Research Papers:

Collagen triple helix repeat containing 1 (CTHRC1) acts via ERK-dependent induction of MMP9 to promote invasion of colorectal cancer cells

Hee Cheol Kim, Yong Sung Kim, Hyun-Woo Oh, Kwoneel Kim, Sang-Seok Oh, Jong-Tae Kim, Bo Yeon Kim, Seon-Jin Lee, Yong-Kyung Choe, Dong Hyeok Kim, Seok-Hyung Kim, Seoung Wan Chae, Kwang Dong Kim and Hee Gu Lee _

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Oncotarget. 2014; 5:519-529. https://doi.org/10.18632/oncotarget.1714

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Hee Cheol Kim3,*, Yong Sung Kim1,*, Hyun-Woo Oh1, Kwoneel Kim1, Sang-Seok Oh2, Jong-Tae Kim1, Bo Yeon Kim1, Seon-Jin Lee1, Yong-Kyung Choe1, Dong Hyeok Kim2, Seok-Hyung Kim4, Seoung Wan Chae5, Kwang Dong Kim2, and Hee Gu Lee1

1 Biomedical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea;

2 Division of Applied Life Science, PMBBRC, Gyeongsang National University, Jinju, South Korea;

3 Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea;

4 Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea;

5 Department of Pathology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea

* These authors equally contributed to this study.


Hee Gu Lee, email:

Kwang Dong Kim, email:

Keywords: CTHRC1, ERK, MMP9, Invasion, Colorectal cancer

Received: December 18, 2013 Accepted: January 18, 2014 Published: January 18, 2014


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.

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