Collagen triple helix repeat containing-1 promotes pancreatic cancer progression by regulating migration and adhesion of tumor cells

Abstract

Collagen triple helix repeat containing-1 (CTHRC1) is a secreted protein involved in vascular remodeling, bone formation and developmental morphogenesis. CTHRC1 has recently been shown to be expressed in human cancers such as breast cancer and melanoma. In this study, we show that CTHRC1 is highly expressed in human pancreatic cancer tissues and plays a role in the progression and metastasis of the disease. CTHRC1 promoted primary tumor growth and metastatic spread of cancer cells to distant organs in orthotopic xenograft tumor mouse models. Overexpression of CTHRC1 in cancer cells resulted in increased motility and adhesiveness, whereas these cellular activities were diminished by down-regulation of the protein. CTHRC1 activated several key signaling molecules, including Src, focal adhesion kinase, paxillin, mitogen-activated protein kinase kinase (MEK), extracellular signal-regulated kinase and Rac1. Treatment with chemical inhibitors of Src, MEK or Rac1 and expression of dominant-negative Rac1 attenuated CTHRC1-induced cell migration and adhesion. Collectively, our results suggest that CTHRC1 has a role in pancreatic cancer progression and metastasis by regulating migration and adhesion activities of cancer cells.

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

“…Previously, we showed that human OSCC specimens display aberrant amplification of the DPAGT1/canonical Wnt signaling positive feedback loop that leads to hyperglycosylation of E-cadherin and diminished intercellular adhesion (6). In this study, we have provided evidence that increased activity of this loop leads to overexpression of CTHRC1, an N-glycoprotein shown to drive tumor progression and metastasis (26). We have demonstrated that in OSCC, DPAGT1 and canonical Wnt synergize to upregulate CTHRC1 through hyperglycosylation/protein stabilization and transcriptional activation, respectively.…”

“…Moreover, Wnt/PCP signaling has been shown to drive breast cancer cell migration (37). We note that CTHRC1 can also activate other oncogenic signaling pathways, including Src/focal adhesion kinase and MEK/ERK (26). Further studies are needed to determine the details of signaling events activated by CTHRC1 in OSCC.…”

“…Recent studies have identified an N-glycoprotein, CTHRC1, as a key regulator of cell motility in cancer (25,26). Thus, we hypothesized that increased DPAGT1-mediated N-glycosylation may promote additional molecular events that influence OSCC progression, such as cell migration.…”

“…Increased N-Glycosylation Drives Overexpression of CTHRC1 in OSCC-Because CTHRC1 is linked to the pathogenesis of several human cancers (25,26), we next examined the mechanisms responsible for its up-regulation in OSCC. CTHRC1 is an N-glycoprotein with one N-glycan consensus addition sequence in the C-terminal region at Asn-188, and N-glycosylation was shown to promote its tethering to the membrane (23).…”

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

“…Moreover, it has been suggested that CTHRC1 may be largely involved in repairing damaged blood vessel tissues by limiting collagen matrix deposition and improving cell migration (Ip et al, 2011). Additionally, it been demonstrated that CTHRC1 can mediate the activities of members of the Rho GTPase family of proteins, including Rac1, RhoA, and Cdc42, which are important in regulating cell migration through their effects on cytoskeletal reorganization and cell adhesion activation (Park et al, 2013;Zhou et al, 2014). Recently, several studies have revealed that CTHRC1 is highly up-regulated in solid tumors, and may have a significant association with the pathogenic mechanisms of several human cancers, including hepatocellular carcinoma, gastric cancer, pancreatic cancer, and colorectal cancer (Kharaishvili et al, 2011;Ren et al, 2011;Wang et al, 2012).…”