Abstract
Collagen is significantly upregulated in colorectal liver metastasis (CRLM) compared to liver tissue. Expression levels of specific collagen types in CRLM resemble those in colorectal cancer (CRC) and colon tissue. We investigated whether the collagen hydroxylation pattern from the primary tumor also migrates with the metastatic tumor. The degree of collagen alpha-1(I) hydroxylation in colon, CRC, liver, and CRLM tissue of the same individuals (n = 14) was studied with mass spectrometry. The degree of hydroxylation was investigated in 36 collagen alpha-1(I) peptides, covering 54% of the triple helical region. The degree of hydroxylation in liver tissue was similar to that in colon tissue. The overall degree of hydroxylation was significantly lower (9 ± 14%) in CRC tissue and also significantly lower (12 ± 22%) in CRLM tissue compared to colon. Furthermore, eleven peptides with a specific number of hydroxylations are significantly different between CRLM and liver tissue; these peptides could be candidates for the detection of CRLM. For one of these eleven peptides, a matching naturally occurring peptide in urine has been identified as being significantly different between patients suffering from CRLM and healthy controls. The hydroxylation pattern in CRLM resembles partly the pattern in liver, primary colorectal cancer and colon.
Highlights
Collagen is a family of proteins that form triple helical structures
4Hyp at the Yaa-position is formed by 4-prolyl hydroxylase, which requires Gly-Xaa-Pro as substrate [2]. 4-hydroxyproline rarely occurs at the Xaa positions (4xHyp), neither the enzyme, nor the substrate required for the formation of 4-hydroxyproline at the Xaa-position (4xHyp) is known [3]. 3Hyp is formed by 3-prolyl hydroxylase, which requires Gly-Pro-4Hyp as substrate [4]. 3Hyp and 4Hyp are involved in triple helix stability and fiber formation, but their specific functions are still not fully understood [5,6,7]
Even though the average number of hydroxylations is comparable between colon and liver tissue, locally along the collagen alpha-1(I) chain the degree of hydroxylation is significantly different
Summary
A triple helix is formed by three protein subunits called alpha-chains. The specific part of an alpha-chain involved in triple helix formation consists of a repeating unit [-Gly-Xaa-Yaa-]n where Xaa and Yaa can be different amino acids, frequently proline and lysine [1]. Proline and lysine can be enzymatically modified prior to triple helix formation.
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