Claudins (CLDNs) are transmembrane proteins, as normal constituents of the architecture of tight junctions. Recent studies support their involvement in carcinogenesis, as changes in CLDNs structure result in alterations in tight junctions' structure and function, facilitating malignant transformation. We aimed CLDN3 investigation in both breast and ovarian carcinoma, targeting the identification of its expression differences. 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. 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. CLDN3 expression in ovarian cancer cells, as well as a mechanism for the silencing of this promoter in tumors lacking expression of claudin-3.