title: Collagen triple helix repeat containing 1 (CTHRC1) acts via ERK-dependent induction of MMP9 to promote invasion of colorectal cancer cells.
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.
authors: Biomedical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea.
authors: Hee Cheol
authors: HC
authors: Kim
authors: Yong Sung
authors: YS
authors: Kim
authors: Hyun-Woo
authors: HW
authors: Oh
authors: Kwoneel
authors: K
authors: Kim
authors: Sang-Seok
authors: SS
authors: Oh
authors: Jong-Tae
authors: JT
authors: Kim
authors: Bo Yeon
authors: BY
authors: Kim
authors: Seon-Jin
authors: SJ
authors: Lee
authors: Yong-Kyung
authors: YK
authors: Choe
authors: Dong Hyeok
authors: DH
authors: Kim
authors: Seok-Hyung
authors: SH
authors: Kim
authors: Seoung Wan
authors: SW
authors: Chae
authors: Kwang Dong
authors: KD
authors: Kim
authors: Hee Gu
authors: HG
authors: Lee
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002465:Cell Movement / Q000502:physiology; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018572:Disease-Free Survival; D004790:Enzyme Induction; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D019073:HT29 Cells; D006801:Humans; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis*; D008875:Middle Aged; D014162:Transfection
chemical_list: C502426:CTHRC1 protein, human; D016326:Extracellular Matrix Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9