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Abstract

OBJECTIVES:

Thus far, biological roles of plasminogen activator inhibitor 1 (PAI1) in hepatocellular carcinoma (HCC) remain controversial. Moreover, its expression, clinicopathologic and prognostic significance in HCC have not been comprehensively investigated, therefore needing further evidence.

METHODS:

PAI1 expression was measured, using tissue microarray-based immunohistochemical staining, in matched HCC and adjacent liver samples from 178 patients with HCC after curative resection. The correlations of PAI1 H-scores with clinicopathologic variables and survival were further evaluated. Its prognostic value was finally confirmed in some public databases.

RESULTS:

It was found that PAI1 expression was significantly higher in HCC than in adjacent liver tissues. Moreover, high PAI1 expression was more frequent in those with multiple lesions. Univariate analyses showed that PAI1 expression was negatively associated with both overall and relapse-free survival. Although PAI1 expression was not statistically significant in multivariate Cox regression test, combination of it with TNM stage effectively distinguished survival and relapse, and served as an independent prognostic factor. In the online available datasets of HCC and liver cancer used, SERPINE1, the gene encoding PAI1, was also revealed to be prognostic.

CONCLUSIONS:

Our data suggested that high PAI1 expression was predictive for unfavorable biological behavior and long-term prognosis in HCC.

Keywords

Hepatocellular carcinoma plasminogen activation plasminogen activator inhibitor 1 prognosis resection

1. Introduction

It has been well known that hepatocellular carcinoma (HCC) is a highly prevalent and poorly prognostic neoplasm [1]. Thus far, post-surgical recurrence of HCC remains to occur frequently [2], although favorable long-term prognosis after radical hepatectomy has been obtained in strictly selected patients [2, 3]. This has become one of main barriers of long-term survival of HCC [4]. Therefore, the underlying molecular mechanisms of HCC recurrence are of great clinical importance. Up to now, many invasion-related factors, such as tumor microenvironment, cancer stem cells and epithelial to mesenchymal transition (EMT) [5, 6, 7], and genes involved in them [8, 9], have been identified in HCC. Of course, novel findings are still needed.

In the proteolytic degradation of extracellular matrix (ECM), one of key processes in cancer spread [10], urokinase-type plasminogen activator (uPA) system was found, by many researchers, to function as an important player [11, 12]. As one of two serine protease inhibitors within the system, plasminogen activator inhibitor 1 (PAI1) was shown to play biological roles not only in benign cell disorders, such as endothelial cell apoptosis and skin fibrosis [13, 14] but also in many cancers [15, 16, 17, 18, 19, 20, 21]. Surprisingly, most papers showed that PAI1 contributed to malignant behaviors, such as cell cycle progression, anti-apoptosis, chemo/radio-resistance, cell proliferation and migration as well as recruitment and polarization of macrophages, through some uPA-independent mechanisms [16, 17, 18, 19, 20, 21]. These, different with its role as an inhibitor of uPA, suggested its pro-oncogenic effects, although opposite report was also shown [15]. In addition, it was revealed to be associated unfavorable prognosis in some malignancies [22, 23, 24]. In HCC, clues from in vitro experiments were also contradictory [25, 26]. We previously found that PAI1 expression was high in HCC tissues [27]. Moreover, it was also related to vascular involvement, poor differentiation and a tendency to dismal prognosis in HCC [28, 29]. However, these works were largely limited by smaller sample sizes and incomprehensive evaluation criteria. Thus, further evidence is needed.

In the present study, we aimed to explore clinicopathologic and prognostic significance in HCC, based on a Chinese cohort and the online publically available datasets, including the The Cancer Genome Atlas (TCGA) database.

2. Materials and methods

2.1 Patients

A total of 178 patients with HCC after curative resection (142 males and 36 females) were included in this study. Their general, etiologic and clinicopathologic parameters are shown in Table 1. This work was approved by the Institutional Ethics Committee and the informed consents were acquired from all patients.

Table 1
Correlations between PAI1 expression and clinicopathologic features of HCC

		PAI1 expression
Variables	$n$	High	Low	$P$
Age				0.852
$>$ 60 years	43	20	23
$\leqslant$ 60 years	135	65	70
Sex				0.413
Male	142	70	72
Female	36	15	21
HBV				0.134
Positive	164	81	83
Negative	14	4	10
HCV				0.952*
Positive	3	2	1
Negative	173	83	90
Cirrhosis				0.649
With	155	73	82
Without	23	12	11
Tumor size				0.169
$>$ 5 cm	78	42	36
$\leqslant$ 5 cm	99	43	56
Tumor number				0.018
Single	143	62	81
Multiple	35	23	12
Vascular invasion				0.352
With	66	33	33
Without	94	40	54
Edmondson-Steiner grade				0.534
I–II	111	51	60
III–IV	67	34	33
TNM stage				0.149
I	115	50	65
II–III	62	34	28
AFP level				0.528
$>$ 20 ng/ml	121	59	62
$\leqslant$ 20 ng/ml	55	24	31

Abbreviations: PAI1, plasminogen activator inhibitor 1; HCC, hepatocellular carcinona; HBV, b-type hepatitis virus; HCV, c-type hepatitis virus; TNM, tumor-node-metastasis; AFP, $\alpha$ -fetoprotein. *: Chi-square test with continuity correction. Note: Partial data are not available, and statistics were based on available data.

2.2 Tissue microarray (TMA) construction

Tissue microarray construction was performed using formalin-fixed paraffin-embedded (FFPE) blocks. After careful review and selection of representative regions, two cores (1.5 mm) of HCC and corresponding adjacent liver (AL) tissues of each patient were punched, by the manual tissue arrayer (Beecher Instruments, 686 Progress Way, Sun Prairie, WI, USA), to construct TMA.

Figure 1.

PAI1 expression in resected hepatocellular carcinoma. (A) High expression in HCC tissue (original magnification $\times$ 200); (B) Low expression in adjacent liver (AL) tissue (original magnification $\times$ 200); (C) Comparison of H-scores between HCC and AL tissues (Mann-Whitney $U$ -test; $P=$ 0.031).

Table 2

Univariate identification of prognostic factors in HCC

	Overall survival				Relapse-free survival
Variables	$n$	HR	95% CI	$P$ *	$n$	HR	95% CI	$P$ *
Age				0.606				0.544
$>$ 60 years	43	1.129	0.713–1.787		43	1.139	0.748–1.736
$\leqslant$ 60 years	135	1			133	1
Sex				0.960				0.770
Male	142	0.987	0.596–1.635		140	1.072	0.672–1.712
Female	36	1			36	1
HBV				0.969				0.483
Positive	164	1.015	0.470–2.195		162	1.316	0.611–2.832
Negative	14	1			14	1
HCV				0.041				0.034
Positive	3	3.353	1.054–10.668		3	3.511	1.102–11.187
Negative	175	1			173	1
Cirrhosis				0.810				0.415
With	155	0.928	0.506–1.703		154	1.296	0.695–2.417
Without	23	1			22	1
Tumor size				$<$ 0.001				0.003
$>$ 5 cm	78	2.116	1.399–3.200		77	1.762	1.206–2.574
$\leqslant$ 5 cm	99	1			98	1
Tumor number				0.002				0.001
Solitary	143	2.081	1.313–3.300		141	2.055	1.333–3.168
Multiple	35	1			35	1
Vascular invasion				0.171				0.061
With	66	1.355	0.877–2.094		64	1.471	0.983–2.201
Without	94	1			94	1
Edmondson-Steiner grade				0.108				0.046
I–II	111	1.404	0.928–2.124		110	1
III–IV	67	1			66	1.476	1.007–2.164
TNM stage				$<$ 0.001				$<$ 0.001
I	115	1			114	1
II–III	62	3.237	2.138–4.900		61	2.535	1.722–3.732
AFP level				0.015				0.008
$>$ 20 ng/ml	121	1.831	1.123–2.986		119	1.787	1.160–2.753
$>$ 20 ng/ml	55	1			55	1
PAI1 expression				0.012				0.041
High	85	1.703	1.127–2.573		84	1.481	1.016–2.158
Low	93	1			92	1

Abbreviations: HCC, hepatocellular carcinoma; HR, hazard ratio; CI, confidence interval; HBV, b-type hepatitis virus; HCV, c-type hepatitis virus; TNM, tumor-node-metastasis; AFP, $\alpha$ -fetoprotein; PAI1, plasminogen activator inhibitor 1. *Partial data were not available, and statistical analyses were performed using available data.

Figure 2.

Prognostic value of PAI1 expression in resected hepatocellular carcinoma. (A) Overall survival of patients according to PAI1 expression (Log-rank test; $P=$ 0.0101); (B) Relapse-free survival of patients according to PAI1 expression (Log-rank test; $P=$ 0.0373).

2.3 Immunohistochemical staining

Immunohistochemistry was carried out, using the mouse monoclonal antibody for human PAI1 (Santa Cruz Biotechnology, Inc., Santa Cruz, CA, USA) and a two-step staining kit (EnVision ${}^{\rm TM}$ $+$ kit, Dako, Denmark). In the first, 4 $\mu$ m-thick sections were mounted, deparaffinized and rehydrated, followed by antigen retrieval in an autoclave. Then, incubation of slides with 3% hydrogen peroxide was done to block endogenous peroxidase. Slides were subsequently incubated with the primary antibody (1:50) overnight at 4 ${}^{\circ}$ C. Horseradish peroxidase (HRP)-labeled secondary antibody was added for a reaction of 30 min. Diaminobenzidine was used as a chromogen. Finally, slides were counterstained with hematoxylin. Pre-immune mouse serum at the same dilution functioned as the negative control.

2.4 Staining evaluation

Two senior pathologists who were blinded to clinicopathologic and follow-up information (Z. Y. L. and W. X. Z.) evaluated the slides, applying the H-score [30], a comprehensive staining evaluation method that considered both positive cell ratio and staining intensity (formula: positive cell ratio $\times$ staining intensity $\times$ 100), and was widely used [31, 32]. The H-score with the largest youden index (YI) within the receiver operating characteristic (ROC) curve for overall survival status was set as the cut-off point.

2.5 Follow-up

Our follow-up, ranging from 2 to 74 months (median: 51 months), was carried out for all the patients. At the last follow-up, 86 patients (48.3%) were still alive, while 92 (51.7%) have died.

Table 3
Multivariate analyses for overall and relapse-free survival of HCC

Variables	HR	95% CI	$P$	HR	95% CI	$P$
	Overall survival			Relapse-free survival
TNM stage	2.891	1.866–4.479	$<$ 0.001	2.156	1.428–3.257	$<$ 0.001
Tumor size	1.998	1.281–3.116	0.002	1.706	1.141–2.553	0.009
HCV	8.071	2.393–27.217	0.001	6.461	1.919–21.757	0.003
Tumor number	1.456	0.891–2.380	0.134	1.619	1.028–2.550	0.037
AFP	1.666	1.016–2.732	0.043	1.548	0.987–2.428	0.057
Edmondson-Steiner grade				1.195	0.800–1.784	0.385
PAI1	1.316	0.850–2.037	0.218	1.268	0.853–1.885	0.240

Abbreviations: HCC, hepatocellular carcinoma; HR, hazard ratio; CI, confidence interval; TNM, Tumor-Node-Metastasis; HCV, c-type hepatitis virus; AFP, $\alpha$ -fetoprotein; PAI1, plasminogen activator inhibitor 1.

2.6 Computational survival analyses

The prognostic value of SERPINE1, the gene encoding PAI1, was analyzed in the publically available Kaplan-Meier plotter (http://kmplot.com/analysis/), and the TCGA data of HCC and liver cancer, using an online biomarker validation tool, SurvExpress [33].

2.7 Statistical analyses

The PAI1 H-scores in HCC and AL tissues were compared using Mann-Whitney $U$ -test. Chi-square test was adopted to explore the correlations between PAI1 expression and clinicopathologic variables. The patient survivals according to PAI1 expression were illustrated by the Kaplan-Meier method and compared by the log-rank test. Univariate and multivariate Cox regression (Proportional hazard model) were used for identification of prognostic factors. Two patients who died of other reasons (1 cardiac disease and 1 suicide) were excluded from analyses for relapse-free survival. All the analyses were performed using the statistical software package SPSS11.5 (SPSS Inc, Chicago, IL, USA). A $P$ value $<$ 0.05 was defined as statistically significant.

3. Results

3.1 PAI1 expression in HCC tissues

It was shown in Fig. 1A and B that the positive PAI1 staining signal was mainly observed in the cytoplasm of both HCC and adjacent liver (AL) cells, especially in the invasive fronts of tumor nodules to the parenchyma (Fig. 1A). The H-score in HCC tissues was statistically higher than that in AL ones (Fig. 1C, $P=$ 0.031, Mann-Whitney $U$ -test).

3.2 Correlations of PAI1 expression with clinicopathologic parameters in HCC

According to the ROC curve (Fig. S1), the H-score of PAI1 in HCC tissues at the largest YI for survival status (38.75) was identified as the cut-off point. Using Chi-square test, high PAI1 expression was significantly more frequent in multiple HCC lesions than that in single ones (Table 1, $P=$ 0.018). However, there was no other clinicopathologic relevance of PAI1 that was found (Table 1, $P>$ 0.05).

3.3 Prognostic significance of PAI1 in HCC

Using the Kaplan-Meier method and the log-rank test, high PAI1 expression in HCC tissues was significantly associated with poorer overall and relapse-free survival in our patient cohort of resectable HCC (Fig. 2, $P=$ 0.0101 and 0.0373).

Figure 3.

Prognostic stratification by combination of PAI1 expression and TNM stage in resected hepatocellular carcinoma. (A) Overall survival; (B) Relapse-free survival.

3.4 Prognostic factor identification in HCC

Univariate Cox regression analyses showed that HCV infection, tumor size, tumor number, TNM stage, $\alpha$ -fetoprotein (AFP) level and PAI1 expression were predictive for both overall and relapse-free survival (Table 2, all $P<$ 0.05), while Edmondson-Steiner grade was significant for relapse-free survival (Table 2, $P=$ 0.046). Multivariately, HCV infection, tumor size and TNM stage remained to be independent prognostic markers for overall and relapse-free survival (Table 3, all $P<$ 0.05), AFP level and tumor number were significant for overall or relapse-free survival (Table 3, $P<$ 0.05). However, PAI1 expression and Edmondson-Steiner grade lost their prognostic significance (Table 3, $P>$ 0.05).

3.5 Combined evaluation of TNM stage and PAI1 expression in HCC

In order to get more accurate prediction of patient survival, TNM stage, the strongest prognostic indicator in the cohort, and PAI1 expression were combined. As shown in Fig. 3, the differences between no risk factor (stage I and PAI1 low), one risk factor (stage II-III or PAI1 high) and two risk factors (stage II-III and PAI1 high) were all univariately significant. In addition, this combination was also significant in multivariate analyses (Overall survival: HR $=$ 1.937, 95%CI $=$ 1.425–2.634, $P<$ 0.001; Relapse-free survival: HR $=$ 1.678, 95%CI $=$ 1.261–2.233, $P<$ 0.001). Other included variables didn’t alter their prognostic value.

3.6 Prognostic value of SERPINE1 in public datasets for HCC and liver cancer

In the Kaplan-Meier plotter, SERPINE1, the PAI1-encoded gene, was found to be prognostic (Fig. S2A, $P=$ 0.0043). Using an online biomarker validation tool, SurvExpress [31], it was also significant for survival in the publically available TCGA data of HCC (Fig. S2B, $P=$ 0.002827). By analyzing the TCGA data for liver cancer by SurvExpress [31], SERPINE1 was also a prognostic determinant for both overall and recurrence-free survival (Fig. S2C and D, $P=$ 0.01628 and 0.0451).

4. Discussion

As one of important hallmarks in cancer [34], invasion/metastasis is a complicated process, in that ECM degradation plays a key role [10], and depends on many active molecules, such as uPA that results in plasminogen activation, so as to accelerate the proteolysis [11, 12]. It has long been established that uPA has two specific inhibitors, PAI1 and PAI2. Among them, PAI1 was found by most investigations to regulate molecular events in benign conditions [13, 14] and to boost proliferation, angiogenesis, EMT and chemoresistance of cancer cells [16, 17, 18, 19, 20], even to modulate tumor microenviroment [21]. This indicated its proto-oncogenic nature, quite different its speculated effects. In the tissue level, PAI1 was also identified as a poor prognostic marker in some cancers, including clear cell renal cell carcinoma, differentiated thyroid carcinoma and pancreatic ductal adenocarcinoma [22, 23, 24]. In HCC, its biological roles remain contradictory. For example, PAI1 were shown to inhibit invasion and proliferation of HCC cells [25], but to promote angiogenesis [26], an important event in the development and pathogenesis of HCC [35]. The previous literatures for high expression of PAI1 and its associations with unfavorable behaviors and mortality supported its function as a tumor-promoting factor in HCC [27, 28, 29]. However, there were obvious limitations for the studies in sample size and evaluation criteria.

To overcome these, we conducted on this work enrolling more patients and using H-score, a more comprehensive and widely used staining evaluation method [30, 31, 32]. The first finding was that PAI1 expression was significantly higher in HCC tissues than in AL ones, similar with previous ones [27, 29]. Also, a positive relationship between high PAI1 expression and multiple tumor nodules, a risk factor of poor survival and post-operative recurrence [36, 37, 38], was found. The results preliminarily support its oncogenic role in HCC.

Then, Kaplan-Meier method and log-rank test show-ed that high PAI1 expression in HCC tissues was predictive for poor overall and relapse-free survival. In univariate Cox regression analysis, PAI1 expression remained to be a predictor of poor prognosis, along with some clinicopathologic parameters. These data indicated the prognostic implication of PAI1 in HCC. Although being different with results by Itoh et al. [29], they were obtained based on a larger sample size and basically confirmed by the positive prognostic value of SERPINE1, the PAI1-encoded gene, for HCC and liver cancer in online available datasets. Therefore, our findings might be solid and easily understood.

However, it might be a bit pity that PAI1 expression was not significant in multivariate analyses. To enhance its prediction power, we attempted to combine it and TNM stage, the most strong prognostic marker in our cohort, that was also proven to be independently significant in other papers [39, 40], to form a risk score. The results revealed that this combination successfully stratified both overall and relapse-free survival. More importantly, it remained significant in the multivariate analyses, while other factors didn’t alter their prognostic value. This finding strengthened the potential of this combination as a promising biomarker for long-term prognosis of HCC. Of course, further validations are quite needed.

Taken together, our data suggested that high PAI1 expression was predictive for unfavorable biological behavior and long-term prognosis in HCC.

Footnotes

Acknowledgments

This study was supported by the National Natural Science Foundation, China (81301845).

Conflict of interest

The authors declare no conflict of interest.

Supplementary data

Figure S1.

Cut-off point determination by the ROC curve of PAI1 staining H-scores for patient overall survival status in resected hepatocellular carcinoma.

Figure S2.

Prognostic value of SERPINE1 gene (PAI1-encoded gene) in hepatocellular carcinoma and liver cancer in the online datasets. (A) Patient survival of hepatocellular carcinoma in the Kaplan-Meier Plotter (Log-rank test; $P=$ 0.0043); (B) Patient survival of hepatocellular carcinoma (TCGA data) in the SurvExpress (Log-rank test; $P=$ 0.002827); (C) Overall survival of liver cancer (TCGA data) in the SurvExpress (Log-rank test; $P=$ 0.01628); (D) Recurrence-free survival of liver cancer (TCGA data) in the SurvExpress (Log-rank test; $P=$ 0.0451).

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Expression,clinicopathologic and prognostic significance of plasminogen activator inhibitor 1 in hepatocellular carcinoma

Abstract

OBJECTIVES:

METHODS:

RESULTS:

CONCLUSIONS:

Keywords

1. Introduction

2. Materials and methods

2.1 Patients

Table 1 Correlations between PAI1 expression and clinicopathologic features of HCC

2.4 Staining evaluation

2.5 Follow-up

Table 3 Multivariate analyses for overall and relapse-free survival of HCC

2.7 Statistical analyses

3. Results

3.1 PAI1 expression in HCC tissues

3.2 Correlations of PAI1 expression with clinicopathologic parameters in HCC

3.3 Prognostic significance of PAI1 in HCC

3.5 Combined evaluation of TNM stage and PAI1 expression in HCC

3.6 Prognostic value of SERPINE1 in public datasets for HCC and liver cancer

4. Discussion

Footnotes

Acknowledgments

Conflict of interest

Supplementary data

References

Table 1
Correlations between PAI1 expression and clinicopathologic features of HCC

Table 3
Multivariate analyses for overall and relapse-free survival of HCC