Collagen Triple Helix Repeat Containing 1, a Novel Secreted Protein in Injured and Diseased Arteries, Inhibits Collagen Expression and Promotes Cell Migration

Abstract

Abstract-Collagen triple helix repeat containing 1 (Cthrc1) was identified in a screen for differentially expressed sequences in balloon-injured versus normal arteries. Cthrc1 expression was not detectable in normal arteries. However, on injury it was transiently expressed by fibroblasts of the remodeling adventitia and by smooth muscle cells of the neointima. It was also found in the matrix of calcifying human atherosclerotic plaques. CTHRC1 is a secreted 28-kDa protein that is glycosylated and highly conserved from lower chordates to mammals. A short collagen motif with 12 Gly-X-Y repeats appears to be responsible for trimerization of the protein and this renders the molecule susceptible to cleavage by collagenase. Cthrc1 mRNA expression levels are increased in response to transforming growth factor-␤ and bone morphogenetic protein-4. Cell migration assays performed with CTHRC1-overexpressing fibroblasts and smooth muscle cells demonstrate that increased CTHRC1 levels are associated with enhanced migratory ability. Furthermore, CTHRC1 overexpression caused a dramatic reduction in collagen type I mRNA and protein levels.

Wnt/Planar cell polarity signaling: A new paradigm for cancer therapy

“…Cthrc1 was first identified as a gene transiently expressed in the arterial wall upon injury, possibly supporting vascular remodeling by limiting collagen matrix deposition and promoting cell migration (51). Cthrc1 is aberrantly upregulated in the majority of human solid tumors and seems to be associated with cancer invasion and metastasis (52,53).…”

N-Glycosylation Induces the CTHRC1 Protein and Drives Oral Cancer Cell Migration

“…Thus, another consequence of amplified DPAGT1/ canonical Wnt signaling could be the activation of key components driving OSCC cell migration. Recently, CTHRC1 (collagen triple helix repeat containing 1), a secreted N-glycoprotein highly conserved in evolution, has emerged as a key player in tumor invasion and metastasis (22). First identified in a screen for novel genes associated with vascular injury and repair, CTHRC1 can be tethered to the cell surface to promote actin polymerization and cell polarity (23).…”

Clinical significance of CTHRC1 protein expression in human cancers: a meta-analysis

“…Nevertheless, the full impact of CTHRC1 expression on cancer has not yet been elucidated. CTHRC1 is widely accepted to be involved in vascular tissue repair and remodeling in response to injury by repressing the deposition of the collagen matrix and by facilitating the migration of cells (Pyagay et al, 2005). Additionally, CTHRC1 anchored in the cell membrane can stabilize the interaction of the Wnt-Frizzled receptor, and can selectively activate the PCP pathway, which was deemed as one part of Wnt signaling (Yamamoto et al, 2008).…”

“…CTHRC1 is a novel 28-kDa cancer-secreted glycosylated protein that is highly conserved in lower chordates and higher mammals (Pyagay et al, 2005). CTHRC1 has been shown to be expressed mainly in neointimal smooth muscle cells and adventitial fibroblasts of balloon-injured vessels (Chen et al, 2013).…”