Elevated Plasma Levels of Matrix Metalloproteinase–9 (92–Kd Type Iv Collagenase/Gelatinase B) in Hepatocellular Carcinoma

Abstract

Background Matrix metalloproteinase 9 (MMP–9), a 92–kd gelatinase/type IV collagenase, has been implicated as playing an important role in cancer invasion and metastasis. A previous study showed that serum type IV collagenase activity correlated with metastasis by hepatocellular carcinoma (HCC). The aims of this study were to determine the plasma levels of immunoreactive MMP–9 in patients with HCC and to compare the levels with the clinical features including vascular invasion. Patients and methods: This study included 100 patients with HCC, 21 patients with chronic hepatitis (CH), 24 patients with liver cirrhosis (LC), and 138 healthy control subjects. Plasma MMP–9 levels were measured with a specific one–step sandwich enzyme immunoassay. Results: Plasma MMP–9 levels in HCC (62 [33 to 130 ng/mL] median [25%, 75%], 13 to 660 ng/mL, minimum, maximum) were significantly elevated compared with those in normal controls (36 [25 to 45], range, 2.8–70 ng/mL), in CH (28 [18 to 30], 13 to 66 ng/mL) and in LC (35 [26 to 58], 16 to 86 ng/mL) ( P < .0000001; P = .0000003; and P = .00205, respectively). When the cut–off level was defined as 60 ng/mL from a receiver operating characteristic curve, plasma MMP–9 concentrations had a sensitivity of 53% and a specificity of 89% for the detection of HCC from CH and LC. The levels were significantly higher in HCC patients with macroscopic portal venous invasion (79 [36 to 160], 15–660 ng/mL) than those without the invasion (44 [27 to 80], 13 to 210 ng/mL) ( P = .00726). Plasma MMP–9 levels in patients with HCC were not correlated with tumor number, size, volume, or serum α–fetoprotein levels. Conclusions: The present data suggest that plasma MMP–9 levels can be a candidate for a novel marker for HCC. The levels appear to reflect its potential and ongoing activity of vascular invasion. A long–term follow–up of the patients will be necessary to determine whether increased plasma MMP–9 levels are predictive of more invasive and metastatic HCC.