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10.1245/ASO.2006.11.035
Annals of Surgical Oncology 13:159-167 (2006)
© 2006 Society of Surgical Oncology
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Original Article

Hepatoma-Derived Growth Factor Is a Novel Prognostic Factor for Hepatocellular Carcinoma

Kenya Yoshida, MD1, Yasuhiko Tomita, MD2, Yorihide Okuda, MD1, Shinji Yamamoto, MD3, Hirayuki Enomoto, MD1, Hirokazu Uyama, MD1, Hiroaki Ito, MD1, Yoshihiko Hoshida, MD2, Katsuyuki Aozasa, MD2, Hiroaki Nagano, MD3, Masato Sakon, MD3, Ichiro Kawase, MD1, Morito Monden, MD3 and Hideji Nakamura, MD1

1 Department of Molecular Medicine, Osaka University Graduate School of Medicine, Yamada-oka 2-2, Suita, 565-0871 Osaka, Japan
2 Department of Pathology, Osaka University Graduate School of Medicine, Yamada-oka 2-2, Suita, 565-0871 Osaka, Japan
3 Department of Surgery and Clinical Oncology, Osaka University Graduate School of Medicine, Yamada-oka 2-2, Suita, 565-0871 Osaka, Japan

Correspondence: Address correspondence and reprint requests to: Hideji Nakamura, MD, Division of Hepatobiliary and Pancreatic Medicine, Department of Internal Medicine, Hyogo College of Medicine. Mukogawa-cho 1-1, Nishinomiya 663-8501, Hyogo, Japan; E-mail: nakamura{at}hyo-med.ac.jp.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Hepatoma-derived growth factor (HDGF) is involved in hepatocarcinogenesis, as well as in liver development and regeneration. This study investigated the correlation of HDGF expression with differentiation and prognosis of hepatocellular carcinoma (HCC).

Methods: HDGF expression in 100 patients with HCC (81 men and 19 women) with ages ranging from 34 to 81 years (median, 61 years) receiving surgical treatment was analyzed by immunohistochemistry. HDGF messenger RNA expression was evaluated in 10 cases by reverse transcription-polymerase chain reaction. The immunostaining pattern in HCCs was categorized as a positive HDGF index (showing positive staining in >90% of tumor cells in both nucleus and cytoplasm) or a negative HDGF index (all others).

Results: Twenty-seven cases (27%) showed a positive and 73 (73%) showed a negative HDGF index. HDGF messenger RNA expression was significantly higher in four cases with a positive HDGF index than in six with a negative index. Cases with well-differentiated histological characteristics showed a higher rate of positive HDGF index than those with a poorly differentiated subtype. Univariate and multivariate analysis revealed significantly poorer disease-free and overall survivals in patients with a positive HDGF index compared with patients with a negative index.

Conclusions: These findings suggest the potential utility of HDGF immunohistochemistry in determining the prognosis of HCC.

Key Words: Hepatoma-derived growth factor • Hepatocellular carcinoma • Prognosis • Recurrence


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Hepatocellular carcinoma (HCC) is one of the most prevalent fatal cancers worldwide, especially in Asia and Africa.1 Surgical resection offers the chance of a cure, but the prognosis remains poor even in curatively resected cases, mainly because of the high recurrence rate.2–4 The recurrence rate of HCC after all forms of therapy other than transplantation is 15% to 20% per year and is due to new lesions but not to local recurrence.2–4 Hence, if surgeons could predict or identify patients at high risk for early recurrence, then these patients might be better treated with nonresection therapy. Therefore, the prognostic factors for recurrence and survival are important to help guide clinicians in the management of patients, in the assessment of long-term prognosis, and in the selection of the treatment modality for HCC. Conventionally, the assessment of prognosis in HCC depends on staging by the tumor-node-metastasis system, including tumor morphology and portal vein thrombosis, and the serum level of alfa fetoprotein (AFP).2–6 Recently, new pathologic and biological factors, including proliferating cell nuclear antigen, Ki-67, and the expression of several genes, including oncogenes and growth factors, have been shown to predict the prognosis of HCC.7

Hepatoma-derived growth factor (HDGF) is a heparin-binding protein purified from the conditioned media of HuH-7 hepatoma cells; it proliferates autonomously in a serum-free chemically defined medium.8,9 HDGF is the first member of the HDGF family of proteins to contain a well-conserved N-terminal amino acid sequence, which is called the hath (homologous to amino terminus of HDGF) region.9,10 HDGF translocates to the nucleus via nuclear localization signals, and its nuclear translocation is essential for the induction of cell growth activity.11,12 HDGF has mitogenic activity for some HCC cells, in addition to fibroblasts, endothelial cells, vascular smooth muscle cells, and fetal hepatocytes.8,9,12–17 HDGF antisense oligonucleotides suppress the proliferation of hepatoma cells that express HDGF endogenously.15 HDGF was more abundantly expressed in HCC than in the nontumorous adjacent liver tissues in human and murine samples.18 HDGF is a unique nuclear/growth factor that may play an important role in the development and progression of HCC. In this study, the expression level of HDGF in HCC was examined by reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemical analysis, and its correlation with recurrence and survival in patients with HCC was evaluated.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients and Tissue Samples
One hundred patients who received curative resection for primary HCC at the Gastroenterological Surgery Division, Osaka University Hospital, from October 1987 to January 2001 were analyzed for this study. There were 81 men and 19 women with ages ranging from 34 to 81 years (median, 61 years). Sixteen patients were positive for hepatitis B virus surface antigen, and 66 were positive for hepatitis C virus antibody. Preoperative diagnostic imaging examinations, including ultrasonography, computed tomographic scan, and angiography, were performed in all patients. Liver function was assessed according to the Child-Pugh classification. Types of surgery used were limited resection in 46 patients, subsegmentectomy in 24, segmentectomy in 17, lobectomy in 12, and extended lobectomy in 1.

Surgically resected specimens were fixed in 10% formalin, macroscopically examined, and sliced at 5-mm intervals. The section containing the largest volume of HCC was processed for paraffin embedding. Four to 43 blocks per case were obtained. Histological sections cut at 4-µm thicknesses were stained with hematoxylin and eosin and reviewed by two of the authors (K.Y. and Y.T.) to determine the following categories: differentiation of tumor cells based on the criteria proposed by Edmondson and Steiner19 (I, well differentiated; II, moderately differentiated; III, poorly differentiated; IV, undifferentiated), pattern of growth (expansive or infiltrative), formation of a fibrous capsule around the tumor, portal vein invasion, tumor multiplicity, and positivity for the surgical margin. The surgical margin was identified as positive when tumor cells were present at the edge. The degree of inflammation and fibrosis in noncancerous hepatic tissues was shown as the histological activity index score.20 The representative one slide per case was used for HDGF immunohistochemistry.

After resection, all patients were followed up by monitoring serum AFP, ultrasonography, and contrast-enhanced computed tomographic scan every 1 and 3 months; for suspicious cases, angiography was performed to verify the recurrence. The follow-up periods for survivors ranged from 2 to 128 months (median, 43 months) after surgery.

Anti-Human HDGF Antibody and Western Blotting
Rabbit polyclonal antibody was raised against C-terminal amino acids (amino acids 231–240) of the human HDGF sequence. The specificity and sensitivity of the antibody have been described previously.10,13 Protein samples were extracted from human cell lines, HepG2, PLC/PRF/5, HuH7, and HT29 by using CelLytic-M Mammalian Cell Lysis/Extraction Reagent (Sigma, St. Louis, MO). Ten micrograms of cell lysates, along with recombinant HDGF, was electrophoresed in sodium dodecyl sulfate polyacrylamide gel and transblotted onto polyvinylidene difluoride transfer membranes (Millipore, Bedford, MA). The blotted membranes were reacted with an affinity-purified polyclonal anti–C-terminus of HDGF antibody generated by rabbit at a dilution of 1/10,000 and then visualized with an electrochemiluminescence detection system (Amersham Pharmacia Biotech, Buckinghamshire, UK).

Immunohistochemical Analysis
Immunohistochemical staining was performed on formalin-fixed, paraffin-embedded sections by using the avidin-biotin complex method. Antigen retrieval was performed with microwave treatment (5 minutes, three times) in 10 mM of citrate buffer (pH 6.0). Anti-HDGF antibody was used as the primary antibody at a dilution of 1/5000. Sections were lightly counterstained with methyl green. Positive staining in the bile ducts in the noncancerous lesions was used as the internal positive control. Stained sections were evaluated in a blinded manner without prior knowledge of the clinicopathologic parameters. The counting of immunohistochemically positive cells was performed by hand under a microscope. For each case, all the HCC area in the slides was carefully examined, and the HDGF-positive rate was determined.

The HDGF expression pattern was independently evaluated for the nucleus and cytoplasm; cells showing a staining intensity similar to or stronger than that in bile ducts in the nucleus or cytoplasm were regarded as nucleus positive or cytoplasm positive, respectively. Samples with >90% of tumor cells that expressed positive immunoreactivity both for nucleus and cytoplasm were regarded as HDGF index positive, and others were regarded as HDGF index negative.

Quantitative RT-PCR Analysis of HDGF
Total RNA was extracted from fresh-frozen samples in 18 cases of HCC with TRIzol reagent (Invitrogen, Carlsbad, CA). Ten micrograms of deoxyribonuclease I–treated total RNA was used for RT with Superscript II (Invitrogen). An aliquot representing 100 ng of input RNA was amplified by quantitative real-time PCR by using a TaqMan PCR Reagent Kit (Applied Biosystems, Foster City, CA) with the ABI PRISM 7700 Sequence Detection System (Applied Biosystems) as follows: 50°C for 2 minutes, 95°C for 10 minutes, and 40 cycles at 95°C for 15 seconds and 60°C for 1 minute. The following were used for amplification of ß-actin: forward primer, 5'-TCACCCACACTGTGCCCATCTACGA-3'; reverse primer, 5'-CAGCGGAACCGCTCATTCGCCAATGG-3'; and probe, 5'—6-carboxy-fluorescein (FAM)-ATGCCC—6-carboxytetramethylrhodamine (TAMRA)-CCCCCATGCCATCCTGCGTp-3'. The forward primer 5'-AAGTTTGGCAAGCCCAACA-3', reverse primer 5'-GGCTCTTCCACACAGCTCTTT-3', and probe 5'-FAM-AACCCTACTGTCAAGGCTTCCGGCT-TAMRA-3' were used for HDGF. RNA extracted from an HCC sample in one case was used as a standard. After RT, standard complementary DNA (cDNA) was serially diluted to obtain five standard solutions for a use in PCR reaction to generate the reference curve. The relative amount of cDNA in each sample was measured by interpolation in the standard curve, and then the relative ratio of HDGF/ß-actin expression was calculated for each HCC sample.

Statistics
Statistical analysis was performed by using JMP (SAS Institute Inc., Cary, NC). The correlation between the expression level of HDGF at quantitative RT-PCR and immunohistochemistry was evaluated by one-way analysis of variance. Correlations between the HDGF expression level by immunohistochemistry and the clinicopathologic parameters were evaluated by {chi}2 test and Fisher’s exact probability test. The overall and disease-free survival rates were calculated by using Kaplan-Meier methods,21 and differences in survival curves were analyzed by the log-rank test. Independent prognostic factors were analyzed by the Cox proportional hazards regression model in a stepwise manner.22 P < .05 was considered statistically significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Western Blotting
Western blotting by using HDGF antibody showed double bands sized 43 and 39 kDa in all lanes, including that of recombinant HDGF. This suggests the specificity and sensitivity of the antibody used in this analysis (Fig. 1Go).


Figure 1
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  		FIG. 1. Western blotting of hepatoma-derived growth factor (HDGF). All four cell lines and recombinant HDGF showed double bands of 43 and 39 kDa.

 
HDGF Expression Pattern in HCC
Forty-two cases (42%) showed strong staining in the nucleus of >90% of tumor cells, which were thus regarded as nucleus-positive; 46 cases with strong cytoplasmic staining in >90% of tumor cells were cytoplasm positive. Among them, 27 cases (27%) were both nucleus and cytoplasm positive and were thus regarded as having a positive HDGF index. The remaining 73 cases (73%) were regarded as having a negative HDGF index (Fig. 2Go).


Figure 2
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  		FIG. 2. Hepatoma-derived growth factor (HDGF) immunohistochemistry. (a and d) Hepatocellular carcinoma (HCC) with a positive HDGF index. More than 90% of the tumor cells showed positive nuclear/cytoplasmic staining. (b and e) HCC with a negative HDGF index. Most tumor cells did not express HDGF. (c) Internal control of HDGF. The bile duct is positively stained in the nucleus and cytoplasm (bar = 100 mm).

 
RNA was extracted from 18 cases with HCC, and they were tested for RNA preservation by ß-actin RT-PCR. Ten of the 18 cases showed an increase of the reaction curve before 25 PCR cycles, and then they were regarded as adequately preserved cases. The remaining eight cases showed an increase of the reaction curve after 25 cycles or showed no increase. They were regarded as having poor RNA preservation and were excluded from this study. The 10 cases consist of 4 positive and 6 negative HDGF indices by immunohistochemistry. The relative ratio of HDGF/ ß.-actin expression in cases with a negative and positive HDGF index was .64 ± .11 and 2.67 ± .71 (mean ± SD), respectively (P < .05; Fig. 3Go).


Figure 3
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  		FIG. 3. Hepatoma-derived growth factor (HDGF)/ß-actin messenger RNA expression ratio in hepatocellular carcinoma–positive and –negative HDGF indexes by immunohistochemistry. All cases with a positive HDGF index showed higher ratios than those with a negative HDGF index (P < .05). Bars are mean ± SD.

 
Relationship Between Clinicopathologic Features and HDGF Expression in HCC
The relationship between HDGF expression and the clinicopathologic features was analyzed (Table 1Go). The HDGF staining pattern was significantly correlated with the differentiation of HCC. Among 87 HCCs with Edmondson’s differentiation grade I, II, and III, 26 (29.9%) had a positive HDGF index, as did 1 (7.7%) of 13 cases with Edmondson’s grade IV (P = .0478). There was no significant relationship between HDGF expression and other clinicopathologic features.


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  		TABLE 1. The relationship between hepatoma-derived growth factor (HDGF) expression and clinicopathologic factors
 
Univariate and Multivariate Analysis for Prognostic Factors for HCC
The 5-year disease-free and overall survival rates of the 100 patients with HCC were 24.0% and 54.0%, respectively. Tumor recurrence was found in 73 patients. The prognostic significance of HDGF expression in HCC was analyzed for disease-free and overall survival. Patients with HDGF-negative HCC showed significantly better 5-year survival rates than those with HDGF-positive HCC (disease-free survival rate, 34.2% vs. 6.56%, P = .0149; overall survival rate, 60.4% vs. 48.9%, P = .0477; Fig. 4Go). Furthermore, when patients with differentiated HCC except for Edmondson’s grade IV were solely analyzed, the prognostic significance of the HDGF index was strong (disease-free survival rate, P = .0087; overall survival rate, P = .0474; Fig. 5Go).


Figure 4
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  		FIG. 4. Disease-free (a) and overall (b) survival curves of patients with hepatocellular carcinoma–positive and –negative hepatoma-derived growth factor (HDGF) indexes. A significant difference was observed between groups (a, P = .0149; b, P = .0477).

 

Figure 5
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  		FIG. 5. Disease-free (a) and overall (b) survival curves of patients with differentiated hepatocellular carcinoma (Edmondson’s grade I, II, and III)–positive and –negative hepatoma-derived growth factor (HDGF) indexes. A significant difference was observed between groups (a, P = .0087; b, P = .0474).

 
Tumor multiplicity, portal vein invasion, and serum AFP level were significant factors for disease-free and overall survival (Table 2Go). The pattern of tumor growth is a prognosticator for disease-free survival but not for overall survival, and the histological stage of fibrosis in the adjacent noncancerous liver tissues (histological activity index: 0 or 1 vs. 3 or 4) significantly affected overall survival but not disease-free survival.


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  		TABLE 2. Univariate analysis of individual clinicopathologic factors for disease-free and overall survival in patients after surgical resection of hepatocellular carcinoma
 
Multivariate analysis was performed with factors proven to be significant in the univariate analysis. HDGF expression, tumor multiplicity, and serum AFP level were independent prognostic factors for disease-free and overall survival (Table 3Go). The pattern of tumor growth and portal vein invasion were independent prognosticators for disease-free survival, but not for overall survival.


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  		TABLE 3. Multivariate analysis of individual clinicopathologic factors for disease-free and overall survival in patients after surgical resection of hepatocellular carcinoma
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Previously, we have demonstrated that exogenous HDGF stimulated the proliferation of HCC cell lines, and its overexpression enhanced the proliferation of HCC cells. Furthermore, the suppression of endogenous HDGF production by antisense oligonucleotides or cDNA inhibited the proliferation of cells expressing HDGF.9,11,13,15 These findings suggest the importance of HDGF in HCC development; therefore, this analysis was designed to investigate the correlation of HDGF expression with other clinicopathologic factors and its potential utility as a prognostic factor for HCC.

Western blotting by using HDGF antibody showed positive bands at the same size of recombinant HDGF in all cell lines examined. HDGF expression in 10 patients was examined by combined quantitative RT-PCR and immunohistochemical analyses, and these showed a correlation of HDGF expression between messenger RNA (RT-PCR) and protein (immunohistochemistry) levels. However, the sample size used for RT-PCR in this analysis was small, and this should be reassessed in a large number of patients.

The characteristics of the patients in this study with HCC, such as sex, age, and 5-year survival rates, were similar to those in previous studies from Japan23 and Western countries.2–4 The present univariate and multivariate analyses confirmed the prognostic significance of tumor multiplicity, serum AFP level, pattern of tumor growth, and portal vein invasion, as reported previously.5–7 These findings suggest that the results obtained from this study are generally applicable to HCC.

The prognostic significance of HDGF staining was evaluated for nucleus, cytoplasm, and combined nucleus and cytoplasm. The HDGF index value was mostly significant when the cases were divided into cases with staining both for nucleus and cytoplasm in >90% of tumor cells as a positive index and and others as a negative index, and then we used this cutoff level in this study. Other cutoff levels used in this study were 75% and 50%. Furthermore, the prognostic value was mostly significant when cases that were HDGF positive for both the nucleus and cytoplasm and others were compared. This categorization was chosen in this study. A significant correlation was observed between the HDGF index and tumor differentiation. Only one HCC with a poorly differentiated subtype (Edmondson grade IV) had a positive HDGF index, whereas 26 of 87 with differentiated group (Edmondson grade I–III) had a positive HDGF index.

Patients with Edmondson’s grade IV differentiation showed the poorest prognosis and the highest rate of portal vein invasion compared with the others; however, the difference was not significant. In addition, the prognostic significance of the HDGF index was stronger when patients with Edmondson’s grade I and II differentiation were solely analyzed. HDGF might be a prognostic marker of HCC, especially for cases with a well-differentiated subtype. Additional studies with more patients are necessary to clarify the inverse effect of HDGF expression and tumor grade on prognosis. It has been demonstrated that HCC initially develops in the form of a well-differentiated subtype in cirrhosis or hepatitis, from which a histologically less-differentiated subgroup might occur and gradually replace the well-differentiated tumor.24–26 Similarly, a significantly decreased expression of transforming growth factor{alpha}, epidermal growth factor receptor, and cyclooxygenase 2 in poorly differentiated HCC was shown when compared with well-differentiated HCC.27,28

The univariate and multivariate analyses demonstrated that the HDGF index was an independent prognosticator for HCC patients. The main cause for the poor prognosis of HCC is tumor recurrence in the liver.2–4 HDGF works for HCC proliferation, and, in addition, stimulation of the endothelial cell proliferation by HDGF was observed in renal and cardiovascular development and tumor formation in vivo, thus suggesting its involvement in angiogenesis.14,16,17 These HDGF functions are convenient for HCC cells to invade into the microvascular system and survive to form recurrent foci. These findings suggest that increased HDGF expression is a sign of poor prognosis in HCC. HDGF index, tumor multiplicity, and serum AFP level were independent prognosticators for both disease-free and overall survival. The combination of these factors might be a useful tool for predicting prognosis and choosing appropriate therapeutic modalities, including liver transplantation, for patients with HCC.29

In summary, this study demonstrates an increased rate of a positive HDGF index in well-differentiated HCC compared with poorly or undifferentiated subtypes and its potential prognostic utility for disease-free and overall survival with HCC.

Received for publication November 25, 2003. Accepted for publication August 25, 2005.


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 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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