Cellular distribution of transcripts for tissue inhibitor of metalloproteinases 1 and 2 in human hepatocellular carcinomas

Abstract

The cellular distribution of tissue inhibitor of metalloproteinases (TIMP)-1, and TIMP-2 was studied by using in situ hybridization in surgically removed human hepatocellular carcinomas (HCCs) and cholangiocellular carcinomas (CCCs). The purpose of this study was to characterize the protein involvement of TIMPs in the development of HCCs and CCCs. All HCCs and CCCs expressed TIMPs. The distribution of transcripts for TIMPs in the tumors was mostly homogeneous. Expression of TIMP in cancer cells was more intense than that in the surrounding noncancerous liver (either, cirrhosis, chronic hepatitis, or normal), and expression of TIMP-1 was stronger than that of TIMP-2. Expression of TIMPs varied among HCC nodules, but there was no obvious association between the expression level of TIMPs and differentiation stages or invasiveness of the HCCs. Transcripts for TIMPs were clearly demonstrated in the metastatic HCC nodules in the lung. Expression of TIMP-1 CCC was strong, and small nodules of CCC were recognized in the liver. Immunohistochemical study for TIMP-1 revealed a consistent staining of the TIMP protein with the transcripts. In the peritumoral histologically normal liver, which was not infected with either hepatitis B or C virus, expression of TIMP-1 was found in various cell types, but that of TIMP-2 was weak. Expression of TIMP-1 in hepatocytes revealed clear zonal distribution. These results suggest that TIMPs may act on modulating the matrix/tumor interaction and may play an important role in growth and invasion of HCCs and CCCs. Expression of TIMP-1 can be a marker of HCC metastasis to the lung, and also that of the extent of CCC invasion. Furthermore, the consistent expression of TIMPs in many cell types of the noncancerous liver suggests some unknown functional role that must be clarified.

The Contribution of Matrix Metalloproteinase-1 Genotypes to Hepatocellular Carcinoma Susceptibility in Taiwan

“…In 2009, Altadill and his colleagues reported that overexpressed MMP-1 by fibroblast cells is correlated with poor prognosis (19), supported by the findings that overexpressed MMP-1 was associated with an elevated metastasis capacity of the HCC cells (53,54). Altadill and his colleagues also reported that overexpressed TIMP1 by stromal cells is correlated with shortened overall survival period (19), and accordingly TIMP-1 overexpression was reported to be associated increased invasive and metastatic capacity of the HCC cells (55,56). In the near future, further analysis of TIMP1 genotype/phenotype may provide further evidence for evaluating the contribution of combined genotypes of MMP-1 and TIMP1 to the carcinogenesis of HCC.…”

Association of E-cadherin, matrix metalloproteinases, and tissue inhibitors of metalloproteinases with the progression and metastasis of hepatocellular carcinoma

“…52 Overexpression of TIMP-1 but underexpression of TIMP-2 and -3 have been reported to be associated with invasion and metastasis in hepatocellular carcinoma. 25,53,54 Early studies using recombinant TIMPs or basic gene transfer system (plasmids or retrovirus) have demonstrated that inhibition of MMPs by TIMPs blocks both tumor growth and local invasion. However, the use of TIMPs in clinical trials has proven largely disappointing.…”

Sinulariolide Suppresses Cell Migration and Invasion by Inhibiting Matrix Metalloproteinase-2/-9 and Urokinase through the PI3K/AKT/mTOR Signaling Pathway in Human Bladder Cancer Cells

“…A balance of TIMPs and MMPs can control the local activities of MMPs in tissues to avoid the degradation of ECM proteins; however, a disturbed balance of TIMPs and MMPs is known to occur in malignant tumors, which leads to cancer cell migration and invasion. Study has shown that TIMP-1/-2 and MMP-9 all play crucial roles in the tumor cell growth and invasion of hepatocellular carcinomas [25,26]. 11-epi-Sinulariolide acetate was originally isolated from cultured-type soft coral Sinularia flexibilis, and has been reported to exert anti-invasion and anti-migration effects on hepatoma HA22T cells [27].…”