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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front. Med.    2019, Vol. 13 Issue (2) : 250-258    https://doi.org/10.1007/s11684-018-0632-1
RESEARCH ARTICLE |
Post-surgical resection prognostic value of combined OPN, MMP7, and PSG9 plasma biomarkers in hepatocellular carcinoma
Weiqi Rong1, Yang Zhang1, Lei Yang2, Lin Feng2, Baojun Wei3, Fan Wu1, Liming Wang1, Yanning Gao2, Shujun Cheng2, Jianxiong Wu1(), Ting Xiao2()
1. Department of Abdominal Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
2. State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
3. Clinical Laboratory, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
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Abstract

Biomarkers for hepatocellular carcinoma (HCC) following curative resection are not currently sufficient for prognostic indication of overall survival (OS) and disease-free survival (DFS). The aim of this study was to investigate the prognostic performance of osteopontin (OPN), matrix metalloproteinase 7 (MMP7), and pregnancy specific glycoprotein 9 (PSG9) in patients with HCC. A total of 179 prospective patients with HCC provided plasma before hepatectomy. Plasma OPN, MMP7, and PSG9 levels were determined by enzyme-linked immunosorbent assay. Correlations between plasma levels, clinical parameters, and outcomes (OS and DFS) were overall analyzed. High OPN (≥149.97 ng/mL), MMP7 (≥2.28 ng/mL), and PSG9 (≥45.59 ng/mL) were prognostic indicators of reduced OS (P<0.001, P<0.001, and P=0.007, respectively). Plasma PSG9 protein level was an independent factor in predicting OS (P=0.008) and DFS (P=0.038). Plasma OPN+MMP7+PSG9 elevation in combination was a prognostic factor for OS (P<0.001). OPN was demonstrated to be a risk factor-associated OS in stage I patients with HCC and patients with low α-fetoprotein levels (<20 ng/mL). These findings suggested that OPN, MMP7, PSG9 and their combined panels may be useful for aiding in tumor recurrence and mortality risk prediction of patients with HCC, particularly in the early stage of HCC carcinogenesis.

Keywords biomarkers      OPN      MMP7      PSG9      HCC      prognosis     
Corresponding Authors: Jianxiong Wu,Ting Xiao   
Just Accepted Date: 11 April 2018   Online First Date: 16 May 2018    Issue Date: 28 March 2019
 Cite this article:   
Weiqi Rong,Yang Zhang,Lei Yang, et al. Post-surgical resection prognostic value of combined OPN, MMP7, and PSG9 plasma biomarkers in hepatocellular carcinoma[J]. Front. Med., 2019, 13(2): 250-258.
 URL:  
http://academic.hep.com.cn/fmd/EN/10.1007/s11684-018-0632-1
http://academic.hep.com.cn/fmd/EN/Y2019/V13/I2/250
Clinical parameters Plasma levels (mean±SD)
OPN MMP7 PSG9
Age (year) ≤55 (n = 91) 138.85±69.86 2.32±4.13 33.96±122.48
>55 (n = 88) 202.95±190.05 4.28±14.20 27.30±50.33
P value 0.007 0.046 0.969
Sex Female (n = 39) 207.08±246.41 1.95±1.98 47.10±182.58
Male (n = 140) 160.14±100.03 3.66±11.70 26.11±45.87
P value 0.620 0.576 0.600
AFP (ng/mL) <20 (n = 116) 167.55±127.00 2.38±3.51 27.47±50.96
≥20 (n = 63) 175.55±175.41 4.96±16.84 36.61±143.14
P value 0.428 0.447 0.894
Hepatitis history Yes (n = 165) 166.78±144.46 3.17±10.62 32.09±97.75
No (n = 14) 212.60±155.86 4.62±7.55 14.11±8.93
P value 0.302 0.597 0.480
Liver cirrhosis Yes (n = 131) 162.48±114.50 3.84±12.05 26.54±46.97
No (n = 48) 191.87±207.86 1.77±2.31 42.01±164.85
P value 0.584 0.073 0.936
Tumor differentiation Well/moderate (n = 140) 161.14±135.00 3.47±11.62 34.03±105.46
Poor (n = 39) 203.48±176.01 2.64±3.48 18.67±22.63
P value 0.086 0.146 0.962
Tumor size (cm) ≤3 (n = 123) 120.18±57.59 2.69±4.05 24.82±52.583
>3 (n = 56) 193.21±166.39 4.59±17.65 3.36±107.80
P value <0.001 0.241 0.251
TNM stage I (n = 86) 137.15±69.55 2.10±3.27 34.38±127.76
II+ III+ IV (n = 93) 201.08±185.67 4.38±14.03 27.27±44.57
P value 0.006 0.285 0.382
Tumor number Single (n = 156) 162.07±108.21 2.84±9.92 30.51±99.09
Multiple (n = 23) 226.66±291.30 6.32±13.07 31.89±47.88
P value 0.889 0.002 0.315
Vascular invasion Yes (n = 66) 180.51±133.81 3.62±14.70 27.40±46.45
No (n = 113) 164.43±152.09 3.09±6.82 32.60±113.04
P value 0.094 0.095 0.747
Capsule invasion Yes (n = 61) 150.55±100.41 2.06±2.52 29.48±59.54
No (n = 118) 180.61±163.40 3.92±12.66 31.31±107.80
P value 0.148 0.314 0.364
OS-Event Yes (n = 29) 200.80±107.73 2.41±2.70 63.23±209.37
?(death) No (n = 150) 164.48±151.24 3.45±11.30 24.39±45.50
P value 0.003 0.302 0.420
DFS-Event Yes (n = 77) 190.23±144.22 2.70±3.99 38.02±133.17
?(recurrence) No (n = 102) 155.37±145.27 3.73±13.35 25.15±46.39
P value 0.006 0.335 0.447
Tab.1  Association of clinical parameters and plasma levels of OPN, MMP7, and PSG9 in HCCa
Fig.1  Estimation of discriminatory performance of OPN, MMP7, PSG9, and AFP optimal cutoff values indicated by time-dependent receiver operating curve (ROC) corresponding to overall survival time. (A) Dynamic AUC plots for OPN, MMP7, PSG9, and AFP. Time-dependent ROC curves for determining optimal cutoff values of OPN (B), MMP7 (C), PSG9 (D), and AFP (E). AUC, area under the ROC curve.
Fig.2  Kaplan–Meier analysis indicated low overall survival (OS) rates with high plasma OPN, MMP7, and PSG9 levels in patients with hepatocellular carcinoma (HCC). Cumulative OS curves for OPN (A), MMP7 (B), and PSG9 (C). (D) Kaplan–Meier analysis of OS for combined plasma levels of OPN, MMP7, or PSG9. Low, all three protein plasma levels were below cutoff (OPN<149.97 ng/mL, MMP7<2.28 ng/mL, PSG9<45.59 ng/mL, n=86). High, at least one of the three protein plasma levels was above cutoff (n=93).
Variables OS DFS
Univariate Multivariate Univariate Multivariate
P HR
(95% CI)
P P HR
(95% CI)
P
Age, year
?(≤55/>55)
0.330 NA 0.228 NA
Sex
?(female/male)
0.499 NA 0.323 NA
HBeAg
?(negative/positive)
0.628 NA 0.800 NA
Liver cirrhosis
?(yes/no)
0.655 NA 0.081 NA
Differentiation
?(well-moderate/ poor)
0.035 1.176
(0.787−3.739)
0.174 0.007 1.808
(1.103−2.964)
0.019
Tumor size
?(≤3/>3, cm)
0.025 0.519
(0.169−1.597)
0.253 0.012 0.683
(0.390−1.199)
0.184
TNM stage
?(I/II+ III+ IV)
0.130 NA 0.295 NA
Tumor number
?(single/multiple)
0.117 NA 0.064 NA
Vascular invasion
?(yes/no)
0.759 NA 0.971 NA
Capsule invasion
?(yes/no)
0.112 NA 0.077 NA
OPN, ng/mL
?(low/high)
<0.001 2.331
(0.991−5.486)
0.053 <0.001 1.658
(0.995−2.763)
0.052
MMP7, ng/mL
?(low/high)
0.009 1.975
(0.893−4.370)
0.093 0.013 1.469
(0.884−2.441)
0.138
PSG9, ng/mL
?(low/high)
0.011 3.563
(1.384−9.172)
0.008 0.059 2.140
(1.042−4.398)
0.038
Combineda <0.001 NA <0.001 NA
Tab.2  Univariate and multivariate analyses of factors associated with survival and recurrence
Fig.3  Prognostic value of OPN in early-stage patients with HCC (stage I) and patients with low AFP levels (<20 ng/mL). (A) Stage I HCC with high plasma OPN levels had significantly shorter OS compared with patients with low OPN levels. (B) OPN was demonstrated to be a risk factor associated with OS in patients with AFP<20 ng/mL.
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