Abstract
ADAMTS18 is a novel tumor suppressor and is critical to the pathology of human colorectal cancer. However, the underlying mechanism is not clear. Here we generated an Adamts18-deficient mouse strain as an in vivo model to investigate the role of ADAMTS18 in the pathogenesis of colorectal cancer. In AOM/DSS–induced colitis-associated colorectal cancer, the deficiency of Adamts18 in mice resulted in enhanced tumorigenesis and colon inflammation that could be attributed in part to enhanced nuclear translocation of β-catenin and elevated expression of its downstream target genes, cyclin D1 and c-myc. Moreover, increased p38MAPK and ERK1/2 activities were detected in colon cancer cells from Adamts18-deficient mice. Further studies revealed that ADAMTS18 deficiency reduced intestinal E-cadherin levels in mice, which ultimately led to intestinal barrier dysfunction. These data indicate that Adamts18 deficiency enhances tumorigenesis and intestinal inflammation through elevated Wnt/β-catenin and p38MAPK/ERK1/2 signaling and promotes colon cancer in this mouse model.
Highlights
A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs) are a family of 19 secreted zinc-metalloendopeptidases, which have been implicated in development, tissue remodeling, inflammation, cancer and vascular biology
Germ line transmission of the LoxP flanked Adamts18 gene allele was verified by Southern blotting and polymerase chain reaction (PCR)
A 402-bp fragment was amplified from wild type (w/w) mice; a 489-bp fragment was amplified from Adamts18 floxed (l/l) mice; and both the 402-bp and 489-bp fragments were amplified from Adamts18 floxed heterozygous (l/w) mice (Figure 1C)
Summary
A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs) are a family of 19 secreted zinc-metalloendopeptidases, which have been implicated in development, tissue remodeling, inflammation, cancer and vascular biology. ADAMTS proteases have multi-domain structural components in common, including an N-terminal signal peptide, followed by a prodomain, a metalloproteinase catalytic domain with a zinc binding motif, a disintegrin-like domain, a central thrombospondin type-1-like repeat (TSR), a cysteine-rich domain (high sequence homology), a spacer region, and a variable number of C-terminal TSR repeats. Some of them have further C-terminal domains These enzymes are located at the pericellular space through interactions of their thrombospondin-1 motifs and spacer regions with extracellular matrix (ECM) components [1, 2]. ADAMTS18 is an orphan ADAMTS, whose physiological substrates have not been identified This metalloproteinase is widely detected in adult tissues including brain, prostate, submaxillary gland, endothelium, retina, heart, lung, skeletal muscle, spleen, pancreas, esophagus, stomach, colon, larynx, breast, cervix, placenta, ovary, bone marrow, and lymph nodes [2]. Mutations of ADAMTS18 have been linked to eye diseases [3,4,5], bone mineral density (BMD) formation [6], white matter integrity of the brain [7], and various malignancies [8,9,10,11,12]
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