The Role of CTHRC1 in Regulation of Multiple Signaling and Tumor Progression and Metastasis

Abstract

Collagen triple helix repeat containing-1 (CTHRC1) has been identified as cancer-related protein. CTHRC1 expresses mainly in adventitial fibroblasts and neointimal smooth muscle cells of balloon-injured vessels and promotes cell migration and tissue repair in response to injury. CTHRC1 plays a pivotal role in some pathophysiological processes, including increasing bone mass, preventing myelination, and reversing collagen synthesis in many tumor cells. The ascended expression of CTHRC1 is related to tumorigenesis, proliferation, invasion, and metastasis in various human malignancies, including gastric cancer, pancreatic cancer, hepatocellular carcinoma, keloid, breast cancer, colorectal cancer, epithelial ovarian cancer, esophageal squamous cell carcinoma, cervical cancer, non-small-cell lung carcinoma, and melanoma. And molecules that regulate the expression of CTHRC1 include miRNAs, lncRNAs, WAIF1, and DPAGT1. Many reports have pointed that CTHRC1 could exert different effects through several signaling pathways such as TGF-β, Wnt, integrin β/FAK, Src/FAK, MEK/ERK, PI3K/AKT/ERK, HIF-1α, and PKC-δ/ERK signaling pathways. As a participant in tissue remodeling or immune response, CTHRC1 may promote early-stage cancer. Several recent studies have identified CTHRC1 as an effectual prognostic biomarker for predicting tumor recurrence or metastasis. It is worth noting that CTHRC1 has different cellular localization and mechanisms of action in different cells and different microenvironments. In this article, we focus on the advances in the signaling pathways mediated by CTHRC1 in tumors.

Figure 1

The structure of the CTHRC1 protein. The construct of CTHRC1 contains an NH2-terminal peptide for extracellular secretion, a short collagen triple helix repeat of 36 amino acids, and a COOH-terminal globular domain. The proline-rich hydrophobic domain lies between the 1st and 30th amino acids and serves as a signal peptide for transport to the endoplasmic reticulum. CTHRC1 comprises a collagen domain between amino acids 57 and 90, and the protein contains 10 cysteine residues, corresponding to about 4.7% cysteine in the final protein. What is more, its only amino acid posttranslational modification is the glycosylation of asparagine at position 188.

Figure 2

Signaling pathways mediated by CTHRC1 involved in the progression and metastasis of tumor. (1) TGF-β signaling pathway is quite complex, especially in terms of its effects, which are often contradictory depending on location and time. There exists a critical negative feedback regulatory loop between TGF-β-smad2/3 signaling pathway and CTHRC1. (2) WNT signaling includes WNT/β-catenin canonical pathway and β-catenin-independent noncanonical pathway. In the canonical WNT signaling, Fzd receptor and LRP5/LRP6 coreceptor are transduced to β-catenin signaling cascade for the maintenance of stem and progenitor cells. In the noncanonical WNT signaling, Fzd receptor and ROR2/PTK7/RYK coreceptor are transduced to RhoA, JNK signaling cascades for the control of tissue polarity, cell adhesion, or cell movement. The downstream molecules of the WNT/PCP pathway mainly include the small GTPase family, such as Rac1, RhoA, and JNK, which play essential roles in cancer cell migration and invasion. (3) CTHRC1 signal via WAIF1 can activate PKCδ, which is an essential component of the WNT/PCP pathway. Furthermore, PKCδ is responsible for the activation of the CTHRC1-induced ERK signaling pathway. (4) In CTHRC1/integrin β signaling pathway, the upregulation of CTHRC1 is related to the progression and metastasis of several cancers through the activation of several key signaling molecules, including Src, FAK, paxillin, MEK, ERK, and Rac1. FAK promotes cancer cell migration by regulating focal adhesion formation and turnover, which involve activation of Src and paxillin. FRA-1 is activated by CTHRC1 through the MAPK/MEK/ERK signaling, which leads to the upregulation of cyclin D1 and that promotes cell proliferation. FRA-1 also induces snail1-mediated MMP14 expression to facilitate ESCC cell invasion, migration, and metastasis. PI3K/AKT signaling pathway induces EMT change and MMP2/MMP9 expression. (5) HIF-1α and VEGF are activated by CTHRC1 through activating the PI3K/AKT/mTOR signaling pathway, which promotes tumor angiogenesis. CTHRC1 also participates in tumor cell migration and invasion through HIF-1α/CXCR4 signals.