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TC1(C8orf4) Correlates with Wnt/ß-Catenin Target Genes and Aggressive Biological Behavior in Gastric Cancer

Authors' Affiliations: Departments of ¹ General Surgery, ² Pathology, and ³ Biochemistry and Molecular Biology; ⁴ Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, Korea, and ⁵ Howard Hughes Medical Institute, Department of Pharmacology, and Center for Developmental Biology, University of Washington School of Medicine, Seattle, Washington

Requests for reprints: Inchul Lee, Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Poongnap-Dong, Songpa-Gu, Seoul 138-736, Korea. Phone: 82-2-3010-4551; Fax: 82-2-472-7898; E-mail: iclee{at}amc.seoul.kr.

Purpose: We have recently reported that TC1(C8orf4), a small protein present in vertebrates, functions as a novel regulator of the Wnt/ß-catenin pathway. TC1 up-regulates ß-catenin target genes that are implicated in the aggressive behavior of cancers. Our aim was to investigate the clinical and pathobiological relevance of TC1 in gastric cancer.

Experimental Design: The expression of TC1 was analyzed using tissue microarray in correlation with clinicopathologic variables and ß-catenin target genes in 299 gastric cancers. The biological effects of TC1 on Matrigel invasiveness and the proliferation of cancer cells were analyzed. TC1 expression was analyzed in gastric cancer cells after serial peritoneal implantation in nude mice.

Results: TC1 expression was present in 111 carcinomas (37.1%), correlating with tumor stage (P < 0.002), poor differentiation (P < 0.001), lymphatic infiltration (P < 0.005), and lymph node metastasis (P < 0.006). TC1 also correlated with poor survival in diffuse type carcinomas (P < 0.0001), and even in patients with lymph node metastasis (P < 0.0014). TC1 also correlated with the expression of ß-catenin target genes including laminin 2, metalloproteinase-7 and metalloproteinase-14, cyclin D1, c-Met, and CD44. TC1 enhanced Matrigel invasiveness and proliferation, supporting its role in the aggressive biological behavior of cancers. The expression of TC1 increased in MKN45 cells after serial peritoneal seeding in nude mice.

Conclusions: Our data suggests that TC1 coordinates the up-regulation of Wnt/ß-catenin target genes that are implicated in the aggressive biological behavior of cancers. The strong clinical relevance, even in patients with lymph node metastasis, suggested that TC1 could be a potential therapeutic target of advanced gastric cancers.

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