- Open Access
Elevated levels of tissue inhibitor of metalloproteinases (TIMPS) in human hepatocellular carcinomas
© Matsumoto et al; licensee BioMed Central Ltd 2004
- Published: 14 January 2004
- Liver Cirrhosis
- Differentiation Grade
- Capsular Invasion
- Alpha Fetoprotein
- Serum Alpha Fetoprotein
Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies in Japan. Invasion and metastasis of HCC are frequently observed during the development of HCCs, and are regulated by matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs). We have previously reported the strong expression of TIMP-1 and TIMP-2, and cellular localization of the transcripts in HCCs . But the mechanisms of invasion and metastasis of HCCs, and particularly the role of TIMPs are still unclear. The purpose of this study was to examine the tissue concentration of the TIMP-1 and to study the potential involvement of TIMP-1 in the development of HCCs.
Patients and Tissue Preparation
Characteristics of the Patients Investigated in this Study
46–75 (median 66)
hepatitis B virus (HBV)
hepatitis C virus (HCV)
HBV and HCV
Serum AFP (ng/ml, mean – SD)
766 – 2935
Tumor size in diameter (mm, mean – SD)
31 – 21
Assay for tissue TIMP-1 concentration
TIMP-1 concentration in the supernatant of tissue homogenate of HCC and non-neoplastic liver was measured by a Enzyme-Linked Immunosorbent Assay system, using a commercial assay kit (Fuji Chemical Co. Japan), which contains two kinds of monoclonal antibodies against bovine TIMP-1.
Difference between the tissue TIMP-1 concentration of HCC and that of non-neoplastic liver was examined by Student's t test. The Mann-Whitney's U-test was performed to compare the relationship between tissue TIMP-1 concentration and clinicopathological features.
Tissue TIMP-1 concentration
The TIMP-1 concentration in HCC was 520 – 602 (mean – SD) ng/mg protein, and was significantly (p < 0.0001) higher than that in the corresponding non-neoplastic liver (114 – 212).
Correlation between tissue TIMP-1 concentration and pathological features
TIMP-1 concentration and pathological features of HCCs
TIMP-1 concentration in
Correlation between tissue TIMP-1 concentration and clinical features
The TIMP-1 concentration in HCC was examined in the various conditions of clinical features, that include the age of the patients, the underlying liver (liver cirrhosis or chronic hepatitis), the type of viral infection (hepatitis B virus or hepatitis C virus), serum alpha fetoprotein (AFP) levels, and tumor size. The TIMP-1 concentration in liver cirrhosis was higher than that in chronic hepatitis (p < 0.01).
The present study demonstrated that tissue TIMP-1 concentration in HCCs was significantly higher than that in non-neoplastic liver and that the TIMP-1 concentration in poorly differentiated HCCs was significantly higher than that of well and moderately differentiated HCCs. We have previously reported by using in situ hybridization that the expression of TIMP-1 in HCCs was stronger than that in non-neoplastic liver . The present study further confirms that TIMP-1 is up-regulated in HCCs not only in the transcription but also in the translation level. The primary biological function of TIMPs is the inhibition of MMPs. When the cancer invades the surrounding non-neoplastic tissue, MMPs may play a major role to degrade extracellular matrices. TIMPs play an important role in the regulation of the action of MMPs. But, it has been reported that tissue TIMP-1 concentration in gastric cancer was associated with various pathological factors, and patients with high tissue TIMP-1 concentration had poor prognosis in comparison to those with low TIMP-1 level . The elevated TIMP-1 level was also associated with poor prognosis in lung cancer . It is intriguing that the TIMP-1 concentration in poorly differentiated HCCs was significantly higher than that of well and moderately differentiated HCCs. Our previous studies on mRNA level have not shown the similar results to the present study on the protein level. Generally, the lower the differentiation grade of HCCs, the stronger potential of growth, invasion and metastasis. TIMP-1 has been reported to be a new cell-growth factor  and also an anti-angiogenic factor . These lines of evidence may be associated with the reason why the TIMP-1 concentration in poorly differentiated HCCs was high. Further studies on the functional role of TIMPs in HCCs are needed.
- Nakatsukasa H, Ashida K, Higashi T, Ohguchi S, Tsuboi S, Hino N, Nouso K, Urabe Y, Kinugasa N, Yoshida K, et al: Cellular distribution of transcripts for tissue inhibitor of metalloproteinases-1 and -2 in human hepatocellular carcinomas. Hepatology. 1996, 24: 82-88. 10.1002/hep.510240115.View ArticlePubMedGoogle Scholar
- Yoshikawa T, Tsuburaya A, Kobayashi O, Sairenji M, Motohashi H, Yanoma S, Noguchi Y: Intratumoral concentrations of tissue inhibitor of matrix metalloproteinase 1 in patients with gastric carcinoma a new biomarker for invasion and its impact on survival. Cancer. 2001, 91: 1739-1744. 10.1002/1097-0142(20010501)91:9<1739::AID-CNCR1192>3.0.CO;2-9.View ArticlePubMedGoogle Scholar
- Ylisirnio S, Hoyhtya M, Makitaro R, Paaakko P, Risteli J, Kinnula V, Turpeenniemi-Hujanen T, Jukkola A: Elevated serum levels of type I collagen degradation marker ICTP and tissue inhibitor of metalloproteinase (TIMP) 1 are associated with poor prognosis in lung cancer. Clin Cancer Res. 2001, 7: 1633-1637.PubMedGoogle Scholar
- Hayakawa T, Yamashita K, Tanzawa K, Uchijima E, Iwata K: Growth-promoting activity of tissue inhibitor of metalloproteinases-1 (TIMP-1) for a wide range of cells. A possible new growth factor in serum. FEBS Lett. 1992, 298: 29-32. 10.1016/0014-5793(92)80015-9.View ArticlePubMedGoogle Scholar
- Schnaper HW, Grant DS, Stetler-Stevenson WG, Fridman R, D'Orazi G, Murphy AN, Bird RE, Hoythya M, Fuerst TR, French DL: Type IV collagenase(s) and TIMPs modulate endothelial cell morphogenesis in vitro. J Cell Physiol. 1993, 156: 235-246. 10.1002/jcp.1041560204.View ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.