Abstract
Collagen triple helix repeat-containing 1 (CTHRC1) is known to be aberrantly upregulated in most human solid tumors, although the functional roles of CTHRC1 in colorectal cancer remain unclear. In this study, we investigated the occurrence of CTHRC1 upregulation and its role in vivo and in vitro. The expression profile and clinical importance of CTHRC1 were examined by reverse transcription-polymerase chain reaction and immunohistochemical analyses in normal and tumor patient samples. CTHRC1 was detectable in normal tissues, but also was highly expressed in tumor specimens. CTHRC1 upregulation was significantly associated with demethylation of the CTHRC1 promoter in colon cancer cell lines and tumor tissues. Clinicopathologic analyses showed that nodal status and expression of CTHRC1 (95% CI 0.999-3.984, p=0.05) were significant prognostic factors for disease-free survival. Promoter CpG methylation and hypermethylation status were measured by bisulfite sequencing and pyrosequencing analysis. Furthermore, we showed that overexpression of CTHRC1 in the SW480 and HT-29 cell lines increased invasiveness, an effect mediated by extracellular signal-regulated kinase (ERK)-dependent upregulation of matrix metalloproteinase 9 (MMP9). Consistent with this, we found that knockdown of CTHRC1 attenuated ERK activation and cancer cell invasivity. These results demonstrate that CTHRC1 expression is elevated in human colon cancer cell lines and clinical specimens, and promotes cancer cell invasivity through ERK-dependent induction of MMP9 expression. Our results further suggest that high levels of CTHRC1 expression are associated with poor clinical outcomes.
Highlights
Colon cancer is a major health problem worldwide, and among colon cancer patients with a clinical onset greater than 55 years of age, mortality rates of have increased
Collagen triple helix repeat-containing 1 (CTHRC1) expression has been observed in human solid cancers [13, 14], and aberrant expression of CTHRC1 is associated with cancer tissue invasion and metastasis in melanoma [13], how CTHRC1 induces these phenotypes has remained unknown
To identify genes regulated under CTHRC1-overexpressed conditions, we examined the expression of epithelial-mesenchymal transition (EMT)-related genes using RT-polymerase chain reaction (PCR)
Summary
Colon cancer is a major health problem worldwide, and among colon cancer patients with a clinical onset greater than 55 years of age, mortality rates of have increased. Changes in the cellular characteristics of transformed cells, such as uncontrolled proliferation and metastatic potential, are the major cause of mortality in tumor patients. Metastasis is associated with changes in cell adherence, levels of metalloprotease expression, and cellular mobility [8, 9]. In addition to functioning in the context of arterial injury, CTHRC1 has been reported to act as a positive regulator of osteoblastic bone formation to increase bone mass [11]. In this latter report, Kimura et al suggested an anabolic approach for the treatment of osteoporosis based on the use of CTHRC1null and transgenic mice. CTHRC1 expression has been observed in human solid cancers [13, 14], and aberrant expression of CTHRC1 is associated with cancer tissue invasion and metastasis in melanoma [13], how CTHRC1 induces these phenotypes has remained unknown
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