Targeting cadherin‐17 inactivates Wnt signaling and inhibits tumor growth in liver carcinoma

Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal malignancies. It is the fifth most common cancer and ranks as the third leading cause of cancer-related deaths worldwide.1 The number of incident cases is over 600,000 per year, which is almost the same as the number of deaths, owing to the difficulty in early detection and high postsurgical recurrence rate. The prognosis of HCC is extremely poor, and only ≈5% of patients survive more than 5 years.2 Patients afflicted with HCC are often asymptomatic, and the lack of sensitive and reliable biomarkers for early detection of HCC and cancer surveillance in at-risk populations (hepatitis B or C virus carriers and those with cirrhosis) means that diagnosis normally occurs late, when surgical intervention is not an option.3 Today, there are no effective drugs for curing liver cancer. Using integrative genomic and proteomic approaches in mouse models,4–6 we have begun to identify novel oncogenes and tumor suppressors in liver cancer. Our previous studies using clinical cohorts identified a cell surface adhesion molecule, cadherin-17 (CDH17), also known as liver-intestine cadherin, as a potential disease marker for HCC.7 It consists of seven cadherin-like ectodomains and a short cytoplasmic tail of 24 amino acid residues.8 Expression of CDH17 is restricted to the colon, intestine, and pancreas in humans; it is not found in the healthy adult liver and stomach.7,9–12 It plays an important role during embryonic gastrointestinal development and also functions as a peptide transporter.13,14 Most, if not all, cadherin molecules interact with the cytosolic β-catenin network and thereby regulate the Wnt signaling pathway, but there are no published reports that CDH17 does so. Increased CDH17 expression has been reported in liver and stomach cancer.7,9,15,16 In our earlier studies, we identified an isoform that lacks exon 7 and correlates with poor prognostic outcomes in HCC patients.11 Furthermore, this specific CDH17 haplotype is associated with increased risk of HCC in Chinese subjects.17 Despite these significant clinical findings, the molecular pathogenesis of CDH17 remains unknown, and its tumorigenic role in HCC has not yet been confirmed. Here, we aimed to dissect the oncogenic signaling mechanisms of CDH17 in the HCC context and evaluated the feasibility of targeting CDH17 using RNA interference (RNAi) as a potential therapeutic approach for HCC.