Elsevier

Digestive and Liver Disease

Volume 39, Issue 2, February 2007, Pages 167-172
Digestive and Liver Disease

Liver, Pancreas and Biliary tract
Prognostic significance of osteopontin in hepatitis B virus-related hepatocellular carcinoma

https://doi.org/10.1016/j.dld.2006.10.015Get rights and content

Abstract

Background and aims

Osteopontin (OPN) is known to be associated with metastasis in many types of cancers. Since OPN is a highly phosphorylated and glycosylated protein, the modification after transcription is very important to its function. In hepatocellular carcinoma (HCC), the elevated expression of OPN at mRNA levels and its relationship with metastasis and poorer prognosis of the patients have been reported. However, the prognostic impact of OPN at protein levels on the patients with hepatitis B virus (HBV)-related HCC after hepatectomy is still limited.

Patients and methods

The expression of OPN was examined at protein level by using immunohistochemistry in 72 patients who underwent hepatectomy for HBV-related HCC, and its prognostic significance in disease-free and overall survival of the patients was also analyzed by log-rank test and multivariate Cox regression analyses.

Results

Thirty-nine of 72 (54.17%) HBV-related HCC specimens were positive for OPN with cytoplasmic staining. OPN was highly expressed in the specimens with capsular infiltration compared to those without (P < 0.05), and also was significantly related with portal vein invasion (P < 0.01) and lymph node invasion (P < 0.01). The mean disease-free survival (DFS) was only 13.55 ± 14.77 months when the HBV-related HCC specimens highly expressed OPN compared to 36.00 ± 18.68 months for those with low expression (P < 0.001). The overall survival (OS) of the patients was 18.63 ± 17.28 months when the HCC over-expressed OPN compared to 42.59 ± 16.85 months for HCC with the low expressed OPN (P < 0.001). Multivariate analysis showed that OPN over-expression was the strongest independent adverse prognostic factor for both DFS (P = 0.01) and OS (P = 0.014).

Conclusions

OPN over-expression was closely related to capsular infiltration, venous invasion, lymph node metastasis, and also with worse prognosis, suggesting that OPN might be deemed as a useful molecular marker for predicting the prognosis of HCC.

Introduction

Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) is one of the most common cancers in the world, especially in China [1]. Despite remarkable advances in diagnostic and therapeutic techniques, the behavior of HBV-related HCC often leads to a fatal outcome. The high mortality is partially due to the fact that by the time symptoms have developed the cancer has exhibited vascular invasion and intrahepatic metastasis [2]. To study the precise mechanisms by which HCC spreads is of great importance. Metastasis initiated in primary HCC is a multi-gene involved, multi-step, and changing process. Current studies have revealed that osteopontin (OPN) is one of possibly significant factors in HCC metastasis [3].

OPN is classified as both a matrix protein and a cytokine, which is comprised of many functional domains, including a high sialic acid content, aspartate-rich domain, calcium-binding domain, thrombin cleavage site, multiple residues with consensus for phosphorylation as well as an integrin-binding arginine-glycineaspartate (RGD) motif [4]. Previous studies found that OPN was expressed widely and had a diverse range of functions. OPN is not only expressed in bone, but also was secreted by many types of cells including osteoclasts, lymphocytes, and macrophages. OPN can promote cell adhesion and migration, inflammatory response, anti-apoptosis, suppression of nitric oxide synthase, and bone calcification by interacting with certain integrins and the hyaluronic acid receptor CD44 [5], [6].

OPN protein or mRNA expression level was increased in many different types of tumors, including breast, lung, prostate and gastric cancers, and also related with tumor progression, and metastasis [7], [8]. In addition, OPN expression level has been reported to be significantly associated with decreased survival of the patients in a variety of cancers, and might be a biomarker of patients’ prognosis [9].

OPN is a highly phosphorylated and glycosylated protein, and the modification after transcription is very important to its function. Although the elevated expression of OPN at mRNA levels and its association with prognosis of the patients with HCC has been reported [10], [11], the expression of OPN at protein levels in human HBV-related HCC, and its prognostic significance of the patients were not fully elucidated. In this study, we investigated OPN expression at protein level in 72 HBV-related HCC cases by using immunohistochemistry, evaluated its role in the progression of HCC, and analyzed the relationship between OPN expression and the prognosis of the patients, hoping to give more clues to the therapy and prevention of HBV-related HCC.

Section snippets

Tumor specimens

HCC tissue samples were obtained from 72 patients who received surgical resection at Xijing Hospital of the Fourth Military Medical University, Xi’an, China, from September 1999 to June 2001 with the patients’ consents. All tissue samples were obtained from the patients before any treatments. All the HCC patients were the secondary disorder of HBV infection, which was confirmed by serological detection of HBV antigens and patients’ history, and 38 patients were present with cirrhosis. 59

Expression of OPN in HCC tissues

In 72 HCC specimens, OPN staining was positive in 39 samples (54.17%), and was intensely positive in the cytoplasm of cancer cells, but not detected in nuclei (Fig. 1). Relationships between clinicopathological features and the immunohistochemical results are shown in Table 1. The OPN protein was significantly overexpressed in HCC patients with capsular infiltration, as compared to those without (P < 0.05). OPN expression was also significantly correlated with portal vein invasion (P < 0.01) and

Discussion

OPN is a multifunctional protein. Elevated OPN protein or gene expressions were found in different types of human tumors, and significantly correlated with clinopathological features such as tumor size, tumor stage, tumor grade and patients’ survival. Enhanced secretion of OPN showed a positive correlation with increased metastatic potential, while reduction of OPN in metastatic cells resulted in a significant reduction of the metastatic potential in transformed cell lines [16]. OPN may also

Conflict of interest statement

None declared.

Acknowledgements

We greatly thank technician Zheng Chen and Baohua Song for their excellent technical assistance, Fucheng Ma for the help in preparing human tissues, Baojun Chen and Taidong Qiao for pathological diagnosis.

References (20)

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This work was supported by the Program for New Century Excellent Talents (NCET) in University and grants (No. 30371585, 30570835) from the National Natural Science Foundation of China to Dr. Jie Liu.

1

Dr. Huahong Xie, Dr. Jiugang Song and Dr. Rui Du contributed equally to this study.

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