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The gene, collagen triple helix repeat containing 1 (CTHRC1), has been reported to increase in several kinds of human solid cancers and is associated with tumor invasion and metastasis. To date, the expression and function of CTHRC1 in gastric cancer (GC) have not been reported. The aim of this study was to investigate the expression levels and regulatory transcription mechanisms of CTHRC1 in GC. Immunohistochemical analysis revealed that CTHRC1 expression was markedly increased in carcinoma compared with normal gastric mucosa, chronic atrophic gastritis, and intestinal metaplasia (P < 0.05 for all), and this overexpression in tumor was related to depth of tumor invasion. Moreover, RNA interference-mediated knockdown and ectopic expression of CTHRC1 showed that CTHRC1 promoted tumor cell invasion in vitro. We then investigated the mechanisms underlying the aberrant expression of CTHRC1 in GC and found that CTHRC1 expression was restored after GC cell lines were treated with the demethylating agent, 5-aza-2'-deoxycytidine. Transforming growth factor-β1 led to an increase in levels of CTHRC1 mRNA and protein. Overall, our data revealed that the upregulated expression of CTHRC1 in gastric carcinogenesis contributes to tumor cell invasion and metastasis, and promoter demethylation and transforming growth factor-β1 may co-regulate the expression of CTHRC1. (Cancer Sci 2012; 103: 1327–1333)