.185)

Notes:

a Age is divided according to the median age of the study.

b The grading and histopathology stage of ESCC specimens are based on the World Health Organization classification published in 2009.²⁵

Abbreviation: ESCC, esophageal squamous cell carcinoma.

Table 4 Multivariate Cox regression analysis for disease-free survival and overall survival in patients with esophageal squamous cell carcinoma

Variables	Disease-free survival		Overall survival
	HR (95% CI)	P-value	HR (95% CI)	P-value
pT statusa		<0.001		<0.001
pT 1	1.000		1.000
pT 2	1.395 (0.330–5.903)		1.665 (0.393–7.057)
pT 3	1.734 (0.426–7.058)		2.137 (0.524–8.718)
pT 4	32845 (5.021–214.879)		69.057 (10.246–465.429)
pN categories		<0.001		<0.001
N0	1.000		1.000
N1–3	3.094 (2.123–4.510)		3.294 (2.258–4.804)
CEP55 expression		0.022		0.017
Low	1.000		1.000
High	1.679 (1.077–2.619)		1.715 (1.100–2.675)

Note:

a The grading and histopathology stage of ESCC specimens are based on the World Health Organization classification published in 2009.²⁵

Abbreviation: ESCC, esophageal squamous cell carcinoma.

Figure S1 Sensitivity analysis.

Notes: Sensitivity test of the meta-analysis (A). “Trim and fill” method to adjust for publication bias in this meta study (B).

Table S1 Quality assessment of the selected papers

Study	Year	Country	Clear description of purpose/objectives	Clear description of patient selection criteria	Clear description of INHBA detection	Predefinition of predictors and outcome measurements	Whether or not multivariate analysis and/or univariate analysis was used	Long enough follow-up period	Limitations considered	Quality (0–6)
Lee et al^Citation3	2014	Taiwan	Yes	No	Yes	No	Yes	Yes	Yes	5
Wang et al^Citation6	2016	People’s Republic of China	Yes	No	Yes	No	Yes	Yes	No	4
Okano et al^Citation1	2013	Japan	Yes	No	Yes	No	Yes	Yes	No	4
Oshima et al^Citation4	2014	Japan	Yes	No	Yes	No	Yes	Yes	No	4
Wang et al^Citation2	2012	People’s Republic of China	Yes	No	Yes	No	Yes	Yes	No	4
Katayama et al^Citation5	2017	Japan	Yes	No	Yes	No	Yes	Yes	No	4

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 PubMed Web of Science ®Google Scholar