TC1(C8orf4) correlates with Wnt/beta-catenin target genes and aggressive biological behavior in gastric cancer.
OBJECTIVE
We have recently reported that TC1(C8orf4), a small protein present in vertebrates, functions as a novel regulator of the Wnt/beta-catenin pathway. TC1 up-regulates beta-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.


METHODS
The expression of TC1 was analyzed using tissue microarray in correlation with clinicopathologic variables and beta-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 beta-catenin target genes including laminin gamma2, 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/beta-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.
Kim
Byungsik
B
Department of General Surgery, University of Ulsan College of Medicine, Seoul, Korea.
Koo
Hyunlyoung
H
Yang
Seunghee
S
Bang
Seunghyun
S
Jung
Yusun
Y
Kim
Youngmi
Y
Kim
Jungtae
J
Park
Juhee
J
Moon
Randall T
RT
Song
Kyuyoung
K
Lee
Inchul
I
D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D009367:Neoplasm Staging; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015996:Survival Rate; D013997:Time Factors; D014183:Transplantation, Heterologous; D015854:Up-Regulation; D051153:Wnt Proteins / Q000235:genetics* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
C495270:CTNNB1 protein, human; D009363:Neoplasm Proteins; C418741:TCIM protein, human; D051153:Wnt Proteins; D051176:beta Catenin