Abstract
PurposeGastric cancer remains one of the leading causes of cancer death worldwide. Patients usually present late with local invasion or metastasis, for which there are no effective therapies available. Following previous studies that identified the adhesion molecule Cadherin-17(CDH17) as a potential marker for gastric carcinoma, we performed proof-of-principle studies to develop rational therapeutic approaches targeting CDH17 for treating this disease.MethodsImmunohistochemistry was used to study the expression of CDH17 in 156 gastric carcinomas, and the relationship between survival and CDH17 expression was studied by multivariate analyses. The effect of RNA interference–mediated knockdown of CDH17 on proliferation of gastric carcinoma cell lines was examined in vitro and in vivo, as well as the effects on downstream signaling by immunoblotting.ResultsCDH17 was consistently up-regulated in human gastric cancers, and overall survival in patients with CDH17 upregulation was poorer than in those without expression of this gene (5 yrs overall survival rate 29.0% vs. 45.0%, P<0.01). Functional assays demonstrated that CDH17 knockdown inhibited cell proliferation, adhesion, migration, invasion, clonogenicity and induce G0/G1 arrest. In mice, shRNA-mediated CDH17 knockdown markedly inhibits tumor growth; intratumoral injection of CDH17 shRNAs results in significant antitumor effects on transplanted tumor models. The antitumor mechanisms underlying CDH17 inhibition involve inactivation of Wnt/β-catenin signaling.ConclusionOur results identify CDH17 as a biomarker of gastric carcinoma and attractive therapeutic target for this aggressive malignancy.
Highlights
Gastric cancer is the fourth most common cause of cancer death in the world
We examined the expression level of CDH17 in 156 gastric carcinoma specimens by IHC: 69 (44.3%) of 156 cases were positive, whereas the remaining 87 cases (55.7%) were negative or weak for CDH17 expression (Fig. 1)
The level of expression was +, 2+ and 3+ in 21 (13.5%), 20 (12.8%) and 28 (17.9%) cases respectively. These findings indicate that CDH17 may play an important role in gastric cancer tumorigenesis
Summary
The incidence of gastric cancer has decreased dramatically in some developed countries over the past decade, a total of one million new cases are estimated to be diagnosed each year [1]. Patients with this disease commonly have a poor outlook, accounting for 10% of total cancer deaths [2]. The process of invasion and metastasis is complex and requires the dysregulation of a variety of cellular elements including critical adhesion molecules. CDH17 has only 20 amino acids in the cytoplasmic domain, whereas classic cadherins have a highly conserved cytoplasmic domain consisting of 150–160 amino acids. CDH17 is expressed in mice and humans almost exclusively in epithelial cells of both embryonic and adult small intestine and colon, with no detectable expression in the stomach and liver [8]
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