TC1(C8orf4) Correlates withWnt/B-CateninTarget Genes and Aggressive Biological Behavior in Gastric Cancer Byungsik Kim, 1 Hyunlyoung Koo, 2 SeungheeYang, 4 Seunghyun Bang, 4 YusunJung, 4 YoungmiKim, 4 Jungtae Kim, 4 JuheePark, 4 RandallT. Moon, 5 Kyuyoung Song, 3 and Inchul Lee 2 Abstract Purpose: We have recently reported thatTC1(C8orf4), a small protein present in vertebrates, functions as a novel regulator of theWnt/h-catenin pathway.TC1up-regulates h-catenin target genes that are implicated in the aggressive behavior of cancers. Our aim was to investigate the clinicalandpathobiologicalrelevanceofTC1ingastriccancer. Experimental Design: The expression ofTC1was analyzed using tissue microarray in correla- tion with clinicopathologic variables and h-catenin target genes in 299 gastric cancers.The bio- logicaleffectsofTC1onMatrigelinvasivenessandtheproliferationofcancercellswereanalyzed. TC1expression was analyzed in gastric cancer cells after serial peritoneal implantation in nude mice. Results: TC1expression was present in111carcinomas (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).TC1also correlated with poor survival in diffuse type carcinomas (P < 0.0001), and even in patients with lymph node metastasis (P < 0.0014).TC1also correlated with the expression of h -catenin target genes including laminin g2, metalloproteinase-7 and metalloproteinase-14, cyclin D1, c-Met, and CD44.TC1enhanced Matrigel invasiveness and proliferation, supporting its role in the aggressive biological behavior of cancers.The expression ofTC1increasedinMKN45cellsafterserialperitonealseedinginnudemice. Conclusions: Our data suggests thatTC1coordinates theup-regulationofWnt/h-catenintarget genes that are implicated in the aggressive biological behavior of cancers.The strong clinical relevance, even in patients with lymph node metastasis, suggested thatTC1could be a potential therapeutic targetofadvanced gastric cancers. Gastric cancer is one of the leading fatal malignancies worldwide (1). Chronic Helicobacter pylori gastritis, ethnic, and dietary factors have been associated with gastric cancers (2–5). The biological behavior and clinical outcome of gastric cancers vary considerably. The molecular pathways involved in its biological variety have not been characterized well. Therefore, searching for the molecular regulators of carcino- genesis and/or clinical progression has been a major goal of gastric cancer research. TC1 (C8orf4 ) was one of the up-regulated genes in high- grade cancers in our previous expression profiling study of gastric cancers (6), suggesting that it might be implicated in the poor differentiation and/or aggressive biological behavior of cancers. TC1 was first described as one of the genes elevated in expression in thyroid cancers (7). It is present in vertebrates and encodes a protein of 106 amino acids without an identified functional domain (7, 8). It has been implicated in cancer and signal transduction (9, 10). However, its clinical relevance and precise biological functions have not heretofore been elucidated. Recently, we have reported that TC1 functions as a novel regulator of the Wnt/h-catenin signaling pathway (11), which has been widely implicated in regulating cell proliferation and differentiation in cancers and in development (12–16). TC1 interacts with Chibby (Cby) and thereby enhances the signaling pathway by relieving the antagonistic function of Cby on h-catenin-mediated transcription (11, 17). TC1 enhances the expression of h-catenin target genes that are implicated in the aggressive biological behavior of cancer. The proposed function of TC1 in the Wnt/h-catenin pathway regulation suggests that it could regulate the downstream genes in cancers and have a significant clinical relevance. Cancer Therapy: Preclinical Authors’Affiliations: Departments of 1 General Surgery, 2 Pathology, and 3 Biochemistry and Molecular Biology; 4 Asan Institute for Life Sciences, University ofUlsanCollegeofMedicine,Seoul,Korea,and 5 HowardHughesMedicalInstitute, DepartmentofPharmacology, andCenter forDevelopmentalBiology, Universityof Washington SchoolofMedicine, Seattle,Washington Received11/9/05;revised2/19/06;accepted3/24/06. Grant support: National Research Laboratory Project (M10400000305- 05J0000-30510) and Molecular and Cellular Function Discovery Project (M10401000003-05N0100-00310) from the Korean Ministry of Science and Technology. R.T. Moonis aninvestigatorof the Howard Hughes Medical Institute. Thecostsofpublicationofthisarticleweredefrayedinpartbythepaymentofpage charges.This article must therefore be hereby marked advertisement in accordance with18U.S.C.Section1734solely toindicatethisfact. Requests for reprints: Inchul Lee, Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, 388-1Poongnap-Dong, Songpa- Gu, Seoul138-736, Korea. Phone: 82-2-3010-4551; Fax: 82-2-472-7898; E-mail: iclee@amc.seoul.kr. F 2006AmericanAssociationforCancerResearch. doi:10.1158/1078-0432.CCR-05-2440 www.aacrjournals.org ClinCancerRes2006;12(11)June1,2006 3541 Downloaded from http://aacrjournals.org/clincancerres/article-pdf/12/11/3541/1964980/3541.pdf by guest on 31 October 2022