Dynamic Expression of EpCAM in Primary and Metastatic Lung Cancer Is Controlled by Both Genetic and Epigenetic Mechanisms

SIMPLE SUMMARY: Epithelial cell adhesion molecule (EpCAM) is a tumor marker widely used in both basic studies and clinics. However, our study demonstrates that EpCAM expression is strongly upregulated by gene amplification and promoter hypomethylation in primary lung tumors, but severely downregulated by epigenetic repression (including promoter hypermethylation and histone deacetylation), tumor-associated macrophages (TAMs), and TAMs-derived TGFβ in metastatic lung tumors. DNMT inhibitor 5-aza-dC, HDAC inhibitor MS-275, and TGFβ neutralizing antibody are able to restore EpCAM expression in highly metastatic lung cancer cells. These findings disclose that multiple mechanisms contribute to the dynamic expression patterns of EpCAM in primary and metastatic lung tumors, redefining the application of EpCAM as a biomarker in tumor cell identification and isolation in specific cancers and clinical stages. ABSTRACT: Although great progress has been achieved in cancer treatment in the past decades, lung cancer remains the leading cause of cancer death, which is partially caused by the fact that most lung cancers are diagnosed at advanced stages. To improve the sensitivity and specificity of lung cancer diagnosis, the underlying mechanisms of current diagnosis methods are in urgent need to be explored. Herein, we find that the expression of EpCAM, the widely used molecular marker for tumor cell characterization and isolation, is strongly upregulated in primary lung tumors, which is caused by both gene amplification and promoter hypomethylation. In contrast, EpCAM expression is severely repressed in metastatic lung tumors, which can be reversed by epigenetic drugs, DNMT inhibitor 5-aza-dC and HDAC inhibitor MS-275. Moreover, tumor-associated macrophages (TAMs) impede EpCAM expression probably through TGFβ-induced EMT signaling. These findings unveil the dynamic expression patterns of EpCAM and differential roles of epigenetic modification in EpCAM expression in primary and metastatic lung tumors, providing novel insights into tumor cell isolation and lung cancer diagnosis.