CLDN3 inhibits cancer aggressiveness via Wnt-EMT signaling and is a potential prognostic biomarker for hepatocellular carcinoma
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Lei Jiang1,*, Yi-Dong Yang1,2,*, Li Fu1, Weiqi Xu1, Dabin Liu1, Qiaoyi Liang1, Xiang Zhang1, Lixia Xu1, Xin-Yuan Guan3, Bin Wu2, Joseph J.Y. Sung1 and Jun Yu1
1 Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, CUHK Shenzhen Research Institute, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong
2 Department of Gastroenterology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
3 Department of Clinical Oncology, The University of Hong Kong, Hong Kong, China
* These authors contributed equally to this work
Jun Yu, email:
Keywords: CLDN3, hepatocellular carcinoma, metastasis, survival
Received: June 25, 2014 Accepted: July 31, 2014 Published: July 31, 2014
Hepatocellular carcinoma (HCC) is one of the most common fatal malignancies but the molecular genetic basis of this disease remains unclear. By using genome-wide methylation profiling analysis, we identified CLDN3 as an epigenetically regulated gene in cancer. Here, we investigated its function and clinical relevance in human HCC. CLDN3 downregulation occurred in 87/114 (76.3%) of primary HCCs, where it was correlated significantly with shorter survival of HCC patients (P=0.021). Moreover, multivariate cyclooxygenase regression analysis showed that CLDN3 was an independent prognostic factor for overall survival (P=0.014). Absent expression of CLDN3 was also detected in 67% of HCC cell lines, which was significantly associated with its promoter hypermethylation. Ectopic expression of CLDN3 in HCC cells could inhibit cell motility, cell invasiveness, and tumor formation in nude mice. Mechanistic investigations suggested through downregulation of GSK3B, CTNNB1, SNAI2, and CDH2, CLDN3 could significantly suppress metastasis by inactivating the Wnt/β-catenin-epithelial mesenchymal transition (EMT) axis in HCC cells. Collectively, our findings demonstrated that CLDN3 is an epigenetically silenced metastasis suppressor gene in HCC. A better understanding of the molecular mechanism of CLDN3 in inhibiting liver cancer cell metastasis may lead to a more effective management of HCC patients with the inactivation of CLDN3.
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