TIMP-1 expression in human colorectal cancer is associated with TGF-B1, LOXL2, INHBA1, TNF-AIP6 and TIMP-2 transcript profiles.
The balance of activity between the endogenous enzyme inhibitors known as tissue inhibitors of metalloproteinases and their targets, the matrix metalloproteinases, in the extracellular matrix is thought to play an important role in tumour cell invasion. Supporting this notion, we have shown that colorectal cancer patients have increased plasma levels of the tissue inhibitor of metalloproteinases-1 (TIMP-1), and that high plasma TIMP-1 levels are associated with short colorectal cancer patient survival. However, although TIMP-1 has been extensively studied in cancer, very little is known about how it is regulated. To further elucidate potential mechanisms of regulation of this protein, we did a number of experiments to look at associations between the transcript profile of TIMP-1 with known matrix metalloproteinases (MMPs) as well as with expression profiles of other genes differentially regulated in human colorectal cancer (CRC) and the other TIMPs 2-4, which have also been associated with the progression of colorectal cancer. Genome-wide expression profiling of 172 CRC and normal mucosa samples was used to identify transcript changes for the genes under investigation. We found that TIMP-1 was up-regulated in CRC samples compared with normal tissue, while TIMP-2 was down-regulated. Eight MMPs were up-regulated in CRC compared with normal tissue. Correlating up-regulated genes with the TIMP-1 transcript, we identified 13 that were also up-regulated in cancerous tissue. Among these were genes associated with the synthesis of extracellullar matrix, genes involved in the TGF-beta signalling pathway, and genes that are likely transcribed by the tumour cells. These insights add to the complex picture emerging about the regulation of TIMPs in colorectal cancer.
Offenberg
Hanne
H
Department of Veterinary Pathobiology, Section of Biomedicine, Faculty of Life Sciences, University of Copenhagen, DK-1870 Frederiksberg C, Denmark.
Brünner
Nils
N
Mansilla
Francisco
F
Orntoft Torben
F
F
Birkenkamp-Demtroder
Karin
K
D000594:Amino Acid Oxidoreductases / Q000235:genetics*; D015815:Cell Adhesion Molecules / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D028322:Inhibin-beta Subunits / Q000235:genetics*; D020782:Matrix Metalloproteinases / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics
D015815:Cell Adhesion Molecules; D012333:RNA, Messenger; C072273:TNFAIP6 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D019714:Tissue Inhibitor of Metalloproteinases; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C103008:inhibin beta A subunit; D019716:Tissue Inhibitor of Metalloproteinase-2; D028322:Inhibin-beta Subunits; D000594:Amino Acid Oxidoreductases; C119091:LOXL2 protein, human; D020782:Matrix Metalloproteinases